Safety and feasibility of 5T4 antibody-coupled allogeneic NK cell therapy for solid tumors: A first-in-human phase 1 trial

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Antibody-guided allogeneic natural killer (NK) cell therapy represents a novel immunotherapeutic strategy to enhance tumor targeting and cytotoxicity by coupling NK cells with tumor-specific antibodies targeting antigens such as 5T4. Objective To evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary efficacy of IBR854, a non-viral, non-genetically modified, 5T4 antibody-coupled allogeneic NK cell therapy, in patients with advanced solid tumors. Patients and Methods This open-label, first-in-human phase 1 dose-escalation study enrolled 19 patients with unresectable locally advanced or metastatic solid tumors across five dose cohorts (3.0×10⁹ to 12.0×10⁹ cells per dose). Patients received intravenous IBR854 in a 3 + 3 escalation design. Safety, dose-limiting toxicities, adverse events, pharmacokinetics, anti-drug antibodies, and antitumor activity (RECIST v1.1) were assessed. Results No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were elevated interleukin levels (42.1%), infusion-related reactions (31.6%), and fever (21.1%). No anti-drug antibodies were detected. The disease control rate was 43.8%. Median progression-free survival was 43 days. Pharmacokinetic analysis based on transgene copy number showed a dose-dependent prolongation of T max (0.867–3.433 h), with a relatively consistent half-life (1.390–2.648 h). Conclusions IBR854 demonstrated an acceptable safety and tolerability profile and achieved disease stabilization in a subset of heavily pretreated patients with advanced solid tumors. These findings support further clinical development of 5T4-targeted antibody-coupled allogeneic NK cell therapy. Trial registration This study was registered at ClinicalTrials.gov (registration number: NCT06001684). IBR854 5T4 antigen Allogeneic NK cell therapy Solid tumors First-in-human trial Figures Figure 1 Figure 3 Figure 4 Introduction The management of patients with unresectable centrally advanced or metastatic solid tumors remains a formidable clinical challenge, with many standard therapies failing to achieve sustained disease control. Adoptive cell‑based immunotherapies have emerged as a promising frontier in oncology, leveraging innate and adaptive immune mechanisms to mediate anti‑tumour effects. In particular, natural killer (NK) cells have garnered increasing interest for cancer immunotherapy owing to their intrinsic cytotoxic capacity and ability to function in a non‑major histocompatibility complex (MHC)-restricted recognition, and favorable safety profile. 1 To improve tumor specificity, chimeric antigen receptor (CAR)-NK cells have been actively developed for solid tumors. At least 40 clinical studies of CAR-NK cells targeting solid cancers have been registered, most of which remain in early-phase testing 2 , 3 . Current trials cover a broad range of targets and tumor types, including NKG2D ligands, mesothelin, CD70, MUC1, ROBO1, and 5T4 in colorectal, ovarian, pancreatic, renal, lung, brain and other solid tumors. However, available clinical data remain limited, and reported efficacy has generally been modest, with disease stabilization more commonly observed than objective tumor regression. 2 , 3 For example, a phase I study of NKG2D CAR-NK cells in advanced colorectal cancer showed acceptable safety but limited antitumor activity, with stable disease as the best response in one of six heavily pretreated patients 4 . These findings suggest that CAR-mediated targeting can enhance NK-cell specificity, but solid tumors continue to impose major barriers, including limited trafficking, short in vivo persistence, antigen heterogeneity, and an immunosuppressive tumor microenvironment. Antibody-guided NK cell therapy represents an alternative strategy to enhance tumor targeting while avoiding genetic modification. By covalently conjugating tumour-specific monoclonal antibodies to the surface of NK cells, this modality achieves precise delivery of effector lymphocytes to antigen-expressing tumour sites, thereby enhancing tumour homing. Upon engagement of antibody-coated tumour cells, the Fc domain of the antibody interacts with Fcγ receptors on NK cells to trigger robust antibody-dependent cellular cytotoxicity (ADCC) in the context of therapeutic antibodies. 5 This dual mechanism of physical targeting and functional activation synergistically amplifies NK-mediated cytotoxicity without requiring genetic modification of the effector cell. 6 , 7 The oncofetal antigen 5T4 (trophoblast glycoprotein, TPBG) is a transmembrane glycoprotein that is broadly overexpressed in a variety of solid malignancies, including colorectal, ovarian, lung and other carcinomas, while displaying limited expression in normal adult tissues. As an oncofetal antigen, 5T4 was originally identified by its shared expression between trophoblast and cancer cells, and its tumour-restricted distribution confers a favourable therapeutic index by minimising on-target off-tumour toxicity. 8 The N-glycosylated cell surface localisation and stable expression of 5T4 make it particularly amenable to antibody engagement and subsequent induction of ADCC via NK cells. Owing to its prevalence across diverse tumour types and restricted normal tissue expression, 5T4 continues to be investigated as a promising target for antibody-based and immune-engaging therapeutic strategies. 9 IBR854 is a novel, non‑genetically‑modified, antibody‑guided allogeneic NK‑cell therapy designed to target 5T4‑expressing solid tumours. IBR854 leverages healthy donor‑derived NK cells conjugated with a monoclonal anti‑5T4 antibody, enabling selective binding to tumour cells and triggering cytotoxicity, while avoiding the risks associated with viral gene transfer or autologous T‑cell manufacturing. Preclinical studies demonstrated that IBR854 exerts potent cytotoxic activity against multiple 5T4-positive solid tumor cell lines and induces dose-dependent tumor growth inhibition in xenograft models, with favorable safety characteristics and minimal off-target binding. Here we report the detailed safety, pharmacokinetics, and exploratory efficacy outcomes of IBR854, together with correlative biomarker analyses of donor–recipient HLA/KIR and clinical outcomes. In this patient cohort, no dose‑limiting toxicity was observed, and the regimen was well tolerated, with a disease control rate (DCR) of 43.8%. Overall, this study supports the further development of IBR854 as a novel “off‑the‑shelf” NK‑cell therapy platform targeting 5T4‑positive solid tumours. Methods Study design This open-label, multicenter phase 1 study (approvals: 2023LP00207, 2023LP00208, 2024LB00345, 2024LB00346) evaluated