Epithelial Cell Adhesion Molecule (EpCAM)-Targeted CAR-T Cells (IMC001) in Patients with Advanced Gastric Cancer: A Phase I Dose-Escalation Trial

Epithelial Cell Adhesion Molecule (EpCAM)-Targeted CAR-T Cells (IMC001) in Patients with Advanced Gastric Cancer: A Phase I Dose-Escalation Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Epithelial Cell Adhesion Molecule (EpCAM)-Targeted CAR-T Cells (IMC001) in Patients with Advanced Gastric Cancer: A Phase I Dose-Escalation Trial Tianhang Luo, Weijia Fang, Zhengmao Lu, Rui Zheng, Weiwei Yin, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4381902/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To evaluate the safety and preliminary efficacy of IMC001, an epithelial cell adhesion molecule (EpCAM)-targeted CAR-T cell therapy, in patients with advanced gastric cancer (GC). Design This was a phase I, open-label, single or multiple infusion, dose escalation study utilizing a classic 3+3 design that included adults (aged ≥18 years) with locally advanced or metastatic GC with positive EpCAM histological staining of a biopsy tumor tissue sample who had failed at least two lines of treatment and were ineligible for a standard treatment. Eligible patients received IMC001 at doses of 3×10 5 (low), 1×10 6 (middle) or 3×10 6 (high) CAR-T cells/kg after lymphodepletion. The primary objective was evaluation of the safety and tolerability of IMC001. Secondary objectives included determination of the recommended phase II dose (RP2D) based on dose-limiting toxicity (DLT), preliminary evaluation of efficacy and characterization of pharmacokinetics and pharmacodynamics. Results From August 18, 2021 to May 8, 2023, 11 patients with advanced GC received IMC001, the median age was 53 (36-70) years and 63.6% (7/11) were male. Most patients 91.9% (10/11) had failed ≥2 lines of chemotherapy and 27.3% (3/11) had received prior immunotherapy. By the cutoff date (March 31 st , 2024), low- and middle-dose IMC001 infusion was associated with a favorable safety profile. The disease control rate was 90% in 10 evaluable patients; 1 patient in the low-dose group (1/3, 33.3%) and 2 in the middle-dose group (2/5, 40%) achieved a partial response (PR). The median PFS was 18.1 weeks (95% CI 7.97, --) and the OS was 55.1 weeks (95% CI 23.78, --) for the middle dose group; 3/5 patients in the middle dose group had survived more than 10 months. One patient in the middle-dose group achieved a confirmed PR by Week 24, culminating in a radical gastrectomy at Week 27 and had survived for more than 22 months by the cutoff date. Tumor immune microenvironment analysis suggested that an inflamed tumor environment may enhance the anti-tumor effects of IMC001. The 1×10 6 CAR-T cells/kg dose was selected as the recommended dose for future study. Conclusion In this phase I dose-escalation trial, IMC001 demonstrated a favorable safety profile and encouraging efficacy in patients with advanced, pre-treated GC. Further investigation is warranted to further evaluate the use of IMC001 for patients with advanced GC. Health sciences/Oncology/Cancer/Cancer therapy/Cancer immunotherapy Health sciences/Gastroenterology/Gastrointestinal diseases/Gastrointestinal cancer/Gastric cancer Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction While chimeric antigen receptor T-cell (CAR-T) cell therapy has demonstrated remarkable efficacy in the treatment of hematologic malignancies 1 , its applicability to solid tumors remains limited 2 . Clinical studies show that CAR-T cells can stimulate potent anti-tumor immune function with high specificity, and are potentially applicable in solid tumors, including gastric cancer. However, current challenges include CAR-T cell associated toxicity 3,4,5 , antigen escape 6,7 , antigen heterogeneity 4 , challenges in CAR-T cell trafficking and tumor infiltration 5, 8, 9, 10 and the immunosuppressive tumor microenvironment (TME) 11, 12, 13, 14 . The epithelial cell adhesion molecule (EpCAM, CD326) is a transmembrane glycoprotein that exhibits prominent expression in various malignancies including gastric, colorectal, prostate, ovarian, lung, and pancreatic cancers 15 . In addition to its well-established role as a biomarker for circulating tumor cells (CTCs) 16,17 and cancer stem cells (CSCs), EpCAM has gained recognition as an appealing therapeutic target. Notably, while EpCAM can be detected on the basolateral membrane of several normal epithelial tissues, such as the colon, small intestine, and hepatic progenitor cells, its accessibility to large-scale constructs such as cellular therapeutics is hindered by confinement within tight cellular junctions. Consequently, EpCAM has emerged as a promising target for the treatment of solid tumors, including gastric cancer and colorectal cancer 18,19 . Numerous drug formulations targeting EpCAM are in development, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADC), and CAR-T therapy 20 . CAR-T therapy targeting EpCAM represents a promising novel approach, with intravenous infusion and a good safety profile with a larger dosage window. In a recently published study, using EpCAM CAR-T cells co-stimulated by Dectin-1 exhibited promising anti-cancer efficacy in various type solid cancers 21 . In this prior study, a dose of 1×10 7 -1.5×10 7 T cells/kg resulted in one partial response (PR) with minor side effects in four patients with stage IV gastric cancer. IMC001 is a novel autologous T cell immunotherapy that is engineered ex vivo by lentiviral transduction to express an EpCAM CAR. The CAR consists of (N-terminal to C-terminal) a single-chain variable fragment (scFV) domain specifically targeting human EpCAM, followed by an extracellular hinge, the entire transmembrane domain, and the intracellular signaling domain of human CD28 (Figure 1). The intracellular domain of CD28 connects with the CD3ζ signaling domain responsible for T cell activation. IMC001 exhibited promising anti-tumor activity in preclinical studies (data on file). The specificity of binding to EpCAM via an extracellular humanized scFV was confirmed by a membrane proteome array using around 6000 membrane proteins. IMC001 exhibited significantly higher cytotoxicity against patient derived organoids than paired adjacent non-tumor tissue derived organoids, indicating a therapeutic window for IMC001. A comprehensive good laboratory practices study in a murine model confirmed a favorable safety profile. IMC001 has received approval for clinical development (IND) in China (CDE) and the USA (FDA). In this study, we conducted the first phase I investigation of IMC001 for patients with advanced gastric cancer. This groundbreaking study provides the initial demonstration of the safety and efficacy of EpCAM CAR-T as a therapeutic target for solid tumors. Study design and patients IMC001-CT03 was a phase I, open-label, single or multiple infusion, dose escalation study conducted at Shanghai Changhai Hospital. The study utilized a classic 3+3 dose escalation trial design (Figure 2). Eligible patients were adults (aged ≥18 years) with locally advanced or metastatic gastric cancer and positive EpCAM histological staining of a biopsy tumor tissue sample who had progressed on at least two lines of prior treatment and had no other standard treatment option. Patients were also required to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, sufficient organ and bone marrow function and meet the screening criteria for routine clinical trial examinations. The protocol was registered in the Chinese clinical trial registry (ChiCTR2100047129) and approved by the local ethics committee of the Shanghai Changhai Hospital Ethics Committee (CHEC2021-068). All patients provided written informed consent. This study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. Patients received compensation for travel and a meal per visit. Manufacturing of the CAR-T cells IMC001 CAR-T manufacturing starts with the collection and transport of leukapheresis blood from a single collection. PBMC are isolated using a closed, automated program and proceed to manufacturing or are cryopreserved for subsequent production. Cells are mixed with CD3/CD28 magnetic beads and CD3+ cells are separated from the mixed samples by a magnetic platform and incubated to undergo activation. Lentiviral transduction is performed on activated cells by incubation with vector at 37 ± 1°C, 5.0 ± 0.5 % CO2 and cells are further expanded for 3-7 days (maximum of 7 days) to reach a target cell number. Harvested cells are washed and concentrated via automated methods before undergoing magnetic bead removal twice. IMC001 cells are again washed and concentrated before being resuspended in cryopreservation media and frozen by controlled rate freezer (CRF). Treatment and dose escalation Eligible patients received IMC001 at escalating doses of 3×10 5 , 1×10 6 or 3×10 6 CAR-T cells/kg, infused intravenously after lymphodepletion. The final dose was based on the actual number of CAR-T cells produced, and the actual number of cells infused was recorded. The lymphodepletion regimen consisted of cyclophosphamide 250 mg/m 2 /day on Day -4, Day -3, and Day -2; fludarabine 25 mg/m 2 /day on Day -4 and Day -3 and nab-paclitaxel 100 mg on Day -3. Patients who could not tolerate nab-paclitaxel received only fludarabine 20-25 mg/m 2 and cyclophosphamide 500 mg/m 2 (on Days -4 and -3). In principle, all patients received a single infusion of IMC001. However, patients were permitted to receive an additional infusion based on safety, CAR-T cell quantity and copy number, and treatment response. After the initial 3×10 5 cells/kg dose, if no dose-limiting toxicity (DLT) occurred, the next dose level was initiated. If ≥2 DLTs occurred at a dose level, the dose was not escalated. If one DLT occurred at a given dose level, three more subjects were enrolled to that dose. If no DLT was observed among the additional three patients, the study moved to the next dose level. Each dose group completed DLT observation before the next dose group was initiated. The definition of a DLT is provided in the Supplementary Materials. After dose escalation, more patients could be recruited to a recommended dose to gain more data about IMC001 treatment, following discussion with the data safety monitoring committee (SMC). Objectives and measurements The primary study objective was to evaluate the safety and tolerability of IMC001 in patients with advanced gastric cancer. Secondary objectives included definition of the recommended Phase II dose (RP2D) based on DLTs, preliminary evaluation of clinical efficacy, the characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of IMC001 and analysis of the tumor immune microenvironment (TME). Safety and tolerability were assessed by recording adverse events (AEs) which were categorized according to ICH MedDRA codes version 23.1 and graded according to the common terminology criteria for adverse events (CTCAE) v5.0. Events of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) were graded using the American Society for Transplantation and Cellular Therapy (ASTCT) criteria 31 . Treatment efficacy was evaluated via the ORR, disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor responses were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The long-term survival follow-up was a maximum of 2 years after the first infusion. The PK and PD profiles of IMC001 were detected by qPCR and CBA assay at each visit after infusion, and the tumor microenvironment environment (TME) profile was detected by Multiplex immunohistochemistry (mIHC). Detailed methods are provided in the Supplementary Materials. Statistical analysis The sample size was based on the “3+3” dose-escalation design. No statistical hypothesis was tested. Results were summarized using descriptive statistics including the number of cases, mean, median, standard deviation, minimum and maximum values for continuous variables and frequency distributions for categorical variables. The number and percentage of patients experiencing a treatment-Related AE (TRAE) were calculated based on system organ classification, preferred term (PT) and different dosage groups. Results Patients From August 18, 2021 to May 8, 2023, a total of 11 were infused with IMC001 CAR-T cells. All 11 patients were included in the safety analysis; 3 patients each in the low-, middle- and high- dose group, with 2 more expansion patients enrolled at the recommended dose of 1×10 6 cells/kg (middle-dose). Ten patients who had at least one efficacy evaluation after IMC001 infusion were included in the efficacy analysis. Among the 11 patients in the safety analysis, 63.6% (7/11) were male, 81.8% had ≥2 organs with metastatic involvement and 18.2% (2/11) had metastasis in ≥3 organs, mainly in the lymph nodes, abdominal cavity and peritoneum, and liver and other organs (Table 1). A total of 54.5% (6/11) patients had ascites in the abdominal cavity, while 45.5% (5/11) had ascites in the pelvic cavity. All patients had received at least two lines of prior therapy (one patient failed 1 st line therapy and refused a 2 nd line treatment) and 27.3% (3/11) had received immunotherapy. The median duration from apheresis to infusion was 22 days (range, 16-33 days). Table 1 Demographics and baseline characteristics (SS) Dose group Pt # Sex Age ECOG Diagnosis EpCAM H-score No. of metastatic organs Metastatic sites Previous treatment Surgery Chemotherapy lines Low 3×10 5 CAR-T cells/kg 1 F 47 1 Gastric adenocarcinoma of stomach body，Stage IV 90% 2.9 4 Pelvis, peritoneum, abdominal cavity, lymph nodes Laparoscopy, peritoneal nodule biopsy 2 2 M 40 0 Distal gastric adenocarcinoma，Stage IV 30% 1.4 1 Lymph nodes Laparoscopy, gastroduodenostomy 2 3 F 36 1 Gastric adenocarcinoma of stomach body, Stage IV 10% 1.05 2 Bone, pelvis Hysterectomy 3 Middle 1×10 6 CAR-T cells/kg 4 M 50 1 Gastric adenocarcinoma of stomach body, Stage IV 10% 1.1 3 Abdominal cavity, pelvis, lymph nodes Laparoscopy 2 5 M 53 0 Distal gastric adenocarcinoma，Stage IV 90% 2.45 2 Liver, abdominal cavity Radical gastrectomy 2 6 M 66 0 Distal gastric adenocarcinoma，Stage IV 90% 2.15 2 Lung Radical gastrectomy 2 7 F 53 1 Gastric adenocarcinoma of stomach body, Stage IV 100% 1.9 2 Lymph nodes, peritoneum? Laparoscopy 1 8 M 60 1 Gastric adenocarcinoma of fundic gland, Stage IV 100% 2.8 1 Lymph nodes None 2 High 3×10 6 CAR-T cells/kg 9 M 70 0 Distal gastric adenocarcinoma, Stage IV 100% 2.3 2 Pancreatic head/neck, lymph nodes Radical gastrectomy 2 10 M 58 0 Gastric adenocarcinoma of stomach body, Stage IV 70% 1.5 2 Pancreatic head/neck, lymph nodes Radical gastrectomy 2 11 F 36 0 Gastric adenocarcinoma, Stage IV 90% 1.9 2 Bilateral appendages, peritoneum Bilateral appendectomy 2 CAR-T, chimeric antigen receptor; ECOG, Eastern Co-operative Oncology Group; EpCAM, epithelial cell adhesion molecule; Pt, patient. Safety and tolerability A DLT was reported in two patients in the high dose (3×10 6 cells/kg) group and the enrolment was stopped, a Grade 4 immune-related hepatitis in one patient and Grade 4 cytokine release syndrome (accompanied by COVID-19 infection) and Grade 4 immune-related pancreatitis in another patient. The low dose (3×10 5 cells/kg) and middle dose (1×10 6 cells/kg) groups prove relative safety and efficacy. As of the analysis cut-off date (March 31 st , 2024), treatment-related adverse events (TRAEs) with an incidence rate ≥10% by PT included decrease in lymphocyte count, white blood cell count, neutrophil count, and platelet count, cytokine release syndrome, fever, abnormal liver function, elevated C-reactive protein, immune-related hepatitis, epidermolysis and anemia. Hematological toxicities such as decrease in lymphocyte count, white blood cell count, neutrophil count, and platelet count were related to lymphodepletion which recorded as TRAEs by the investigators. Grade ≥3 TRAE included cytokine release syndrome, abnormal liver function, and immune-related hepatitis (Table 2). Table 2 Summary of Treatment-Related Adverse Events (TRAE) with an Overall Incidence Rate ≥10% or an Incidence Rate ≥10% and CTCAE Grade ≥3 SS (N=11) 3×10 5 CAR-T cells/kg (N=3) 1×10 6 CAR-T cells/kg (N=5) 3×10 6 CAR-T cells/kg (N=3) Total (N=11) Preferred Term (PT) Any Grade Grade 3 or Higher Any Grade Grade 3 or Higher Any Grade Grade 3 or Higher Any Grade Grade 3 or Higher At least one occurrence with an incidence rate ≥10% or an incidence rate ≥10% and CTCAE ≥3 for TRAE 3 3 5 5 3 3 11 11 Lymphocyte count decreased 3 2 4 4 3 3 10 9 Neutrophil count decreased 3 2 4 2 2 0 9 4 White blood cell count decreased 3 3 2 2 3 2 8 7 Platelet count decreased 2 2 2 1 2 1 6 4 Cytokine release syndrome 1 0 2 1 2 2 5 3 Fever 2 0 2 0 0 0 4 0 Abnormal liver function 0 0 3 2 1 1 4 3 Elevated C-reactive protein 0 0 3 0 0 0 3 0 epidermolysis 0 0 0 0 2 0 2 0 Immune-related hepatitis 0 0 1 1 1 1 2 2 Anemia 0 0 0 0 2 0 2 0 CAR-T, chimeric antigen receptor; CTCAE, common terminology criteria for adverse events. No IMC001 infusion related deaths or serious adverse events (SAEs) were reported. However, three patients (27.2%) experienced treatment emergent SAEs: respiratory failure and disseminated intravascular coagulation (33.3%, 1/3), pancreatitis (20%, 1/5) and infectious pneumonia (33.3%, 1/3), in the low-, middle-, and high-dose groups, respectively, which were considered not related to IMC001 treatment by the investigator. A total of five patients experienced at least one CRS event, including one patient in the low-dose group (1/3, 33.3%), two patients in the middle-dose group (2/5, 40%; one of which was Grade 3) and two in the high-dose group (2/3, 66.7%; both Grade 4). Immune-related hepatitis was observed in one patient in the middle-dose group (1/5, Grade 3) and one in the high-dose group (1/3, Grade 4). Generally, CRS or immune-related hepatitis occurred in the first week of treatment administration and the majority of patients responded to supportive therapy. Preliminary efficacy Among ten patients included in the efficacy analysis, the ORR and DCR were 30% (3/10) and 90% (9/10), respectively (Figure 3); the median PFS was 18.1 weeks (95% CI 5.27, --) and the median OS was 33.5 weeks (95% CI 5.27, 67.77). One patient in the low-dose group (3×10 5 cells/kg) achieved a PR at week 32 and received a second infusion with a higher dose of 1×10 6 cells/kg at week 53, who survived for 67.9 weeks since first infusion. In the middle-dose group (1×10 6 cells/kg), the ORR was 40% (2/5); the median PFS was 18.1 weeks (95% CI 7.97, --) and the median OS was 55.1 weeks (95% CI 23.78, --) with a maximum follow-up time of 21.8 months. One of the patients in the middle-dose group achieved a 15% reduction in tumor size at Week 4 and a 26% reduction at Week 8. This response evolved into a confirmed PR by Week 24, culminating in a radical gastrectomy at Week 27 and, as of Week 16 post-surgery, the patient had survived for more than 22 months by the cutoff date (Figure 4). The other patient in the middle dose group achieving a PR exhibited a 48% reduction in target lesion size at Week 16. The survival times of the other two patients in the middle-dose group, who achieved stable disease (SD), were 55 weeks and 43 weeks, respectively. Pharmacokinetics and pharmacodynamics After a single infusion of IMC001, cell expansion and cytokine release were detected in the peripheral blood. Pharmacokinetic analysis demonstrated a dose-dependent proliferation of CAR-T cells post IMC001 infusion, with a median C max value of 58, 394, and 4808 copies per microgame genomic DNA for the low-does, middle-does and high-doses respectively. The median T max value was 7 days (7-28); and the median persistence in peripheral blood was 11days (7-56) (Figure 5A). In a further analysis, patients were categorized into two groups based on clinical response: PR (responders), and PD or SD (non-responders). Although the response group exhibited a higher median C max compared to the non-response group (394 vs. 90 copies per microgram genomic DNA), the difference did not reach statistical significance (Figure 5B). An analysis of cytokine release profiles post-treatment revealed no significant correlation between efficacy and serum cytokine levels (Figure 5C-5F). These results indicate that CAR-T expansion in peripheral blood correlates with dose, while the potential correlation with clinical efficacy warrants further investigation in large scale trials. Tumor microenvironment In our study, we investigated the correlation between the TME and the response of IMC001. Previous reports have highlighted the role of the TME, particularly stromal cells and cancer-associated fibroblasts (CAFs); their interaction with immune cells constitutes a major driver of tumor progression and therapy response 23 . Notably, α-smooth muscle actin (α-SMA), a marker of activated CAFs, has been implicated in tumor progression and immunosuppression. Building upon this knowledge, we performed α-SMA staining of tissue from nine patients to characterize the pattern of CAFs within the TME, categorized as poor or rich α-SMA staining 24 . Remarkably, all three patients who achieved a PR exhibited poor α-SMA staining. In contrast, among patients with SD or PD, only 1/6 exhibited poor α-SMA staining, while the majority (5/6) displayed a rich α-SMA staining pattern (Figure 6A, 6B). These findings suggest that the presence of poor α-SMA staining within the TME may contribute to enhanced efficacy of IMC001 therapy. In addition to assessing the role of CAFs, we investigated the presence of CD4 positive T cells and their potential correlation with IMC001 efficacy. CD4 positive T cells play a crucial role in orchestrating immune responses within the TME and have been implicated in tumor surveillance and regulation of anti-tumor immunity. Our analysis revealed that CD4 levels were slightly higher in patients who achieved a PR compared to those with SD or PD following IMC001 therapy (Figure 6C, 6D). While the exact mechanisms underlying this observation require further elucidation, it suggests a potential association between CD4 positive T cell infiltration and favorable clinical outcomes in response to IMC001 treatment. These findings underscore the complexity of the TME and highlight the importance of investigating multiple immune cell populations to better understand the mechanisms underlying immunotherapeutic responses in advanced gastric cancer. Further studies are warranted to validate these observations and elucidate the functional significance of α-SMA staining patterns and CD4 positive T cells in the context of IMC001 therapy. Discussion This Phase I study is the first investigation of the EpCAM-targeted CAR-T cell therapy IMC001 in patients with advanced gastric cancer. All 11 patients who received treatment experienced transient toxicities which were manageable with supportive treatment. Two patients in the high dose (3×10 6 cells/kg) group experienced dose-limiting toxicities (DLTs) and the incidence of TRAEs and DLTs showed an association with higher levels of cytokine changes and higher CAR-T expansion copy numbers in this group. For patients in the low- and middle-dose groups, all TRAEs were tolerable. Most of the AEs observed during/after IMC001 treatment were expected and reflect its mechanism of action. Based on these safety findings, the preliminary efficacy evaluation, and discussions with the safety monitoring committee, the middle-dose (1×10 6 cells/kg) was selected as the recommended dose for further investigations of IMC001. In adults, EpCAM is expressed in most organs and glands and the immune-related hepatitis and skin toxicity observed in the middle- and high-dose groups is potentially related to on-target, off-tumor activity and the immune effect of a CRS. In addition, the intravenous infusion of IMC001 appears to be better tolerated than the intravenous infusion of catumaxomab, a bispecific antibody targeting EpCAM 25 . In a phase I trial, the treatment of EpCAM + tumor patients with catumaxomab caused dose dependent hepatitis with elevations in serum alanine transaminase, aspartate transaminase, bilirubin, γ-GT and induction of the C-reactive protein and IL-6 and IL-8. The first patient receiving 10µg catumaxomab experienced fatal acute liver failure which led to the termination of the study. The development and clinical use of catumaxomab and other EpCAM bi-specific antibodies was focused on intraperitoneal route to avoid system exposure and adverse effects 26,27 . Preliminary efficacy data from our study demonstrated an anti-tumor effect of IMC001 in patients with gastric cancer. Among the 10 patients with a response evaluation post-IMC001 treatment, six exhibited SD, and three achieved a PR. Among the three patients with confirmed PRs, these occurred at post-treatment Week 16 to Week 32, respectively, suggesting a gradual enhancement in the anti-tumor effect of IMC001 after administration, and the middle dose of 1×10 6 /kg resulted in a quicker response than the low dose at Week 32. In gastric cancer, immunotherapies such as programmed death-1 (PD-1) and VEGFR inhibitors have shown only limited effectiveness as 3rd -line treatments, with ORRs ranging from 1.7%-13.3%, median PFS of 1.6–2.6 months and median OS of around 6 months 28–30 . The medium PFS and OS for