IBR854 in patients with advanced solid tumors. The primary objectives were to assess safety, tolerability, and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D); secondary objectives included preliminary efficacy, pharmacokinetics (PK), and immunogenicity; exploratory objectives assessed donor–recipient HLA/KIR matching and 5T4 expression in relation to clinical outcomes. The study included screening (≤ 28 days), treatment, and follow-up phases, as illustrated in Fig. 1 . A standard 3 + 3 dose-escalation design was used across five dose levels The starting dose of 3.0×10⁹ cells was selected based on preclinical safety evaluations and a conservative approach commonly applied in first-in-human studies of cell-based therapies, with subsequent dose escalation guided by emerging safety, PK, and efficacy data. IBR854 was administered on days 1 and 8 of each 21-day cycle. Dose escalation proceeded after completion of a 21-day dose-limiting toxicity (DLT) evaluation period in the preceding cohort. The starting dose was selected based on preclinical safety data and prior experience with NK cell-based therapies. Considering the potential risk of on-target off-tumor toxicity due to 5T4 expression in certain normal tissues, comprehensive safety monitoring and predefined stopping criteria were incorporated into the study design. DLTs were predefined ( Table S2 ), and safety was continuously reviewed by a Safety Review Committee to guide dose escalation and determine MTD/RP2D, with specific monitoring for potential on-target off-tumor effects related to 5T4 expression. Patient eligibility Eligible patients were adults aged 18–75 years with unresectable locally advanced or metastatic solid tumors without standard treatment options, including at least one measurable target lesion per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2, and an expected survival of > 3 months. Adequate organ function was required, including an absolute neutrophil count (ANC) of ≥ 1.5×10⁹/L, a platelet count (PLT) of ≥ 75×10⁹/L, a hemoglobin (HGB) of ≥ 80 g/L, and normal renal, hepatic, and coagulation function as specified. Fertile patients and their partners agreed to use effective contraception for 6 months after the last dose of study drug. Detailed inclusion and exclusion criteria are listed in Table S1 . NK cell preparation IBR854 cell injection is a non-genetically edited, antibody-guided biochemically activated NK cell product. Its core structure consists of a full-length monoclonal anti-5T4 antibody conjugated to allogeneic NK cells derived from peripheral blood of healthy donors via an L2 linker (based on click chemistry), enabling specific recognition of the 5T4 antigen and tumor cell killing. The product was stored at ≤-150℃, with strict cold chain management during transportation and use to maintain cell viability. The manufacturing cycle was approximately 18–23 days, and products were delivered to study centers only after passing quality release tests (including cell viability, purity, and sterility). Immunological response assessment Immunogenicity was assessed by detecting ADA against 5T4 in peripheral blood, with blood samples collected at pre-dose on cycle 1 day 1 (C1D1), C1D16 ± 1, C1D21 ± 1, and at EOT. Samples were sent to MEDx Translational Medicine Research (Suzhou) Co., Ltd. for quantitative analysis via enzyme-linked immunosorbent assay (ELISA). The immunogenicity analysis set included patients who received at least one dose of study drug and had post-treatment immunogenicity data. Exploratory analyses included: retrospective immunohistochemistry testing of 3–5 unstained tumor pathological sections collected at enrollment to assess the percentage, intensity, and distribution of 5T4 antigen expression, and its correlation with objective response rate (ORR) and disease control rate (DCR); and genotyping of donor-recipient HLA (HLA-A, B, C) and killer cell immunoglobulin-like receptor (KIR) via polymerase chain reaction-sequence-specific primer (PCR-SSP) to analyze the association between donor-recipient matching and efficacy. Statistics This phase 1 study was not powered for formal hypothesis testing, and the sample size was determined based on dose-escalation requirements. Safety and efficacy analyses were descriptive. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA, version 25.0) and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. Efficacy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. ORR and DCR were summarized with two-sided 95% confidence intervals (CIs). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Pharmacokinetic parameters were derived using non-compartmental analysis. Exploratory analyses of biomarker associations with clinical outcomes were descriptive. Results Patient characteristics The first patient signed the ICF on August 31, 2023, and the last patient completed the final visit on December 26, 2024, with data cutoff on August 08, 2025. A total of 31 patients were screened, 12 (38.7%) of whom failed screening (11 due to ineligibility, 1 due to ICF withdrawal). Nineteen patients were successfully enrolled and received at least one infusion of IBR854 ( Figure 2 ), with cohort enrollment as follows: 3.0×10⁹ viable cells (n=4), 5.0×10⁹ viable cells (n=3), 7.0×10⁹ viable cells (n=3), 9.0×10⁹ viable cells (n=6), and 12.0×10⁹ viable cells (n=3). The study population comprised predominantly older adults, with a median age in the early 60s, and a slight predominance of female patients. Most participants had a good performance status (ECOG 0–1), indicating relatively preserved functional capacity at baseline. Tumor involvement was heterogeneous, with metastases most frequently observed in lymph nodes and lungs, while other sites such as the liver, colon, and peritoneum were less common. Pathologically, adenocarcinoma represented the largest subgroup, although a range of other histological types was also included, reflecting a diverse tumor spectrum. The majority of patients had advanced disease, with nearly all presenting at stage IV. Patients were heavily pretreated (median, 3 prior lines), with a notable proportion having received ≥4 lines of therapy, consistent with a refractory population. In this setting, disease stabilization may represent a clinically meaningful outcome despite the absence of objective responses. ( Table 1 ) Favorable safety profile Treatment-emergent adverse events (TEAEs) occurred in all 19 patients (100%), with treatment-related adverse events (TRAEs) reported in 16 patients (84.2%). Grade ≥3 TEAEs were observed in 5 patients (26.3%), while only one patient (5.3%) experienced a grade ≥3 TRAE. A total of four serious adverse events (SAEs) were reported in three patients (15.8%), including one patient (5.3%) with a drug-related SAE. No treatment-related deaths occurred. ( Table S3 ) Notably, no DLTs were observed across all dose cohorts, and the MTD was not reached, indicating a favorable safety margin and supporting further dose exploration within the evaluated range. The incidence of grade ≥3 TEAEs was relatively low (26.3%), and treatment-related high-grade events were infrequent (5.3%), suggesting that severe toxicity attributable to the study treatment was limited despite the heavily pretreated nature of the study population. All CRS events were grade 1-2, and no grade ≥3 CRS was observed. As CRS represents a critical safety concern in cellular immunotherapy, these findings further support the favorable tolerability profile of IBR854. ( Table 2 ) Overall, the safety profile observed in this first-in-human study compares favorably with that reported for many T cell-based therapies, which are often associated with higher rates of severe immune-mediated toxicities, and is consistent with or potentially improved relative to existing NK cell-based approaches. This favorable tolerability may be attributable to the non-genetically modified design, the use of allogeneic NK cells with inherently lower toxicity risk, and the antibody-coupled strategy that enables targeted activation without excessive immune stimulation. Evidence of disease stabilization Among 16 evaluable patients, no objective responses were observed. Disease control was achieved in 43.8% of patients, all of whom had stable disease ( Figure 3 ). Given that the study population was heavily pretreated (median, 3 prior lines), with a substantial proportion having received ≥4 lines of therapy, these findings are indicative of a refractory clinical setting in which disease stabilization may represent a clinically meaningful outcome. At the data cutoff, disease progression had occurred in 9 patients (56.3%), with a median PFS of 43 days (95% CI, 35.0-NE) ( Figure S1a ). No apparent dose-response relationship was observed. Three patients (18.8%) had died, and the median OS was not reached (range, 61-282 days) ( Figure S1a ). Pharmacokinetics Mean concentration–time profiles following IBR854 infusion were characterized using 5T4 NK cell counts and DNA copy number measurements ( Figure 4 ). Across all dose cohorts, both parameters showed a similar kinetic profile, with peak levels observed shortly after the end of infusion (EOI), followed by a rapid decline to near-baseline levels within hours. A comparable pattern was observed after the second infusion, with transient re-elevation and no evidence of accumulation between dosing days. Notably, exposure was consistently achieved across dose levels without a clear dose-dependent trend. The lack of accumulation and controlled persistence may support a favorable safety profile and allow for flexible repeat dosing. Pharmacokinetic analysis further indicated that, despite the absence of a clear dose–exposure relationship in terms of peak concentration or overall exposure, there was a trend toward prolonged time to peak concentration (0.867-3.433 h) with increasing dose. In contrast, the elimination half-life remained relatively consistent across dose cohorts (1.390-2.648 h), suggesting similar clearance kinetics. Consistent with this observation, exploratory analyses of dose–exposure relationships based on normalized PK parameters for both single and multiple infusions ( Figure S2 ) did not demonstrate a clear association between dose and exposure (C max or AUC), likely reflecting the limited number of evaluable PK samples and substantial inter-individual variability. Immunological responses No anti-drug antibodies (ADAs) were detected at any scheduled timepoint across all dose cohorts. Interpretation of cytokine analyses was limited by the high proportion of missing data and the small number of patients with evaluable post-treatment samples. Nevertheless, among the available samples, a temporal increase in circulating cytokine levels relative to baseline was observed following IBR854 administration. IL-6 concentrations showed a gradual elevation over time, with a more pronounced increase at later timepoints, while IFN-γ levels demonstrated a modest and transient rise, peaking at C2D1 before declining thereafter. These findings suggest a treatment-associated immune activation signal, although results should be interpreted with caution given the limited sample size and variability ( Figure S3 ). Association between donor-recipient HLA/KIR matching and disease control An exploratory analysis was performed to evaluate the association between NK cell donor-recipient HLA/KIR matching and disease control. Patients were stratified according to HLA/KIR matching scores ( Table 3, Table S4 ). Disease control was observed predominantly in patients with intermediate matching scores. Specifically, stable disease was achieved in 2 of 5 patients with matching scores of 1~2 (DCR 40.0%, 95% CI: 5.3-85.3), and in 5 of 7 patients with scores of 2~3 (DCR 71.4%, 95% CI: 29.0-96.3). In contrast, no disease control was observed in patients with either low (0~1) or high (≥3) matching scores. These findings suggest a non-linear relationship between HLA/KIR matching and disease control, with intermediate matching associated with more favorable outcomes. In a separate exploratory analysis, tumor tissue samples from 7 patients were successfully evaluated for 5T4 expression by retrospective immunohistochemistry. No apparent association between 5T4 expression and clinical outcomes was observed ( Table S5 ). Discussion This first-in-human study demonstrates that IBR854, an antibody-coupled allogeneic NK cell therapy targeting 5T4, has an acceptable safety and tolerability profile across the evaluated dose range. No dose-limiting toxicities were observed, and treatment-related adverse events were generally manageable and consistent with the known safety profile of NK cell-based therapies. These findings support the feasibility of this non-genetically modified, antibody-guided NK cell platform in patients with advanced solid tumors. Despite the absence of objective responses, a subset of patients achieved disease stabilization, suggesting preliminary antitumor activity in a heavily pretreated population. This pattern of clinical benefit is consistent with the known biological characteristics of NK cells, which typically mediate rapid but transient cytotoxic effects and may preferentially delay tumor progression rather than induce deep tumor regression, particularly in the absence of sustained in vivo persistence or expansion. In addition, the immunosuppressive tumor microenvironment in advanced solid tumors likely limits the durability and magnitude of NK cell-mediated responses. Pharmacokinetic analyses indicated measurable but transient in vivo