patients receiving IMC001 1×10 6 cells/kg in the present study of 18.1 weeks and 55.1 weeks, with an ORR of 40% were better than historical data for patients with advanced gastric cancer who failed at least 2nd -line chemotherapy. Translational surgery was available for one patient (#4) after IMC001 infusion with an OS more than 94 weeks, which may also provide longer survival for this group of patients. In summary, these encouraging preliminary efficacy data for IMC001 in patients with advanced gastric cancer suggest it may provide an anti-tumor effect and offer a novel treatment option, which is important given the currently limited choice of treatments. The patient #4 was a 50-year-old male with stage IV gastric adenocarcinoma, intraperitoneal lymph node metastasis and symptoms for > 1 year before IMC001 infusion (middle-dose). Histological examination revealed an EpCAM expression of 10% and a H-score of 1.1. Previous treatment included left gastric arteriography plus arterial perfusion chemoembolization (raltitrexed regimen), and prior anti-cancer therapies included first-line tegafur/gimeracil/oteracil potassium (SOX) + Herceptin, and 2nd line therapy with oxaliplatin + trastuzumab. The patient had a diagnosis of cT4a-4bN2-3M0-1 with no indication for surgery. After IMC001 infusion, the lymph nodes decreased significantly and pelvic effusion disappeared, allowing a conversion to radical gastrectomy and achievement of a surgical complete response 27 weeks after CAR-T cell infusion. The ability to regain the opportunity for surgery opportunity may present a potential benefit for patients with late-stage gastric cancer. The pharmacokinetic profile of IMC001 observed in our study, by peak CAR copy numbers at approximately 10 days post-infusion, aligns with the peak time observed for CAR-T cell therapies in hematopoietic malignancies targeting CD19 and CT041, a CLDN18.2-targeting CAR-T cell product 31 . Notably, the observed peak CAR copy numbers were modestly lower compared to those previously reported for CD19-directed CAR-T therapies. This observation, coupled with the lack of correlation between peak CAR copy numbers (C max ) and clinical efficacy observed in our study, diverges from the well-established relationship for CAR-T therapies in hematologic malignancies, where higher C max values are typically associated with improved outcomes. Our findings may reflect the unique characteristics of CAR-T cell therapy in solid tumors, where the expansion and persistence of CAR-T cells within the tumor microenvironment, rather than in peripheral blood, are more critical determinants of therapeutic efficacy. This hypothesis is supported by the low levels of peripheral CAR-T cells and the absence of correlation between their levels and antitumor responses. Given the small sample size of our study, these findings warrant validation in larger clinical trials to better understand the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of IMC001 and efficacy in a solid tumor setting. Our translational research investigated the relationship between the TME and the efficacy of IMC001. An analysis of stromal-rich TMEs, characterized by an abundance of network-style CAFs, was associated with less likelihood of a response to IMC001. This is the first clinical evidence supporting the notion that the presence of CAFs within the TME may negatively influence the therapeutic response to CAR-T cell therapy in solid tumors. This finding is in line with reported preclinical data and further underscores the importance of considering the TME when evaluating the efficacy of CAR-T cell therapies. Additionally, our study explored the intra-tumoral levels of CD4 + T cells and observed a non-significant trend towards higher CD4 density in patients achieving PR. This observation, if confirmed in larger cohorts, could provide insights into the immune cell dynamics within the TME and their potential prognostic potential in predicting CAR-T cell therapy outcomes in patients with solid tumors. Conclusions In conclusion, EpCAM-targeted CAR-T therapy (IMC001) holds promise as a novel treatment modality for patients with gastric cancer. With a favorable safety profile and promising anti-cancer effect, IMC001 may prolong survival and provide the opportunity for surgery in patients with advanced gastric cancers. Given these promising preliminary findings in gastric cancer, the investigation of IMC001 in other epithelial tumors is a direction for future research. Declarations Inclusion and ethics The protocol was registered in the Chinese Clinical Trial Registry (ChiCTR2100047129) and approved by the local ethics committee of the Shanghai Changhai Hospital Ethics Committee (CHEC2021-068). All patients provided written informed consent. Competing interests All authors declare no competing financial and/or non-financial interests in relation to the work described. Funding This clinical trial was supported by Immunofoco Co., Ltd and China Zhongguancun Precision Medicine Science and Technology Foundation (CPMF). Author contributions The manuscript was written by GQ Ai, YP Zhong and SS Zhang and critically reviewed and revised by the other authors. All authors contributed to the analysis and interpretation of the data. The authors affirm the accuracy and completeness of the data and adherence of the study to the protocol. Acknowledgements Medical writing support was provided by Jake Burrell, PhD, on behalf of Rude Health Consulting Ltd. This support was funded by Immunofoco Co., Ltd. Data availability The data underlying this paper are available from the corresponding authors upon reasonable request. Code availability Not applicable to this manuscript. References Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705–716. Doi: 10.1056/NEJMoa2024850 Alcantara M, Du Rusquec P, Romano E. Current Clinical Evidence and Potential Solutions to Increase Benefit of CAR T-Cell Therapy for Patients with Solid Tumors. Oncoimmunology. 2020;9(1):1777064. Doi: 10.1080/2162402X.2020.1777064 Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25. Doi: 10.1126/scitranslmed.3008226 Kailayangiri S, Altvater B, Wiebel M, et al. Overcoming Heterogeneity of Antigen Expression for Effective CAR T Cell Targeting of Cancers. Cancers (Basel). 2020;12(5):1075. Doi: 10.3390/cancers12051075 Kochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–20. Doi: 10.1182/blood-2011-10-384388 Hegde M, Mukherjee M, Grada Z, et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest. 2016;126(8):3036–52. Doi: 10.1172/JCI83416 Zah E, Lin MY, Silva-Benedict A, et al. T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells. Cancer Immunol Res. 2016;4(6):498–508. Doi: 10.1158/2326-6066.CIR-15-0231 Poznansky MC, Olszak IT, Evans RH, et al. Thymocyte emigration is mediated by active movement away from stroma-derived factors. J Clin Invest. 2002;109(8):1101–10. Doi: 10.1172/JCI13853 Salmon H, Franciszkiewicz K, Damotte D, et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest. 2012;122(3):899–910. Doi: 10.1172/JCI45817 Spranger S, Dai D, Horton B, et al. Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell. 2017;31(5):711–723.e4. doi: 10.1016/j.ccell.2017.04.003 Chong EA, Melenhorst JJ, Lacey SF, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood. 2017;129(8):1039–1041. Doi: 10.1182/blood-2016-09-738245 Yin Y, Boesteanu AC, Binder ZA, et al. Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas. Mol Ther Oncolytics. 2018;11:20–38. Doi: 10.1016/j.omto.2018.08.002 Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. Doi: 10.1038/s41408-021-00459-7 Bagaev A, Kotlov N, Nomie K, et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell. 2021;39(6):845–865.e7. doi: 10.1016/j.ccell.2021.04.014 Gires O, Pan M, Schinke H, et al. Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years? Cancer Metastasis Rev. 2020;39(3):969–987. Doi: 10.1007/s10555-020-09898-3 Müller V, Riethdorf S, Rack B, et al. Prognostic impact of circulating tumor cells assessed with the CellSearch System™ and AdnaTest Breast™ in metastatic breast cancer patients: the DETECT study. Breast Cancer Res. 2012;14(4):R118. Doi: 10.1186/bcr3243 Wang L, Balasubramanian P, Chen AP, et al. Promise and limits of the CellSearch platform for evaluating pharmacodynamics in circulating tumor cells. Semin Oncol. 2016;43(4):464–75. Doi: 10.1053/j.seminoncol.2016.06.004 Ma X, Kang X, He L, et al. Identification of Tumor Specific Peptide as EpCAM Ligand and Its Potential Diagnostic and Therapeutic Clinical Application. Mol Pharm. 2019;16(5):2199–2213. Doi: 10.1021/acs.molpharmaceut.9b00185 Bębnowska D, Grywalska E, Niedźwiedzka-Rystwej P, et al. CAR-T Cell Therapy-An Overview of Targets in Gastric Cancer. J Clin Med. 2020;9(6):1894. Doi: 10.3390/jcm9061894 Liu Y, Wang Y, Sun S, et al. Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside. Exp Hematol Oncol. 2022;11(1):97. Doi: 10.1186/s40164-022-00352-4 Li D, Guo X, Yang K, Yang Y, Zhou W, Huang Y, Liang X, Su J, Jiang L, Li J, Fu M, He H, Yang J, Shi H, Yang H, Tong A, Chen N, Hu J, Xu Q, Wei YQ, Wang W. EpCAM-targeting CAR-T cell immunotherapy is safe and efficacious for epithelial tumors. Sci Adv. 2023;9(48):eadg 9721. Lee, Daniel W., Bianca D. Santomasso, Frederick L. Locke, Armin Ghobadi, Cameron J. Turtle, Jennifer N. Brudno, Marcela V. Maus et al. “ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells.” Biology of blood and marrow transplantation 25, no. 4 (2019): 625–638. Maia A, Schöllhorn A, Schuhmacher J, Gouttefangeas C. CAF-immune cell crosstalk and its impact in immunotherapy. Semin Immunopathol. 2023;45(2):203–214. Doi: 10.1007/s00281-022-00977-x . Epub 2022 Dec 8. PMID: 36480035; PMCID: PMC10121542. Parajuli H, I MT, Abrahamsen S, Christoffersen I, Neppelberg E, Lybak S, Osman T, Johannessen AC, Gullberg D, Skarstein K, Costea DE. Integrin α11 is overexpressed by tumour stroma of head and neck squamous cell carcinoma and correlates positively with alpha smooth muscle actin expression. J Oral Pathol Med. 2017;46(4):267–275. doi: 10.1111/jop.12493 . Epub 2016 Oct 4. PMID: 27699902; PMCID: PMC5396328. Morten Mau–Sørensen et al. A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3. Cancer Chemother Pharmacol (2015) 75:1065–1073. Linke R, Klein A, Seimetz D. Catumaxomab: clinical development and future directions. MAbs. 2010 Mar-Apr;2(2):129–36. Liu Y, Wang Y, Sun S, Chen Z, Xiang S, Ding Z, Huang Z, Zhang B. Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside. Exp Hematol Oncol. 2022;11(1):97. Kang, Y.-K. et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2):XXXandomizedsed, double-blind, placebo-controlled, phase 3 trial. Lancet 390, 2461–2471 (2017). Fuchs, C. S. et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer. JAMA Oncol. 4, e180013 (2018). Li, J. et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J. Clin. Oncol. 34, 1448–1454 (2016). Qi C, Gong J, Li J, Liu D, Qin Y, Ge S, Zhang M, Peng Z, Zhou J, Cao Y, Zhang X, Lu Z, Lu M, Yuan J, Wang Z, Wang Y, Peng X, Gao H, Liu Z, Wang H, Yuan D, Xiao J, Ma H, Wang W, Li Z, Shen L. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022;28(6):1189–1198. Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryInformation.docx rsllo.