persistence of infused NK cells, characterized by rapid post-infusion peaks, lack of accumulation upon repeat dosing, and no clear dose-exposure relationship, with a trend toward delayed peak concentration and relatively consistent elimination kinetics. These findings suggest that increasing cell dose may influence early distribution or trafficking dynamics without substantially prolonging systemic persistence. The lack of clear dose-exposure proportionality further highlights the complexity of cellular pharmacokinetics, which is influenced by host factors, immune clearance, and tissue distribution. The absence of detectable anti-drug antibodies suggests a low risk of classical humoral immunogenicity. However, the observed cytokine elevations, although limited by small sample size and missing data, suggest a treatment-associated innate immune activation occurs following infusion, likely reflecting NK cell activation and immune crosstalk rather than antigen-specific adaptive responses. This distinction is important for interpreting immunogenicity and safety in cell-based therapies. Exploratory analyses suggest that donor-recipient HLA/KIR interactions may influence clinical outcomes, with intermediate matching associated with more favorable disease control. This observation is consistent with current understanding of NK cell education and activation, in which a balance between inhibitory and activating signals is required for optimal function 10 , 11 . Excessive inhibitory signaling may suppress cytotoxicity, whereas excessive mismatch may limit persistence or promote premature clearance. These findings warrant further investigation in larger, biomarker-driven studies. Several limitations should be acknowledged. The small sample size, tumor heterogeneity, and short follow-up inherent to a phase 1 design limit definitive conclusions regarding efficacy. In addition, incomplete biomarker data restricted the ability to identify predictors of response or resistance. The absence of a control arm further limits interpretation of disease stabilization in this population. Future studies should incorporate larger, more homogeneous patient cohorts and prospective biomarker strategies, including standardized assessment of 5T4 expression and comprehensive immune profiling. Given the favorable safety profile, combination approaches with immune checkpoint inhibitors or agents that modulate the tumor microenvironment may enhance NK cell persistence and antitumor activity. Such strategies may be critical to translating disease stabilization into more durable and clinically meaningful responses. Declarations Ethics approval statement This FIH study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee and Institutional Review Boards of National Cancer Center/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (approvals No. 2023LP00207/2023LP00208 and updated approvals No. 2024LB00345/2024LB00346). Conflict of Interest Statement The authors declare that Z.M, N.S, and J.B are employees of Inbright (Hangzhou) Biopharmaceutical Co., which sponsored the manufacturing of the investigational product used in this study. The authors confirm that no conflicts of interest that are directly relevant to the content of this article. Funding statement N.L. reports financial support for this clinical trial from Inbright (Hangzhou) Biopharmaceutical Co.. This study was also supported by the National Key Research and Development Program of China (2023YFC2508500), the National Natural Science Foundation of China (82272951 and 82272953), the National High Level Hospital Clinical Research Funding (2025-LYZX-C-A03), and the Innovation Project for Medical and Health Sciences and Technology of the Chinese Academy of Medical Sciences (2024-I2M-TS-005). Authors' contributions L.S: analyzed data, wrote and revised the manuscript. P.M: performed research and collected data. Z.M, N.S, and J.B: contributed products. S.W. and N.L. conceived of or designed study; funding acquisition. All authors read and approved the final manuscript. Availability of Data and Material The datasets supporting the conclusions of this article are available from the corresponding author upon reasonable request. References Chu J, Gao F, Yan M et al (2022) Natural killer cells: a promising immunotherapy for cancer. 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Subject demographic and baseline characteristics Characteristics Number of patients, % Age (years) Median (range) 62 (20–75) Mean (SD) 57.3 (15.60) Sex Male 8 (42.1) Female 11 (57.9) ECOG score 0 1 (5.3) 1 18 (94.7) Tumor site Lungs 8 (23.5) Mediastinum 2 (5.9) Liver 2 (5.9) Colon 3 (8.8) Lymph nodes 9 (26.5) Peritoneum 2 (5.9) Neck 1 (2.9) Others 7 (20.6) Pathological type Adenocarcinoma 9 (47.4) Mucinous adenocarcinoma 1 (5.3) Squamous cell carcinoma 2 (10.5) Others 7 (36.8) Latest TNM stage III 1 (5.3) IV 17 (89.4) Number of previous lines 1~2 7 (43.76) ≥3 9 (56.3) Mean (SD) 3.25 (1.69) ECOG, Eastern Cooperative Oncology Group Table 2. Summary of treatment-emergent adverse events Adverse Event Any grade n (%) Grade ≥3 n (%) Cytokine elevation 8 (42.1) 1 (5.3) Infusion-related reaction 6 (31.6) 1 (5.3) Pyrexia 4 (21.1) 0 Cytokine release syndrome 2 (10.5) 0 Anemia 1 (5.3) 0 Gastrointestinal hemorrhage 1 (5.3) 0 Oxygen saturation decreased 1 (5.3) 0 Chills 1 (5.3) 0 Table 3. Exploratory analysis of donor-recipient HLA/KIR matching, dose level, and disease control HLA/KIR matching score Dose (live cells) No. of patients (n) Efficacy Disease control rate, n (%) [95% CI] 0~1 3.0 ×10⁹ 0 - 5.0 ×10⁹ 0 - 7.0 ×10⁹ 1 PD 9.0 ×10⁹ 0 - 12.0 ×10⁹ 0 - Total 1 PD 100 (0.0, 97.5) 1~2 3.0 ×10⁹ 1 PD 5.0 ×10⁹ 2 SD 7.0 ×10⁹ 1 PD 9.0 ×10⁹ 0 - 12.0 ×10⁹ 1 PD Total 5 SD 40 (5.3, 85.3) 2~3 3.0 ×10⁹ 2 SD 5.0 ×10⁹ 1 SD 7.0 ×10⁹ 1 SD 9.0 ×10⁹ 2 SD, PD 12.0 ×10⁹ 1 PD Total 7 SD 71.4 (29.0, 96.3) ≥3 3.0 ×10⁹ 0 - 5.0 ×10⁹ 0 - 7.0 ×10⁹ 0 - 9.0 ×10⁹ 1 PD 12.0 ×10⁹ 1 PD Total 3 PD 0 (0.0, 70.8) HLA, human leukocyte antigen; KIR, killer cell immunoglobulin-like receptor; BOR, best overall response; SD, stable disease; PD, progressive disease; DCR, disease control rate; CI, confidence interval. Additional Declarations No competing interests reported. Supplementary Files Supplementmaterials.