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4381902","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":310879638,"identity":"d8d346cb-d2e7-4bb2-9275-1be88c60d448","order_by":0,"name":"Tianhang Luo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYBACAxCRAEYM7D8+VEjI8ROhhbEBqoVBcsYZC2PJBmK0MEC1SPO2VSRuIKhFIvn4gwc1d/L4Z7dfMJw5T4JxAwPzw0c38GpJS2xIOPasWOLOmYKEj9skmM0Z2IyNc/BqyTFsSGA7nNhwIyfh4MxtEmyWDTxs0oS1/DucOP9GTmIz7xwJHoMDxGhJbDucuOFG+mFm3gYJCcJaeJ4lzkjsO5y48UYOG+OMYxIGks0E/GLfnnzg449vhxPn3Uh/xvChpq6+n7354WN8WpAAjwGEZiZOOQiwPyBe7SgYBaNgFIwoAABl71Nbeg95mwAAAABJRU5ErkJggg==","orcid":"","institution":"Department of General Surgery, Shanghai Changhai Hospital, The Naval Medical University","correspondingAuthor":true,"prefix":"","firstName":"Tianhang","middleName":"","lastName":"Luo","suffix":""},{"id":310879640,"identity":"4bbc31c8-a615-4be2-bd4d-eb35ae18cc4d","order_by":1,"name":"Weijia Fang","email":"","orcid":"https://orcid.org/0000-0001-9849-347X","institution":"The First Affiliated Hospital of Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Weijia","middleName":"","lastName":"Fang","suffix":""},{"id":310879642,"identity":"c4fa103c-f1b2-425c-a2fd-c909a2c7a41e","order_by":2,"name":"Zhengmao Lu","email":"","orcid":"","institution":"Department of Gastrointestinal Surgery, Shanghai Changhai Hospital, The Second Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhengmao","middleName":"","lastName":"Lu","suffix":""},{"id":310879645,"identity":"e197e016-8f14-4b83-8f44-635383de7d00","order_by":3,"name":"Rui Zheng","email":"","orcid":"","institution":"Department of Gastrointestinal Surgery, Shanghai Changhai Hospital, The Second Military Medical University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Zheng","suffix":""},{"id":310879648,"identity":"4ed215c5-0c5f-4411-b07d-289253f53cb0","order_by":4,"name":"Weiwei Yin","email":"","orcid":"","institution":"College of Biomedical Engineering and Instrument Science, Zhejiang University","correspondingAuthor":false,"prefix":"","firstName":"Weiwei","middleName":"","lastName":"Yin","suffix":""},{"id":310879652,"identity":"a3697465-6e96-4a10-9dcd-3b80d9f8ee58","order_by":5,"name":"Suqiong Wang","email":"","orcid":"","institution":"Suzhou Immunofoco Biotechnology Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Suqiong","middleName":"","lastName":"Wang","suffix":""},{"id":310879655,"identity":"96f899b4-764e-4292-bb7c-8eb228334308","order_by":6,"name":"Guojiang Ai","email":"","orcid":"","institution":"Suzhou Immunofoco Biotechnology Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Guojiang","middleName":"","lastName":"Ai","suffix":""},{"id":310879656,"identity":"88cd0155-0996-4de1-ae4a-25c07c8195e3","order_by":7,"name":"Yunpeng Zhong","email":"","orcid":"","institution":"Suzhou Immunofoco Biotechnology Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Yunpeng","middleName":"","lastName":"Zhong","suffix":""},{"id":310879657,"identity":"f4f63661-16ae-4f7e-a1bd-f37f61ef048a","order_by":8,"name":"Shuangshuang Zhang","email":"","orcid":"","institution":"Suzhou Immunofoco Biotechnology Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Shuangshuang","middleName":"","lastName":"Zhang","suffix":""},{"id":310879658,"identity":"ce6368c5-7d74-44ac-8688-3ab251b4843a","order_by":9,"name":"Ruidong Hao","email":"","orcid":"","institution":"Suzhou Immunofoco Biotechnology Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Ruidong","middleName":"","lastName":"Hao","suffix":""},{"id":310879659,"identity":"88967274-7eb9-4e57-8af3-41d337ba2dff","order_by":10,"name":"Minmin Sun","email":"","orcid":"","institution":"Suzhou Immunofoco Biotechnology Co. Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Minmin","middleName":"","lastName":"Sun","suffix":""}],"badges":[],"createdAt":"2024-05-07 09:32:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4381902/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4381902/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57863580,"identity":"94af3175-a753-46fc-bf5a-854c80119baa","added_by":"auto","created_at":"2024-06-06 15:18:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46653,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStructure of IMC001\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/768000b70342608334ef99dd.png"},{"id":57864130,"identity":"d43c3fe4-0c93-47a3-bc2a-d8e51a59e340","added_by":"auto","created_at":"2024-06-06 15:26:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44438,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of this trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCAR-T, chimeric antigen receptor; ECOG, Eastern Co-operative Oncology Group.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/9bdc0a791aef435d011618a8.png"},{"id":57863583,"identity":"5021a64e-2a4b-4c3e-97f8-18068bfbe2bc","added_by":"auto","created_at":"2024-06-06 15:18:38","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":59088,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eWaterfall and swimmer plots of best overall response and duration of response in individual subjects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWaterfall plots (A) and swimmer plots (B) showing the best overall response and duration of response in individual patients with advanced gastric cancer following IMC001 treatment. The clinical cutoff date was March 31\u003csup\u003est\u003c/sup\u003e, 2024. In plot A, the dashed line at 20% signifies disease progression, while the dashed line at -30% indicates a partial response. Tumor response was determined by investigators using the RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1.\u003c/p\u003e\n\u003cp\u003ePD, progressive disease; PR, partial response; Pt, patient; SD, stable disease.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/a1be1ccadd885585dfbf39d3.png"},{"id":57863585,"identity":"2108482f-9afb-4d71-a238-361a559553f5","added_by":"auto","created_at":"2024-06-06 15:18:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":127244,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCT images and gastroscopy images of patient #4, showing a partial response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn patient #4, ascites started to reduce after 8 weeks and remained disappeared at 40 weeks after IMC001 infusion, as observed in the CT scans (A). The tumor lesion also shrank at 40 weeks post-infusion, as observed through a gastroscope (B).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/67fe113bece422c8cd6f2edc.png"},{"id":57863582,"identity":"6e62f68f-53f6-46e2-bd0b-cc3ccc19edac","added_by":"auto","created_at":"2024-06-06 15:18:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":43640,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation of CAR-T cell expansion and cytokine release with dose or clinical response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCAR proliferation was measured by vector transgene copies per microgram of genomic DNA in peripheral blood, according to dose group. Each dot represents a measurement for one patient at one time point. Measurements for individual patients are connected using dashed lines. The solid lines represent the mean values for each group. (B) The correlation between CAR-T C\u003csub\u003emax\u003c/sub\u003e and tumor response.. (C-F) The correlation between serum cytokine peak values and tumor response. (C) IP-10, (D) MCP-1, (E) IL-6, (F) IFN-γ. Patients with response, n= 3; patients with non-response, n= 7. Horizontal lines and boxes show the medians and interquartile ranges (IQRs), respectively. Response = PR; non-response = PD or SD.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/00e59b17c7a632e4ae064e09.png"},{"id":57864132,"identity":"b0ab5126-4acb-4563-a394-02650ba065d9","added_by":"auto","created_at":"2024-06-06 15:26:38","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":125723,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTumor microenvironment of baseline tumor samples and clinical response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) α-SMA staining of representative subjects. Stromal-rich was defined as more than three concentric layers of spindle-shaped positively stained fibroblasts around the tumor with a crossing network pattern (PT#5 as a representative example), while stromal-poor was defined as 1-3 concentric layers of spindle-shaped positively stained fibroblasts around tumor islands (PT#2 as a representative example). (B) Statistical analysis of α-SMA staining indifferent response groups. (C) CD4 staining of representative subjects. (D) Statistical analysis of CD4 proportion in tumors (CD4 cells number/total cell number).\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/509937e595103c85a3f0fbc7.png"},{"id":59251626,"identity":"e27dd4a2-b0a6-49c0-a801-8366d54baf6d","added_by":"auto","created_at":"2024-06-28 07:48:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1198615,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/ff99c385-e668-4b49-9a27-e51c72afd9b0.pdf"},{"id":57864131,"identity":"a2c91abd-f4ec-4072-a77f-b62ffaae10fe","added_by":"auto","created_at":"2024-06-06 15:26:38","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":295062,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/2e60e198649a3716ab8afcf1.docx"},{"id":57863588,"identity":"749013a4-90ec-49b7-adbb-3e2d751bb41a","added_by":"auto","created_at":"2024-06-06 15:18:39","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2623434,"visible":true,"origin":"","legend":"","description":"","filename":"rsllo.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4381902/v1/9e95135786e3e286a0a62459.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Epithelial Cell Adhesion Molecule (EpCAM)-Targeted CAR-T Cells (IMC001) in Patients with Advanced Gastric Cancer: A Phase I Dose-Escalation Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eWhile\u0026nbsp;chimeric antigen receptor T-cell (CAR-T) cell therapy has demonstrated remarkable efficacy in the treatment of hematologic malignancies\u003csup\u003e1\u003c/sup\u003e, its applicability to solid tumors remains limited\u003csup\u003e2\u003c/sup\u003e. \u0026nbsp;Clinical studies show that CAR-T cells can stimulate potent anti-tumor immune function with high specificity, and are potentially applicable in solid tumors, including gastric cancer. However, current challenges include CAR-T cell associated toxicity\u003csup\u003e3,4,5\u003c/sup\u003e, antigen escape\u003csup\u003e6,7\u003c/sup\u003e, antigen heterogeneity\u003csup\u003e4\u003c/sup\u003e,\u003csup\u003e\u0026nbsp;\u003c/sup\u003echallenges in CAR-T cell trafficking and tumor infiltration\u003csup\u003e5, 8, 9, 10\u0026nbsp;\u003c/sup\u003eand the immunosuppressive tumor microenvironment (TME)\u003csup\u003e11, 12, 13, 14\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe epithelial cell adhesion molecule (EpCAM, CD326) is a transmembrane glycoprotein that exhibits prominent expression in various malignancies including gastric, colorectal, prostate, ovarian, lung, and pancreatic cancers\u003csup\u003e15\u003c/sup\u003e.\u003csup\u003e\u0026nbsp;\u003c/sup\u003eIn addition to its well-established role as a biomarker for circulating tumor cells (CTCs)\u003csup\u003e16,17\u0026nbsp;\u003c/sup\u003eand cancer stem cells (CSCs), EpCAM has gained recognition as an appealing therapeutic target. Notably, while EpCAM can be detected on the basolateral membrane of several normal epithelial tissues, such as the colon, small intestine, and hepatic progenitor cells, its accessibility to large-scale constructs such as cellular therapeutics is hindered by confinement within tight cellular junctions. Consequently, EpCAM has emerged as a promising target for the treatment of solid tumors, including gastric cancer and colorectal cancer\u003csup\u003e18,19\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eNumerous drug formulations targeting EpCAM are in development, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADC), and CAR-T therapy\u003csup\u003e20\u003c/sup\u003e.\u003csup\u003e\u0026nbsp;\u003c/sup\u003eCAR-T therapy targeting EpCAM represents a promising novel approach, with intravenous infusion and a good safety profile with a larger dosage window. In a recently published study, using EpCAM CAR-T cells co-stimulated by Dectin-1 exhibited promising anti-cancer efficacy in various type solid cancers\u003csup\u003e21\u003c/sup\u003e. In this prior study, a dose of 1\u0026times;10\u003csup\u003e7\u003c/sup\u003e-1.5\u0026times;10\u003csup\u003e7\u003c/sup\u003e T cells/kg resulted in one partial response (PR) with minor side effects in four patients with stage IV gastric cancer.\u003c/p\u003e\n\u003cp\u003eIMC001 is a novel autologous T cell immunotherapy that is engineered \u003cem\u003eex vivo\u003c/em\u003e by lentiviral transduction to express an EpCAM CAR. The CAR consists of (N-terminal to C-terminal) a single-chain variable fragment (scFV) domain specifically targeting human EpCAM, followed by an extracellular hinge, the entire transmembrane domain, and the intracellular signaling domain of human CD28 (Figure 1). The intracellular domain of CD28 connects with the CD3\u0026zeta; signaling domain responsible for T cell activation. IMC001 exhibited promising anti-tumor activity in preclinical studies (data on file). The specificity of binding to EpCAM via an extracellular humanized scFV was confirmed by a membrane proteome array using around 6000 membrane proteins. IMC001 exhibited significantly higher cytotoxicity against patient derived organoids than paired adjacent non-tumor tissue derived organoids, indicating a therapeutic window for IMC001. A comprehensive good laboratory practices study in a murine model confirmed a favorable safety profile. IMC001 has received approval for clinical development (IND) in China (CDE) and the USA (FDA).