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 06 May, 2026 Editor assigned by journal 04 May, 2026 Submission checks completed at journal 04 May, 2026 First submitted to journal 02 May, 2026 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-9597110","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":638087766,"identity":"94f0b40e-9520-4edf-9e48-9fb065810ac8","order_by":0,"name":"Liangjie Sun","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Liangjie","middleName":"","lastName":"Sun","suffix":""},{"id":638087767,"identity":"05d82d8f-3daa-4c40-b557-f79b4e058552","order_by":1,"name":"Peiwen Ma","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Peiwen","middleName":"","lastName":"Ma","suffix":""},{"id":638087768,"identity":"37438774-727b-45c8-b99b-b55eeab3abeb","order_by":2,"name":"Zhenwei Miao","email":"","orcid":"","institution":"Imbioray (Hangzhou) Biomedicine Co., LTD","correspondingAuthor":false,"prefix":"","firstName":"Zhenwei","middleName":"","lastName":"Miao","suffix":""},{"id":638087769,"identity":"92d203b0-5a58-4897-b2a5-019d4a938443","order_by":3,"name":"Na Su","email":"","orcid":"","institution":"Imbioray (Hangzhou) Biomedicine Co., LTD","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Su","suffix":""},{"id":638087770,"identity":"d47ffe5e-4eb0-468a-a999-1f822ca67dc7","order_by":4,"name":"Jinduo Bian","email":"","orcid":"","institution":"Imbioray (Hangzhou) Biomedicine Co., LTD","correspondingAuthor":false,"prefix":"","firstName":"Jinduo","middleName":"","lastName":"Bian","suffix":""},{"id":638087771,"identity":"25c7e2ef-dd6c-4421-ac69-e5c303576ba0","order_by":5,"name":"Shuhang Wang","email":"","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Shuhang","middleName":"","lastName":"Wang","suffix":""},{"id":638087772,"identity":"51893846-3438-4d61-bf64-5f5bfb37edea","order_by":6,"name":"Ning Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYBACPmYGhgMMDDYMbERrYYNoSSNFC4Q6TILD2Nh5Dx4u+HVeno/98NONPxjs5BnYzx4g4DC+hMMz+24btvGkmd3mYUg2bODJSyCghcfgMG/P7QQ2CQaz2wwMzAkMEjwGxGg5B9TC/u3mD4Z6IrXw/DgA1MJjdoOH4TCxtjQkA/2SU3abx+A4iIFfCz//GePPPH/s5OXbj2+7+aOiWp6f/Qx+LWDA2AZjGTAQG6d/iFM2CkbBKBgFIxQAAMANN4YNqWe4AAAAAElFTkSuQmCC","orcid":"","institution":"National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Ning","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2026-05-03 03:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9597110/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9597110/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109337725,"identity":"bef19474-ff4e-4472-b721-1e32596f52ab","added_by":"auto","created_at":"2026-05-15 17:46:41","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":336537,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the clinical trial workflow\u003c/p\u003e\n\u003cp\u003eThis flowchart depicts the three core phases of the IBR854 phase 1 trial: (1) screening period (days -28 to enrollment), during which eligibility confirmation, laboratory assessments and baseline tumor imaging were completed after ICF signing; (2) treatment period (21-day cycles, C1-Cn), with IBR854 administered on cycle day 1 (C1D1) and cycle day 8 (C1D8) per cohort, and the first cycle designated as the dose-limiting toxicity (DLT) observation window; (3) follow-up period, including end-of-treatment (EOT) assessment within 7 days of last infusion, 30-day safety follow-up, and survival surveillance every 4 weeks until 3 months post-first dose. Adverse events (AEs) and concomitant medications/treatments were recorded throughout the study, with follow-up terminated at 30 days post-last cycle or initiation of new anti-tumor therapy (whichever occurred first). Abbreviations: DLT, dose-limiting toxicity; ICF, informed consent form; EOT, end of treatment; AE, adverse event.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9597110/v1/2c72fa1ce450ca34a1e85a41.jpeg"},{"id":109405469,"identity":"5f0517d1-0d9d-4a3a-9085-cdb19e78ddb0","added_by":"auto","created_at":"2026-05-17 13:18:21","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":254779,"visible":true,"origin":"","legend":"\u003cp\u003eWaterfall plot of best percentage change in target lesion size\u003c/p\u003e\n\u003cp\u003eThis waterfall plot illustrates the maximum percentage change in target lesion diameter for all evaluable subjects (n=16) per RECIST v1.1 criteria, stratified by treatment cohort (C1=3.0×10⁹, C2=5.0×10⁹, C3=7.0×10⁹, C4=9.0×10⁹, C5=12.0×10⁹ viable cells per infusion; horizontal axis). The vertical axis denotes the percentage change from baseline tumor size (negative values = reduction, positive values = enlargement). Each bar is color-coded by best overall response (BOR): complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), not evaluable (NE), or study limitation (SL). Subjects with ongoing treatment at data cutoff are marked with “Ongoing”, enabling direct visualization of treatment-induced tumor size dynamics across cohorts.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9597110/v1/4a4d8f30df8adb87179924ae.jpeg"},{"id":109337727,"identity":"077fe4b8-eff4-4e10-8300-09e9d284b1b4","added_by":"auto","created_at":"2026-05-15 17:46:41","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":391784,"visible":true,"origin":"","legend":"\u003cp\u003eMean concentration-time profiles of IBR854 post-infusion\u003c/p\u003e\n\u003cp\u003eMean (±standard deviation, SD) concentration-time curves of IBR854 in peripheral blood, plotted for each dose cohort (3.0×10⁹ to 12.0×10⁹ viable cells per infusion). \u003cstrong\u003e(a)\u003c/strong\u003e Concentration quantified as absolute NK cell count (cells/unit volume) at key time points: 0.5 h, 2 h, 4 h, 8 h, 24 h post-infusion on C1D1 and C1D8, plus C1D16±1 and C1D21±1. \u003cstrong\u003e(b)\u003c/strong\u003eConcentration quantified as NK cell-specific gene copy number (copies/μg gDNA) at identical time points. Curves are color-coded by dose cohort, with error bars representing inter-individual variability (SD). Abbreviation: EOI, end of infusion.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-9597110/v1/8bc9db676a23956d84fa579d.jpeg"},{"id":109337730,"identity":"49ccaded-c3bf-40de-8e2d-ebac1bcfd6b7","added_by":"auto","created_at":"2026-05-15 17:46:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":975636,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9597110/v1/2a510a62-b180-4fae-a1d2-3d2a78661781.pdf"},{"id":109405713,"identity":"ee65e903-8555-43bc-8b0d-863c21494260","added_by":"auto","created_at":"2026-05-17 13:19:54","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":453137,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementmaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-9597110/v1/9b2c70b953c18d005d069446.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety and feasibility of 5T4 antibody-coupled allogeneic NK cell therapy for solid tumors: A first-in-human phase 1 trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe management of patients with unresectable centrally advanced or metastatic solid tumors remains a formidable clinical challenge, with many standard therapies failing to achieve sustained disease control. Adoptive cell‑based immunotherapies have emerged as a promising frontier in oncology, leveraging innate and adaptive immune mechanisms to mediate anti‑tumour effects. In particular, natural killer (NK) cells have garnered increasing interest for cancer immunotherapy owing to their intrinsic cytotoxic capacity and ability to function in a non‑major histocompatibility complex (MHC)-restricted recognition, and favorable safety profile.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTo improve tumor specificity, chimeric antigen receptor (CAR)-NK cells have been actively developed for solid tumors. At least 40 clinical studies of CAR-NK cells targeting solid cancers have been registered, most of which remain in early-phase testing\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Current trials cover a broad range of targets and tumor types, including NKG2D ligands, mesothelin, CD70, MUC1, ROBO1, and 5T4 in colorectal, ovarian, pancreatic, renal, lung, brain and other solid tumors. However, available clinical data remain limited, and reported efficacy has generally been modest, with disease stabilization more commonly observed than objective tumor regression.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e For example, a phase I study of NKG2D CAR-NK cells in advanced colorectal cancer showed acceptable safety but limited antitumor activity, with stable disease as the best response in one of six heavily pretreated patients\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. These findings suggest that CAR-mediated targeting can enhance NK-cell specificity, but solid tumors continue to impose major barriers, including limited trafficking, short in vivo persistence, antigen heterogeneity, and an immunosuppressive tumor microenvironment.\u003c/p\u003e \u003cp\u003e Antibody-guided NK cell therapy represents an alternative strategy to enhance tumor targeting while avoiding genetic modification. By covalently conjugating tumour-specific monoclonal antibodies to the surface of NK cells, this modality achieves precise delivery of effector lymphocytes to antigen-expressing tumour sites, thereby enhancing tumour homing. Upon engagement of antibody-coated tumour cells, the Fc domain of the antibody interacts with Fcγ receptors on NK cells to trigger robust antibody-dependent cellular cytotoxicity (ADCC) in the context of therapeutic antibodies.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This dual mechanism of physical targeting and functional activation synergistically amplifies NK-mediated cytotoxicity without requiring genetic modification of the effector cell.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe oncofetal antigen 5T4 (trophoblast glycoprotein, TPBG) is a transmembrane glycoprotein that is broadly overexpressed in a variety of solid malignancies, including colorectal, ovarian, lung and other carcinomas, while displaying limited expression in normal adult tissues. As an oncofetal antigen, 5T4 was originally identified by its shared expression between trophoblast and cancer cells, and its tumour-restricted distribution confers a favourable therapeutic index by minimising on-target off-tumour toxicity.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e The N-glycosylated cell surface localisation and stable expression of 5T4 make it particularly amenable to antibody engagement and subsequent induction of ADCC via NK cells. Owing to its prevalence across diverse tumour types and restricted normal tissue expression, 5T4 continues to be investigated as a promising target for antibody-based and immune-engaging therapeutic strategies.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e IBR854 is a novel, non‑genetically‑modified, antibody‑guided allogeneic NK‑cell therapy designed to target 5T4‑expressing solid tumours. IBR854 leverages healthy donor‑derived NK cells conjugated with a monoclonal anti‑5T4 antibody, enabling selective binding to tumour cells and triggering cytotoxicity, while avoiding the risks associated with viral gene transfer or autologous T‑cell manufacturing. Preclinical studies demonstrated that IBR854 exerts potent cytotoxic activity against multiple 5T4-positive solid tumor cell lines and induces dose-dependent tumor growth inhibition in xenograft models, with favorable safety characteristics and minimal off-target binding.\u003c/p\u003e \u003cp\u003eHere we report the detailed safety, pharmacokinetics, and exploratory efficacy outcomes of IBR854, together with correlative biomarker analyses of donor\u0026ndash;recipient HLA/KIR and clinical outcomes. In this patient cohort, no dose‑limiting toxicity was observed, and the regimen was well tolerated, with a disease control rate (DCR) of 43.8%. Overall, this study supports the further development of IBR854 as a novel \u0026ldquo;off‑the‑shelf\u0026rdquo; NK‑cell therapy platform targeting 5T4‑positive solid tumours.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis open-label, multicenter phase 1 study (approvals: 2023LP00207, 2023LP00208, 2024LB00345, 2024LB00346) evaluated IBR854 in patients with advanced solid tumors. The primary objectives were to assess safety, tolerability, and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D); secondary objectives included preliminary efficacy, pharmacokinetics (PK), and immunogenicity; exploratory objectives assessed donor\u0026ndash;recipient HLA/KIR matching and 5T4 expression in relation to clinical outcomes.\u003c/p\u003e \u003cp\u003eThe study included screening (\u0026le;\u0026thinsp;28 days), treatment, and follow-up phases, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A standard 3\u0026thinsp;+\u0026thinsp;3 dose-escalation design was used across five dose levels The starting dose of 3.0\u0026times;10⁹ cells was selected based on preclinical safety evaluations and a conservative approach commonly applied in first-in-human studies of cell-based therapies, with subsequent dose escalation guided by emerging safety, PK, and efficacy data. IBR854 was administered on days 1 and 8 of each 21-day cycle. Dose escalation proceeded after completion of a 21-day dose-limiting toxicity (DLT) evaluation period in the preceding cohort. The starting dose was selected based on preclinical safety data and prior experience with NK cell-based therapies.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eConsidering the potential risk of on-target off-tumor toxicity due to 5T4 expression in certain normal tissues, comprehensive safety monitoring and predefined stopping criteria were incorporated into the study design. DLTs were predefined (\u003cb\u003eTable S2\u003c/b\u003e), and safety was continuously reviewed by a Safety Review Committee to guide dose escalation and determine MTD/RP2D, with specific monitoring for potential on-target off-tumor effects related to 5T4 expression.