\u003c/p\u003e\n\u003cp\u003eIn this study, we conducted the first phase I investigation of IMC001 for patients with advanced gastric cancer. This groundbreaking study provides the initial demonstration of the safety and efficacy of EpCAM CAR-T as a therapeutic target for solid tumors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design and patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIMC001-CT03 was a phase I, open-label, single or multiple infusion, dose escalation study conducted at Shanghai Changhai Hospital. The study utilized a classic 3+3 dose escalation trial design (Figure 2). Eligible patients were adults (aged \u0026ge;18 years) with locally advanced or metastatic gastric cancer and positive EpCAM histological staining of a biopsy tumor tissue sample who had progressed on at least two lines of prior treatment and had no other standard treatment option. Patients were also required to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, sufficient organ and bone marrow function and meet the screening criteria for routine clinical trial examinations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe protocol was registered in the Chinese clinical trial registry (ChiCTR2100047129) and\u0026nbsp;approved by the local ethics committee of the Shanghai Changhai Hospital Ethics Committee (CHEC2021-068). All patients provided written informed consent. This study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. Patients received compensation for travel and a meal per visit.\u003c/p\u003e\n\u003ch2\u003eManufacturing of the CAR-T cells\u003c/h2\u003e\n\u003cp\u003eIMC001 CAR-T manufacturing starts with the collection and transport of leukapheresis blood from a single collection. PBMC are isolated using a closed, automated program and proceed to manufacturing or are cryopreserved for subsequent production. Cells are mixed with CD3/CD28 magnetic beads and CD3+ cells are separated from the mixed samples by a magnetic platform and incubated to undergo activation. Lentiviral transduction is performed on activated cells by incubation with vector at 37 \u0026plusmn; 1\u0026deg;C, 5.0 \u0026plusmn; 0.5 % CO2 and cells are further expanded for 3-7 days (maximum of 7 days) to reach a target cell number. Harvested cells are washed and concentrated via automated methods before undergoing magnetic bead removal twice. IMC001 cells are again washed and concentrated before being resuspended in cryopreservation media and frozen by controlled rate freezer (CRF).\u003c/p\u003e\n\u003ch2\u003eTreatment and dose escalation\u003c/h2\u003e\n\u003cp\u003eEligible patients received IMC001 at escalating doses of 3\u0026times;10\u003csup\u003e5\u003c/sup\u003e, 1\u0026times;10\u003csup\u003e6\u003c/sup\u003e or 3\u0026times;10\u003csup\u003e6\u003c/sup\u003e CAR-T cells/kg, infused intravenously after lymphodepletion.\u0026nbsp;The final dose was based on the actual number of CAR-T cells produced, and the actual number of cells infused was recorded.\u0026nbsp;The lymphodepletion regimen consisted of cyclophosphamide 250 mg/m\u003csup\u003e2\u003c/sup\u003e/day on Day -4, Day -3, and Day -2; fludarabine 25 mg/m\u003csup\u003e2\u003c/sup\u003e/day on Day -4 and Day -3 and nab-paclitaxel 100 mg on Day -3. Patients who could not tolerate nab-paclitaxel received only fludarabine 20-25 mg/m\u003csup\u003e2\u003c/sup\u003e and cyclophosphamide 500 mg/m\u003csup\u003e2\u003c/sup\u003e (on Days -4 and -3).\u0026nbsp;In principle, all patients received a single infusion of IMC001. However, patients were permitted to receive an additional infusion based on safety, CAR-T cell quantity and copy number, and treatment response.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter the initial 3\u0026times;10\u003csup\u003e5\u003c/sup\u003e cells/kg dose, if no dose-limiting toxicity (DLT) occurred, the next dose level was initiated. If \u0026ge;2 DLTs occurred at a dose level, the dose was not escalated. If one DLT occurred at a given dose level, three more subjects were enrolled to that dose. If no DLT was observed among the additional three patients, the study moved to the next dose level. Each dose group completed DLT observation before the next dose group was initiated. The definition of a DLT is provided in the Supplementary Materials. After dose escalation, more patients could be recruited to a recommended dose to gain more data about IMC001 treatment, following discussion with the data safety monitoring committee (SMC).\u003c/p\u003e\n\u003ch2\u003eObjectives and measurements\u003c/h2\u003e\n\u003cp\u003eThe primary study objective was to evaluate the safety and tolerability of IMC001 in patients with advanced gastric cancer. Secondary objectives included definition of the recommended Phase II dose (RP2D) based on DLTs, preliminary evaluation of clinical efficacy, the characterization of the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of IMC001 and analysis of the tumor immune microenvironment (TME).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSafety and tolerability were assessed by recording adverse events (AEs) which were categorized according to ICH MedDRA codes version 23.1 and graded according to the common terminology criteria for adverse events (CTCAE) v5.0. Events of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) were graded using the American Society for Transplantation and Cellular Therapy (ASTCT) criteria\u003csup\u003e31\u003c/sup\u003e. Treatment efficacy was evaluated via the ORR, disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor responses were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The long-term survival follow-up was a maximum of 2 years after the first infusion. The PK and PD profiles of IMC001 were detected by qPCR and CBA assay at each visit after infusion, and the tumor microenvironment environment (TME) profile was detected by Multiplex immunohistochemistry (mIHC). Detailed methods are provided in the Supplementary Materials.\u003c/p\u003e\n\u003ch2\u003eStatistical analysis\u003c/h2\u003e\n\u003cp\u003eThe sample size was based on the \u0026ldquo;3+3\u0026rdquo; dose-escalation design. No statistical hypothesis was tested. Results were summarized using descriptive statistics including the number of cases, mean, median, standard deviation, minimum and maximum values for continuous variables and frequency distributions for categorical variables. The number and percentage of patients experiencing a treatment-Related AE (TRAE) were calculated based on system organ classification, preferred term (PT) and different dosage groups.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003e\u003cem\u003ePatients\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eFrom August 18, 2021 to May 8, 2023, a total of 11 were infused with IMC001 CAR-T cells. All 11 patients were included in the safety analysis; 3 patients each in the low-, middle- and high- dose group, with 2 more expansion patients enrolled at the recommended dose of 1\u0026times;10\u003csup\u003e6\u003c/sup\u003e cells/kg (middle-dose). Ten patients who had at least one efficacy evaluation after IMC001 infusion were included in the efficacy analysis.\u003c/p\u003e\n\u003cp\u003eAmong the 11 patients in the safety analysis, 63.6% (7/11) were male, 81.8% had \u0026ge;2 organs with metastatic involvement and 18.2% (2/11) had metastasis in \u0026ge;3 organs, mainly in the lymph nodes, abdominal cavity and peritoneum, and liver and other organs (Table 1). A total of 54.5% (6/11) patients had ascites in the abdominal cavity, while 45.5% (5/11) had ascites in the pelvic cavity. All patients had received at least two lines of prior therapy (one patient failed 1\u003csup\u003est\u003c/sup\u003e line therapy and refused a 2\u003csup\u003end\u003c/sup\u003e line treatment) and 27.3% (3/11) had received immunotherapy. The median duration from apheresis to infusion was 22 days (range, 16-33 days).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 Demographics and baseline characteristics (SS)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.291666666666667%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.0833333333333335%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePt #\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.125%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.125%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.25%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.333333333333334%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eEpCAM\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eH-score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.375%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of metastatic organs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.458333333333334%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastatic sites\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.291666666666664%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrevious treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"60%\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40%\"\u003e\n \u003cp\u003eChemotherapy lines\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.368421052631579%\" rowspan=\"3\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003cp\u003e3\u0026times;10\u003csup\u003e5\u0026nbsp;\u003c/sup\u003eCAR-T cells/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1052631578947367%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.1578947368421053%\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.1578947368421053%\"\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.842105263157894%\"\u003e\n \u003cp\u003eGastric adenocarcinoma of stomach body，Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003ePelvis, peritoneum, abdominal cavity, lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.94736842105263%\"\u003e\n \u003cp\u003eLaparoscopy, peritoneal nodule biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.631578947368421%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.272727272727273%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.818181818181818%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003eDistal gastric adenocarcinoma，Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\"\u003e\n \u003cp\u003e30%\u003c/p\u003e\n \u003cp\u003e1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.227272727272727%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eLymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eLaparoscopy, gastroduodenostomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.636363636363637%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.272727272727273%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.818181818181818%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003eGastric adenocarcinoma of stomach body, Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\"\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003cp\u003e1.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.227272727272727%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eBone, pelvis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eHysterectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.636363636363637%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.368421052631579%\" rowspan=\"5\"\u003e\n \u003cp\u003eMiddle\u003c/p\u003e\n \u003cp\u003e1\u0026times;10\u003csup\u003e6\u0026nbsp;\u003c/sup\u003eCAR-T cells/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1052631578947367%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.1578947368421053%\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.1578947368421053%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.842105263157894%\"\u003e\n \u003cp\u003eGastric adenocarcinoma of stomach body, Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e10%\u003c/p\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003eAbdominal cavity, pelvis, lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.94736842105263%\"\u003e\n \u003cp\u003eLaparoscopy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.631578947368421%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.272727272727273%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.818181818181818%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003eDistal gastric adenocarcinoma，Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\"\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003cp\u003e2.45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.227272727272727%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eLiver, abdominal cavity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eRadical gastrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.636363636363637%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.272727272727273%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.818181818181818%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003eDistal gastric adenocarcinoma，Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\"\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003cp\u003e2.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.227272727272727%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eLung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eRadical gastrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.636363636363637%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.272727272727273%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.818181818181818%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003eGastric adenocarcinoma of stomach body, Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\"\u003e\n \u003cp\u003e100%\u003cbr\u003e\u0026nbsp;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.227272727272727%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eLymph nodes, peritoneum?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eLaparoscopy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.636363636363637%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.272727272727273%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.818181818181818%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003eGastric adenocarcinoma of fundic gland, Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\"\u003e\n \u003cp\u003e100%\u003cbr\u003e\u0026nbsp;2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.227272727272727%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eLymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eNone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.636363636363637%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.368421052631579%\" rowspan=\"3\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003cp\u003e3\u0026times;10\u003csup\u003e6\u0026nbsp;\u003c/sup\u003eCAR-T cells/kg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.1052631578947367%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.1578947368421053%\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.1578947368421053%\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.842105263157894%\"\u003e\n \u003cp\u003eDistal gastric adenocarcinoma,\u0026nbsp;Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.421052631578947%\"\u003e\n \u003cp\u003e100%\u003c/p\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.473684210526315%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.578947368421053%\"\u003e\n \u003cp\u003ePancreatic head/neck, lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.94736842105263%\"\u003e\n \u003cp\u003eRadical gastrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.631578947368421%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.272727272727273%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.818181818181818%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003eGastric adenocarcinoma of stomach body,\u0026nbsp;Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\"\u003e\n \u003cp\u003e70%\u003c/p\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.227272727272727%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003ePancreatic head/neck, lymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eRadical gastrectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.636363636363637%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"2.272727272727273%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.409090909090909%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.818181818181818%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.181818181818183%\"\u003e\n \u003cp\u003eGastric adenocarcinoma,\u0026nbsp;Stage IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\"\u003e\n \u003cp\u003e90%\u003c/p\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.227272727272727%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\"\u003e\n \u003cp\u003eBilateral appendages, peritoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.454545454545453%\"\u003e\n \u003cp\u003eBilateral appendectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.636363636363637%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCAR-T, chimeric antigen receptor; ECOG, Eastern Co-operative Oncology Group; EpCAM, epithelial cell adhesion molecule; Pt, patient.\u003c/p\u003e\n\u003ch2\u003eSafety and tolerability\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eA DLT was reported in two patients in the high dose (3\u0026times;10\u003csup\u003e6\u0026nbsp;\u003c/sup\u003ecells/kg) group and the enrolment was stopped, a Grade 4 immune-related hepatitis in one patient and Grade 4 cytokine release syndrome (accompanied by COVID-19 infection) and Grade 4 immune-related pancreatitis in another patient. The low dose (3\u0026times;10\u003csup\u003e5\u0026nbsp;\u003c/sup\u003ecells/kg) and middle dose (1\u0026times;10\u003csup\u003e6\u0026nbsp;\u003c/sup\u003ecells/kg) groups prove relative safety and efficacy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs of the analysis cut-off date (March 31\u003csup\u003est\u003c/sup\u003e, 2024), treatment-related adverse events (TRAEs) with an incidence rate \u0026ge;10% by PT included decrease in lymphocyte count, white blood cell count, neutrophil count, and platelet count, cytokine release syndrome, fever, abnormal liver function, elevated C-reactive protein, immune-related hepatitis, epidermolysis and anemia. Hematological toxicities such as decrease in lymphocyte count, white blood cell count, neutrophil count, and platelet count were related to lymphodepletion which recorded as TRAEs by the investigators. Grade \u0026ge;3 TRAE included cytokine release syndrome, abnormal liver function, and immune-related hepatitis (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Summary of Treatment-Related Adverse Events (TRAE) with an Overall Incidence Rate \u0026ge;10% or an Incidence Rate \u0026ge;10% and CTCAE Grade \u0026ge;3 SS (N=11)\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.370883882149048%\" colspan=\"2\"\u003e\n \u003cp\u003e3\u0026times;10\u003csup\u003e5\u003c/sup\u003e CAR-T cells/kg\u003cbr\u003e\u0026nbsp;(N=3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.890814558058924%\" colspan=\"2\"\u003e\n \u003cp\u003e1\u0026times;10\u003csup\u003e6\u003c/sup\u003e CAR-T cells/kg\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(N=5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.890814558058924%\" colspan=\"2\"\u003e\n \u003cp\u003e3\u0026times;10\u003csup\u003e6\u003c/sup\u003e CAR-T cells/kg\u003cbr\u003e\u0026nbsp;(N=3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.890814558058924%\" colspan=\"2\"\u003e\n \u003cp\u003eTotal\u003cbr\u003e\u0026nbsp;(N=11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003ePreferred Term (PT)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003eAny Grade\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003eGrade 3 or Higher\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003eAny Grade\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003eGrade 3 or Higher\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003eAny Grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003eGrade 3 or Higher\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003eAny Grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003eGrade 3 or Higher\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eAt least one occurrence with an incidence rate \u0026ge;10% or an incidence rate \u0026ge;10% and CTCAE \u0026ge;3 for TRAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eLymphocyte count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eNeutrophil count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eWhite blood cell count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003ePlatelet count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eCytokine release syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eAbnormal liver function\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eElevated C-reactive protein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eepidermolysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eImmune-related hepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.956672443674176%\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.358752166377815%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.01213171577123%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.878682842287695%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCAR-T, chimeric antigen receptor; CTCAE, common terminology criteria for adverse events.\u003c/p\u003e\n\u003cp\u003eNo IMC001 infusion related deaths or serious adverse events (SAEs) were reported. However, three patients (27.2%) experienced treatment emergent SAEs: respiratory failure and disseminated intravascular coagulation (33.3%, 1/3), pancreatitis (20%, 1/5) and infectious pneumonia (33.3%, 1/3), in the low-, middle-, and high-dose groups, respectively, which were considered not related to IMC001 treatment by the investigator.\u003c/p\u003e\n\u003cp\u003eA total of five patients experienced at least one CRS event, including one patient in the low-dose group (1/3, 33.3%), two patients in the middle-dose group (2/5, 40%; one of which was Grade 3) and two in the high-dose group (2/3, 66.7%; both Grade 4). Immune-related hepatitis was observed in one patient in the middle-dose group (1/5, Grade 3) and one in the high-dose group (1/3, Grade 4). Generally, CRS or immune-related hepatitis occurred in the first week of treatment administration and the majority of patients responded to supportive therapy.\u003c/p\u003e\n\u003ch2\u003ePreliminary efficacy\u003c/h2\u003e\n\u003cp\u003eAmong ten patients included in the efficacy analysis, the ORR and DCR were 30% (3/10) and 90% (9/10), respectively (Figure 3); the median PFS was 18.1 weeks (95% CI 5.27, --) and the median OS was 33.5 weeks (95% CI 5.27, 67.77).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne patient in the low-dose group (3\u0026times;10\u003csup\u003e5\u0026nbsp;\u003c/sup\u003ecells/kg) achieved a PR at week 32 and received a second infusion with a higher dose of 1\u0026times;10\u003csup\u003e6\u0026nbsp;\u003c/sup\u003ecells/kg at week 53, who survived for 67.9 weeks since first infusion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the middle-dose group (1\u0026times;10\u003csup\u003e6\u003c/sup\u003e cells/kg), the ORR was 40% (2/5); the median PFS was 18.1 weeks (95% CI 7.97, --) and the median OS was 55.1 weeks (95% CI 23.78, --) with a maximum follow-up time of 21.8 months. One of the patients in the middle-dose group achieved a 15% reduction in tumor size at Week 4 and a 26% reduction at Week 8. This response evolved into a confirmed PR by Week 24, culminating in a radical gastrectomy at Week 27 and, as of Week 16 post-surgery, the patient had survived for more than 22 months by the cutoff date (Figure 4). The other patient in the middle dose group achieving a PR exhibited a 48% reduction in target lesion size at Week 16. The survival times of the other two patients in the middle-dose group, who achieved stable disease (SD), were 55 weeks and 43 weeks, respectively. \u0026nbsp;\u003c/p\u003e\n\u003ch2\u003ePharmacokinetics and pharmacodynamics\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eAfter a single infusion of IMC001, cell expansion and cytokine release were detected in the peripheral blood. Pharmacokinetic analysis demonstrated a dose-dependent proliferation of CAR-T cells post IMC001 infusion, with a median C\u003csub\u003emax\u003c/sub\u003e value of 58, 394, and 4808 copies per microgame genomic DNA for the low-does, middle-does and high-doses respectively. The median T\u003csub\u003emax\u003c/sub\u003e value was 7 days (7-28); and the median persistence in peripheral blood was 11days (7-56) (Figure 5A). In a further analysis, patients were categorized into two groups based on clinical response: PR (responders), and PD or SD (non-responders). Although the response group exhibited a higher median C\u003csub\u003emax\u003c/sub\u003e compared to the non-response group (394 vs. 90 copies per microgram genomic DNA), the difference did not reach statistical significance (Figure 5B). An analysis of cytokine release profiles post-treatment revealed no significant correlation between efficacy and serum cytokine levels (Figure 5C-5F). These results indicate that CAR-T expansion in peripheral blood correlates with dose, while the potential correlation with clinical efficacy warrants further investigation in large scale trials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTumor microenvironment \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn our study, we investigated the correlation between the TME and the response of IMC001. Previous reports have highlighted the role of the TME, particularly stromal cells and cancer-associated fibroblasts (CAFs); their interaction with immune cells constitutes a major driver of tumor progression and therapy response\u003csup\u003e23\u003c/sup\u003e. Notably, \u0026alpha;-smooth muscle actin (\u0026alpha;-SMA), a marker of activated CAFs, has been implicated in tumor progression and immunosuppression. Building upon this knowledge, we performed \u0026alpha;-SMA staining of tissue from nine patients to characterize the pattern of CAFs within the TME, categorized as poor or rich \u0026alpha;-SMA staining\u003csup\u003e24\u003c/sup\u003e. Remarkably, all three patients who achieved a PR exhibited poor \u0026alpha;-SMA staining. In contrast, among patients with SD or PD, only 1/6 exhibited poor \u0026alpha;-SMA staining, while the majority (5/6) displayed a rich \u0026alpha;-SMA staining pattern (Figure 6A, 6B). These findings suggest that the presence of poor \u0026alpha;-SMA staining within the TME may contribute to enhanced efficacy of IMC001 therapy.