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient eligibility\u003c/h3\u003e\n\u003cp\u003eEligible patients were adults aged 18\u0026ndash;75 years with unresectable locally advanced or metastatic solid tumors without standard treatment options, including at least one measurable target lesion per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of \u0026le;\u0026thinsp;2, and an expected survival of \u0026gt;\u0026thinsp;3 months. Adequate organ function was required, including an absolute neutrophil count (ANC) of \u0026ge;\u0026thinsp;1.5\u0026times;10⁹/L, a platelet count (PLT) of \u0026ge;\u0026thinsp;75\u0026times;10⁹/L, a hemoglobin (HGB) of \u0026ge;\u0026thinsp;80 g/L, and normal renal, hepatic, and coagulation function as specified. Fertile patients and their partners agreed to use effective contraception for 6 months after the last dose of study drug. Detailed inclusion and exclusion criteria are listed in \u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e.\u003c/p\u003e\n\u003ch3\u003eNK cell preparation\u003c/h3\u003e\n\u003cp\u003e IBR854 cell injection is a non-genetically edited, antibody-guided biochemically activated NK cell product. Its core structure consists of a full-length monoclonal anti-5T4 antibody conjugated to allogeneic NK cells derived from peripheral blood of healthy donors via an L2 linker (based on click chemistry), enabling specific recognition of the 5T4 antigen and tumor cell killing. The product was stored at \u0026le;-150℃, with strict cold chain management during transportation and use to maintain cell viability. The manufacturing cycle was approximately 18\u0026ndash;23 days, and products were delivered to study centers only after passing quality release tests (including cell viability, purity, and sterility).\u003c/p\u003e\n\u003ch3\u003eImmunological response assessment\u003c/h3\u003e\n\u003cp\u003eImmunogenicity was assessed by detecting ADA against 5T4 in peripheral blood, with blood samples collected at pre-dose on cycle 1 day 1 (C1D1), C1D16\u0026thinsp;\u0026plusmn;\u0026thinsp;1, C1D21\u0026thinsp;\u0026plusmn;\u0026thinsp;1, and at EOT. Samples were sent to MEDx Translational Medicine Research (Suzhou) Co., Ltd. for quantitative analysis via enzyme-linked immunosorbent assay (ELISA). The immunogenicity analysis set included patients who received at least one dose of study drug and had post-treatment immunogenicity data.\u003c/p\u003e \u003cp\u003eExploratory analyses included: retrospective immunohistochemistry testing of 3\u0026ndash;5 unstained tumor pathological sections collected at enrollment to assess the percentage, intensity, and distribution of 5T4 antigen expression, and its correlation with objective response rate (ORR) and disease control rate (DCR); and genotyping of donor-recipient HLA (HLA-A, B, C) and killer cell immunoglobulin-like receptor (KIR) via polymerase chain reaction-sequence-specific primer (PCR-SSP) to analyze the association between donor-recipient matching and efficacy.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eThis phase 1 study was not powered for formal hypothesis testing, and the sample size was determined based on dose-escalation requirements. Safety and efficacy analyses were descriptive. Adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA, version 25.0) and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. Efficacy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. ORR and DCR were summarized with two-sided 95% confidence intervals (CIs). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Pharmacokinetic parameters were derived using non-compartmental analysis. Exploratory analyses of biomarker associations with clinical outcomes were descriptive.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e\n\u003cp\u003eThe first patient signed the ICF on August 31, 2023, and the last patient completed the final visit on December 26, 2024, with data cutoff on August 08, 2025. A total of 31 patients were screened, 12 (38.7%) of whom failed screening (11 due to ineligibility, 1 due to ICF withdrawal). Nineteen patients were successfully enrolled and received at least one infusion of IBR854 (\u003cstrong\u003eFigure 2\u003c/strong\u003e), with cohort enrollment as follows: 3.0×10⁹ viable cells (n=4), 5.0×10⁹ viable cells (n=3), 7.0×10⁹ viable cells (n=3), 9.0×10⁹ viable cells (n=6), and 12.0×10⁹ viable cells (n=3).\u003c/p\u003e\n\u003cp\u003eThe study population comprised predominantly older adults, with a median age in the early 60s, and a slight predominance of female patients. Most participants had a good performance status (ECOG 0–1), indicating relatively preserved functional capacity at baseline. Tumor involvement was heterogeneous, with metastases most frequently observed in lymph nodes and lungs, while other sites such as the liver, colon, and peritoneum were less common. Pathologically, adenocarcinoma represented the largest subgroup, although a range of other histological types was also included, reflecting a diverse tumor spectrum. The majority of patients had advanced disease, with nearly all presenting at stage IV. Patients were heavily pretreated (median, 3 prior lines), with a notable proportion having received ≥4 lines of therapy, consistent with a refractory population. In this setting, disease stabilization may represent a clinically meaningful outcome despite the absence of objective responses. (\u003cstrong\u003eTable 1\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003eFavorable safety profile\u003c/p\u003e\n\u003cp\u003eTreatment-emergent adverse events (TEAEs) occurred in all 19 patients (100%), with treatment-related adverse events (TRAEs) reported in 16 patients (84.2%). Grade ≥3 TEAEs were observed in 5 patients (26.3%), while only one patient (5.3%) experienced a grade ≥3 TRAE. A total of four serious adverse events (SAEs) were reported in three patients (15.8%), including one patient (5.3%) with a drug-related SAE. No treatment-related deaths occurred. (\u003cstrong\u003eTable S3\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003eNotably, no DLTs were observed across all dose cohorts, and the MTD was not reached, indicating a favorable safety margin and supporting further dose exploration within the evaluated range. The incidence of grade ≥3 TEAEs was relatively low (26.3%), and treatment-related high-grade events were infrequent (5.3%), suggesting that severe toxicity attributable to the study treatment was limited despite the heavily pretreated nature of the study population. All CRS events were grade 1-2, and no grade ≥3 CRS was observed. As CRS represents a critical safety concern in cellular immunotherapy, these findings further support the favorable tolerability profile of IBR854. (\u003cstrong\u003eTable 2\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003eOverall, the safety profile observed in this first-in-human study compares favorably with that reported for many T cell-based therapies, which are often associated with higher rates of severe immune-mediated toxicities, and is consistent with or potentially improved relative to existing NK cell-based approaches. This favorable tolerability may be attributable to the non-genetically modified design, the use of allogeneic NK cells with inherently lower toxicity risk, and the antibody-coupled strategy that enables targeted activation without excessive immune stimulation.