\u003c/p\u003e\n\u003cp\u003eIn addition to assessing the role of CAFs, we investigated the presence of CD4 positive T cells and their potential correlation with IMC001 efficacy. CD4 positive T cells play a crucial role in orchestrating immune responses within the TME and have been implicated in tumor surveillance and regulation of anti-tumor immunity. Our analysis revealed that CD4 levels were slightly higher in patients who achieved a PR compared to those with SD or PD following IMC001 therapy (Figure 6C, 6D). While the exact mechanisms underlying this observation require further elucidation, it suggests a potential association between CD4 positive T cell infiltration and favorable clinical outcomes in response to IMC001 treatment. These findings underscore the complexity of the TME and highlight the importance of investigating multiple immune cell populations to better understand the mechanisms underlying immunotherapeutic responses in advanced gastric cancer. Further studies are warranted to validate these observations and elucidate the functional significance of \u0026alpha;-SMA staining patterns and CD4 positive T cells in the context of IMC001 therapy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis Phase I study is the first investigation of the EpCAM-targeted CAR-T cell therapy IMC001 in patients with advanced gastric cancer. All 11 patients who received treatment experienced transient toxicities which were manageable with supportive treatment. Two patients in the high dose (3\u0026times;10\u003csup\u003e6\u003c/sup\u003e cells/kg) group experienced dose-limiting toxicities (DLTs) and the incidence of TRAEs and DLTs showed an association with higher levels of cytokine changes and higher CAR-T expansion copy numbers in this group. For patients in the low- and middle-dose groups, all TRAEs were tolerable. Most of the AEs observed during/after IMC001 treatment were expected and reflect its mechanism of action. Based on these safety findings, the preliminary efficacy evaluation, and discussions with the safety monitoring committee, the middle-dose (1\u0026times;10\u003csup\u003e6\u003c/sup\u003e cells/kg) was selected as the recommended dose for further investigations of IMC001.\u003c/p\u003e \u003cp\u003eIn adults, EpCAM is expressed in most organs and glands and the immune-related hepatitis and skin toxicity observed in the middle- and high-dose groups is potentially related to on-target, off-tumor activity and the immune effect of a CRS. In addition, the intravenous infusion of IMC001 appears to be better tolerated than the intravenous infusion of catumaxomab, a bispecific antibody targeting EpCAM \u003csup\u003e25\u003c/sup\u003e. In a phase I trial, the treatment of EpCAM\u0026thinsp;+\u0026thinsp;tumor patients with catumaxomab caused dose dependent hepatitis with elevations in serum alanine transaminase, aspartate transaminase, bilirubin, γ-GT and induction of the C-reactive protein and IL-6 and IL-8. The first patient receiving 10\u0026micro;g catumaxomab experienced fatal acute liver failure which led to the termination of the study. The development and clinical use of catumaxomab and other EpCAM bi-specific antibodies was focused on intraperitoneal route to avoid system exposure and adverse effects \u003csup\u003e26,27\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePreliminary efficacy data from our study demonstrated an anti-tumor effect of IMC001 in patients with gastric cancer. Among the 10 patients with a response evaluation post-IMC001 treatment, six exhibited SD, and three achieved a PR. Among the three patients with confirmed PRs, these occurred at post-treatment Week 16 to Week 32, respectively, suggesting a gradual enhancement in the anti-tumor effect of IMC001 after administration, and the middle dose of 1\u0026times;10\u003csup\u003e6\u003c/sup\u003e/kg resulted in a quicker response than the low dose at Week 32. In gastric cancer, immunotherapies such as programmed death-1 (PD-1) and VEGFR inhibitors have shown only limited effectiveness as 3rd -line treatments, with ORRs ranging from 1.7%-13.3%, median PFS of 1.6\u0026ndash;2.6 months and median OS of around 6 months \u003csup\u003e28\u0026ndash;30\u003c/sup\u003e. The medium PFS and OS for patients receiving IMC001 1\u0026times;10\u003csup\u003e6\u003c/sup\u003e cells/kg in the present study of 18.1 weeks and 55.1 weeks, with an ORR of 40% were better than historical data for patients with advanced gastric cancer who failed at least 2nd -line chemotherapy. Translational surgery was available for one patient (#4) after IMC001 infusion with an OS more than 94 weeks, which may also provide longer survival for this group of patients. In summary, these encouraging preliminary efficacy data for IMC001 in patients with advanced gastric cancer suggest it may provide an anti-tumor effect and offer a novel treatment option, which is important given the currently limited choice of treatments.\u003c/p\u003e \u003cp\u003eThe patient #4 was a 50-year-old male with stage IV gastric adenocarcinoma, intraperitoneal lymph node metastasis and symptoms for \u0026gt;\u0026thinsp;1 year before IMC001 infusion (middle-dose). Histological examination revealed an EpCAM expression of 10% and a H-score of 1.1. Previous treatment included left gastric arteriography plus arterial perfusion chemoembolization (raltitrexed regimen), and prior anti-cancer therapies included first-line tegafur/gimeracil/oteracil potassium (SOX)\u0026thinsp;+\u0026thinsp;Herceptin, and 2nd line therapy with oxaliplatin\u0026thinsp;+\u0026thinsp;trastuzumab. The patient had a diagnosis of cT4a-4bN2-3M0-1 with no indication for surgery. After IMC001 infusion, the lymph nodes decreased significantly and pelvic effusion disappeared, allowing a conversion to radical gastrectomy and achievement of a surgical complete response 27 weeks after CAR-T cell infusion. The ability to regain the opportunity for surgery opportunity may present a potential benefit for patients with late-stage gastric cancer.\u003c/p\u003e \u003cp\u003eThe pharmacokinetic profile of IMC001 observed in our study, by peak CAR copy numbers at approximately 10 days post-infusion, aligns with the peak time observed for CAR-T cell therapies in hematopoietic malignancies targeting CD19 and CT041, a CLDN18.2-targeting CAR-T cell product \u003csup\u003e31\u003c/sup\u003e. Notably, the observed peak CAR copy numbers were modestly lower compared to those previously reported for CD19-directed CAR-T therapies. This observation, coupled with the lack of correlation between peak CAR copy numbers (C\u003csub\u003emax\u003c/sub\u003e) and clinical efficacy observed in our study, diverges from the well-established relationship for CAR-T therapies in hematologic malignancies, where higher C\u003csub\u003emax\u003c/sub\u003e values are typically associated with improved outcomes. Our findings may reflect the unique characteristics of CAR-T cell therapy in solid tumors, where the expansion and persistence of CAR-T cells within the tumor microenvironment, rather than in peripheral blood, are more critical determinants of therapeutic efficacy. This hypothesis is supported by the low levels of peripheral CAR-T cells and the absence of correlation between their levels and antitumor responses. Given the small sample size of our study, these findings warrant validation in larger clinical trials to better understand the relationship between the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of IMC001 and efficacy in a solid tumor setting.\u003c/p\u003e \u003cp\u003eOur translational research investigated the relationship between the TME and the efficacy of IMC001. An analysis of stromal-rich TMEs, characterized by an abundance of network-style CAFs, was associated with less likelihood of a response to IMC001. This is the first clinical evidence supporting the notion that the presence of CAFs within the TME may negatively influence the therapeutic response to CAR-T cell therapy in solid tumors. This finding is in line with reported preclinical data and further underscores the importance of considering the TME when evaluating the efficacy of CAR-T cell therapies. Additionally, our study explored the intra-tumoral levels of CD4\u0026thinsp;+\u0026thinsp;T cells and observed a non-significant trend towards higher CD4 density in patients achieving PR. This observation, if confirmed in larger cohorts, could provide insights into the immune cell dynamics within the TME and their potential prognostic potential in predicting CAR-T cell therapy outcomes in patients with solid tumors.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, EpCAM-targeted CAR-T therapy (IMC001) holds promise as a novel treatment modality for patients with gastric cancer. With a favorable safety profile and promising anti-cancer effect, IMC001 may prolong survival and provide the opportunity for surgery in patients with advanced gastric cancers. Given these promising preliminary findings in gastric cancer, the investigation of IMC001 in other epithelial tumors is a direction for future research.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eInclusion and ethics\u003c/p\u003e\n\u003cp\u003eThe protocol was registered in the Chinese Clinical Trial Registry (ChiCTR2100047129) and approved by the local ethics committee of the Shanghai Changhai Hospital Ethics Committee (CHEC2021-068). All patients provided written informed consent.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eAll authors declare no competing financial and/or non-financial interests in relation to the work described.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis clinical trial was supported by Immunofoco Co., Ltd and China Zhongguancun Precision Medicine Science and Technology Foundation (CPMF).\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eThe manuscript was written by GQ Ai, YP Zhong and SS Zhang and critically reviewed and revised by the other authors. All authors contributed to the analysis and interpretation of the data. The authors affirm the accuracy and completeness of the data and adherence of the study to the protocol.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eMedical writing support was provided by Jake Burrell, PhD, on behalf of Rude Health Consulting Ltd. This support was funded by Immunofoco Co., Ltd.\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eThe data underlying this paper are available from the corresponding authors upon reasonable request.\u003c/p\u003e\n\u003cp\u003eCode availability\u003c/p\u003e\n\u003cp\u003eNot applicable to this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMunshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705\u0026ndash;716. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2024850\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2024850\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlcantara M, Du Rusquec P, Romano E. Current Clinical Evidence and Potential Solutions to Increase Benefit of CAR T-Cell Therapy for Patients with Solid Tumors. Oncoimmunology. 2020;9(1):1777064. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/2162402X.2020.1777064\u003c/span\u003e\u003cspan address=\"10.1080/2162402X.2020.1777064\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDavila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):224ra25. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/scitranslmed.3008226\u003c/span\u003e\u003cspan address=\"10.1126/scitranslmed.3008226\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKailayangiri S, Altvater B, Wiebel M, et al. Overcoming Heterogeneity of Antigen Expression for Effective CAR T Cell Targeting of Cancers. Cancers (Basel). 2020;12(5):1075. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cancers12051075\u003c/span\u003e\u003cspan address=\"10.3390/cancers12051075\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKochenderfer JN, Dudley ME, Feldman SA, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709\u0026ndash;20. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood-2011-10-384388\u003c/span\u003e\u003cspan address=\"10.1182/blood-2011-10-384388\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHegde M, Mukherjee M, Grada Z, et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest. 2016;126(8):3036\u0026ndash;52. Doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/JCI83416\u003c/span\u003e\u003cspan address=\"10.1172/JCI83416\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZah E, Lin MY, Silva-Benedict A, et al. T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells. Cancer Immunol Res. 2016;4(6):498\u0026ndash;508. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1158/2326-6066.CIR-15-0231\u003c/span\u003e\u003cspan address=\"10.1158/2326-6066.CIR-15-0231\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoznansky MC, Olszak IT, Evans RH, et al. Thymocyte emigration is mediated by active movement away from stroma-derived factors. J Clin Invest. 2002;109(8):1101\u0026ndash;10. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/JCI13853\u003c/span\u003e\u003cspan address=\"10.1172/JCI13853\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalmon H, Franciszkiewicz K, Damotte D, et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest. 2012;122(3):899\u0026ndash;910. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/JCI45817\u003c/span\u003e\u003cspan address=\"10.1172/JCI45817\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpranger S, Dai D, Horton B, et al. Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell. 2017;31(5):711\u0026ndash;723.e4. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ccell.2017.04.003\u003c/span\u003e\u003cspan address=\"10.1016/j.ccell.2017.04.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChong EA, Melenhorst JJ, Lacey SF, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood. 2017;129(8):1039\u0026ndash;1041. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood-2016-09-738245\u003c/span\u003e\u003cspan address=\"10.1182/blood-2016-09-738245\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin Y, Boesteanu AC, Binder ZA, et al. Checkpoint Blockade Reverses Anergy in IL-13Rα2 Humanized scFv-Based CAR T Cells to Treat Murine and Canine Gliomas. Mol Ther Oncolytics. 2018;11:20\u0026ndash;38. Doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.omto.2018.08.002\u003c/span\u003e\u003cspan address=\"10.1016/j.omto.2018.08.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41408-021-00459-7\u003c/span\u003e\u003cspan address=\"10.1038/s41408-021-00459-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBagaev A, Kotlov N, Nomie K, et al. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell. 2021;39(6):845\u0026ndash;865.e7. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ccell.2021.04.014\u003c/span\u003e\u003cspan address=\"10.1016/j.ccell.2021.04.014\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGires O, Pan M, Schinke H, et al. Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years? Cancer Metastasis Rev. 2020;39(3):969\u0026ndash;987. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10555-020-09898-3\u003c/span\u003e\u003cspan address=\"10.1007/s10555-020-09898-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM\u0026uuml;ller V, Riethdorf S, Rack B, et al. Prognostic impact of circulating tumor cells assessed with the CellSearch System\u0026trade; and AdnaTest Breast\u0026trade; in metastatic breast cancer patients: the DETECT study. Breast Cancer Res. 2012;14(4):R118. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/bcr3243\u003c/span\u003e\u003cspan address=\"10.1186/bcr3243\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang L, Balasubramanian P, Chen AP, et al. Promise and limits of the CellSearch platform for evaluating pharmacodynamics in circulating tumor cells. Semin Oncol. 2016;43(4):464\u0026ndash;75. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.seminoncol.2016.06.004\u003c/span\u003e\u003cspan address=\"10.1053/j.seminoncol.2016.06.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa X, Kang X, He L, et al. Identification of Tumor Specific Peptide as EpCAM Ligand and Its Potential Diagnostic and Therapeutic Clinical Application. Mol Pharm. 2019;16(5):2199\u0026ndash;2213. Doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1021/acs.molpharmaceut.9b00185\u003c/span\u003e\u003cspan address=\"10.1021/acs.molpharmaceut.9b00185\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBębnowska D, Grywalska E, Niedźwiedzka-Rystwej P, et al. CAR-T Cell Therapy-An Overview of Targets in Gastric Cancer. J Clin Med. 2020;9(6):1894. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/jcm9061894\u003c/span\u003e\u003cspan address=\"10.3390/jcm9061894\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Wang Y, Sun S, et al. Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside. Exp Hematol Oncol. 2022;11(1):97. Doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s40164-022-00352-4\u003c/span\u003e\u003cspan address=\"10.1186/s40164-022-00352-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi D, Guo X, Yang K, Yang Y, Zhou W, Huang Y, Liang X, Su J, Jiang L, Li J, Fu M, He H, Yang J, Shi H, Yang H, Tong A, Chen N, Hu J, Xu Q, Wei YQ, Wang W. EpCAM-targeting CAR-T cell immunotherapy is safe and efficacious for epithelial tumors. Sci Adv. 2023;9(48):eadg 9721.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee, Daniel W., Bianca D. Santomasso, Frederick L. Locke, Armin Ghobadi, Cameron J. Turtle, Jennifer N. Brudno, Marcela V. Maus et al. \u0026ldquo;ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells.\u0026rdquo; Biology of blood and marrow transplantation 25, no. 4 (2019): 625\u0026ndash;638.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaia A, Sch\u0026ouml;llhorn A, Schuhmacher J, Gouttefangeas C. CAF-immune cell crosstalk and its impact in immunotherapy. Semin Immunopathol. 2023;45(2):203\u0026ndash;214. Doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00281-022-00977-x\u003c/span\u003e\u003cspan address=\"10.1007/s00281-022-00977-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2022 Dec 8. PMID: 36480035; PMCID: PMC10121542.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParajuli H, I MT, Abrahamsen S, Christoffersen I, Neppelberg E, Lybak S, Osman T, Johannessen AC, Gullberg D, Skarstein K, Costea DE. Integrin α11 is overexpressed by tumour stroma of head and neck squamous cell carcinoma and correlates positively with alpha smooth muscle actin expression. J Oral Pathol Med. 2017;46(4):267\u0026ndash;275. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/jop.12493\u003c/span\u003e\u003cspan address=\"10.1111/jop.12493\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2016 Oct 4. PMID: 27699902; PMCID: PMC5396328.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorten Mau\u0026ndash;S\u0026oslash;rensen et al. A phase I trial of intravenous catumaxomab: a bispecific monoclonal antibody targeting EpCAM and the T cell coreceptor CD3. Cancer Chemother Pharmacol (2015) 75:1065\u0026ndash;1073.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLinke R, Klein A, Seimetz D. Catumaxomab: clinical development and future directions. MAbs. 2010 Mar-Apr;2(2):129\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Wang Y, Sun S, Chen Z, Xiang S, Ding Z, Huang Z, Zhang B. Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside. Exp Hematol Oncol. 2022;11(1):97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKang, Y.-K. et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2):XXXandomizedsed, double-blind, placebo-controlled, phase 3 trial. Lancet 390, 2461\u0026ndash;2471 (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuchs, C. S. et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer. JAMA Oncol. 4, e180013 (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi, J. et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J. Clin. Oncol. 34, 1448\u0026ndash;1454 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQi C, Gong J, Li J, Liu D, Qin Y, Ge S, Zhang M, Peng Z, Zhou J, Cao Y, Zhang X, Lu Z, Lu M, Yuan J, Wang Z, Wang Y, Peng X, Gao H, Liu Z, Wang H, Yuan D, Xiao J, Ma H, Wang W, Li Z, Shen L. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med. 2022;28(6):1189\u0026ndash;1198.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4381902/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4381902/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the safety and preliminary efficacy of IMC001, an epithelial cell adhesion molecule (EpCAM)-targeted CAR-T cell therapy, in patients with advanced gastric cancer (GC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a phase I, open-label, single or multiple infusion, dose escalation study utilizing a classic 3+3 design that included adults (aged ≥18 years) with locally advanced or metastatic GC with positive EpCAM histological staining of a biopsy tumor tissue sample who had failed at least two lines of treatment and were ineligible for a standard treatment. Eligible patients received IMC001 at doses of 3×10\u003csup\u003e5\u003c/sup\u003e (low), 1×10\u003csup\u003e6\u003c/sup\u003e (middle) or 3×10\u003csup\u003e6\u003c/sup\u003e (high) CAR-T cells/kg after lymphodepletion. The primary objective was evaluation of the safety and tolerability of IMC001. Secondary objectives included determination of the recommended phase II dose (RP2D) based on dose-limiting toxicity (DLT), preliminary evaluation of efficacy and characterization of pharmacokinetics and pharmacodynamics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrom August 18, 2021 to May 8, 2023, 11 patients with advanced GC received IMC001, the median age was 53 (36-70) years and 63.6% (7/11) were male. Most patients 91.9% (10/11) had failed ≥2 lines of chemotherapy and 27.3% (3/11) had received prior immunotherapy. By the cutoff date (March 31\u003csup\u003est\u003c/sup\u003e, 2024), low- and middle-dose IMC001 infusion was associated with a favorable safety profile. The disease control rate was 90% in 10 evaluable patients; 1 patient in the low-dose group (1/3, 33.3%) and 2 in the middle-dose group (2/5, 40%) achieved a partial response (PR). The median PFS was 18.1 weeks (95% CI 7.97, --) and the OS was 55.1 weeks (95% CI 23.78, --) for the middle dose group; 3/5 patients in the middle dose group had survived more than 10 months. One patient in the middle-dose group achieved a confirmed PR by Week 24, culminating in a radical gastrectomy at Week 27 and had survived for more than 22 months by the cutoff date. Tumor immune microenvironment analysis suggested that an inflamed tumor environment may enhance the anti-tumor effects of IMC001. The 1×10\u003csup\u003e6\u003c/sup\u003e CAR-T cells/kg dose was selected as the recommended dose for future study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this phase I dose-escalation trial, IMC001 demonstrated a favorable safety profile and encouraging efficacy in patients with advanced, pre-treated GC. Further investigation is warranted to further evaluate the use of IMC001 for patients with advanced GC.\u003c/p\u003e","manuscriptTitle":"Epithelial Cell Adhesion Molecule (EpCAM)-Targeted CAR-T Cells (IMC001) in Patients with Advanced Gastric Cancer: A Phase I Dose-Escalation Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-06 15:18:33","doi":"10.21203/rs.3.rs-4381902/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"76dec95e-c29d-4870-a3ba-08c41323d0cc","owner":[],"postedDate":"June 6th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":32854348,"name":"Health sciences/Oncology/Cancer/Cancer therapy/Cancer immunotherapy"},{"id":32854349,"name":"Health sciences/Gastroenterology/Gastrointestinal diseases/Gastrointestinal cancer/Gastric cancer"}],"tags":[],"updatedAt":"2024-06-28T07:40:16+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-06 15:18:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4381902","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4381902","identity":"rs-4381902","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}