\u003c/p\u003e\n\u003cp\u003eEvidence of disease stabilization\u003c/p\u003e\n\u003cp\u003eAmong 16 evaluable patients, no objective responses were observed. Disease control was achieved in 43.8% of patients, all of whom had stable disease (\u003cstrong\u003eFigure 3\u003c/strong\u003e). Given that the study population was heavily pretreated (median, 3 prior lines), with a substantial proportion having received ≥4 lines of therapy, these findings are indicative of a refractory clinical setting in which disease stabilization may represent a clinically meaningful outcome.\u003c/p\u003e\n\u003cp\u003eAt the data cutoff, disease progression had occurred in 9 patients (56.3%), with a median PFS of 43 days (95% CI, 35.0-NE) (\u003cstrong\u003eFigure S1a\u003c/strong\u003e). No apparent dose-response relationship was observed. Three patients (18.8%) had died, and the median OS was not reached (range, 61-282 days) (\u003cstrong\u003eFigure S1a\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003ePharmacokinetics\u003c/p\u003e\n\u003cp\u003eMean concentration–time profiles following IBR854 infusion were characterized using 5T4 NK cell counts and DNA copy number measurements (\u003cstrong\u003eFigure 4\u003c/strong\u003e). Across all dose cohorts, both parameters showed a similar kinetic profile, with peak levels observed shortly after the end of infusion (EOI), followed by a rapid decline to near-baseline levels within hours. A comparable pattern was observed after the second infusion, with transient re-elevation and no evidence of accumulation between dosing days. Notably, exposure was consistently achieved across dose levels without a clear dose-dependent trend. The lack of accumulation and controlled persistence may support a favorable safety profile and allow for flexible repeat dosing.\u003c/p\u003e\n\u003cp\u003ePharmacokinetic analysis further indicated that, despite the absence of a clear dose–exposure relationship in terms of peak concentration or overall exposure, there was a trend toward prolonged time to peak concentration (0.867-3.433 h) with increasing dose. In contrast, the elimination half-life remained relatively consistent across dose cohorts (1.390-2.648 h), suggesting similar clearance kinetics.\u003c/p\u003e\n\u003cp\u003eConsistent with this observation, exploratory analyses of dose–exposure relationships based on normalized PK parameters for both single and multiple infusions (\u003cstrong\u003eFigure S2\u003c/strong\u003e) did not demonstrate a clear association between dose and exposure (C\u003csub\u003emax\u003c/sub\u003e or AUC), likely reflecting the limited number of evaluable PK samples and substantial inter-individual variability.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmunological responses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo anti-drug antibodies (ADAs) were detected at any scheduled timepoint across all dose cohorts. Interpretation of cytokine analyses was limited by the high proportion of missing data and the small number of patients with evaluable post-treatment samples. Nevertheless, among the available samples, a temporal increase in circulating cytokine levels relative to baseline was observed following IBR854 administration. IL-6 concentrations showed a gradual elevation over time, with a more pronounced increase at later timepoints, while IFN-γ levels demonstrated a modest and transient rise, peaking at C2D1 before declining thereafter. These findings suggest a treatment-associated immune activation signal, although results should be interpreted with caution given the limited sample size and variability (\u003cstrong\u003eFigure S3\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAssociation between donor-recipient HLA/KIR matching and disease control\u003c/p\u003e\n\u003cp\u003eAn exploratory analysis was performed to evaluate the association between NK cell donor-recipient HLA/KIR matching and disease control. Patients were stratified according to HLA/KIR matching scores (\u003cstrong\u003eTable 3, Table S4\u003c/strong\u003e). Disease control was observed predominantly in patients with intermediate matching scores. Specifically, stable disease was achieved in 2 of 5 patients with matching scores of 1~2 (DCR 40.0%, 95% CI: 5.3-85.3), and in 5 of 7 patients with scores of 2~3 (DCR 71.4%, 95% CI: 29.0-96.3). In contrast, no disease control was observed in patients with either low (0~1) or high (≥3) matching scores. These findings suggest a non-linear relationship between HLA/KIR matching and disease control, with intermediate matching associated with more favorable outcomes.\u003c/p\u003e\n\u003cp\u003eIn a separate exploratory analysis, tumor tissue samples from 7 patients were successfully evaluated for 5T4 expression by retrospective immunohistochemistry. No apparent association between 5T4 expression and clinical outcomes was observed (\u003cstrong\u003eTable S5\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis first-in-human study demonstrates that IBR854, an antibody-coupled allogeneic NK cell therapy targeting 5T4, has an acceptable safety and tolerability profile across the evaluated dose range. No dose-limiting toxicities were observed, and treatment-related adverse events were generally manageable and consistent with the known safety profile of NK cell-based therapies. These findings support the feasibility of this non-genetically modified, antibody-guided NK cell platform in patients with advanced solid tumors.\u003c/p\u003e \u003cp\u003eDespite the absence of objective responses, a subset of patients achieved disease stabilization, suggesting preliminary antitumor activity in a heavily pretreated population. This pattern of clinical benefit is consistent with the known biological characteristics of NK cells, which typically mediate rapid but transient cytotoxic effects and may preferentially delay tumor progression rather than induce deep tumor regression, particularly in the absence of sustained in vivo persistence or expansion. In addition, the immunosuppressive tumor microenvironment in advanced solid tumors likely limits the durability and magnitude of NK cell-mediated responses.\u003c/p\u003e \u003cp\u003ePharmacokinetic analyses indicated measurable but transient in vivo persistence of infused NK cells, characterized by rapid post-infusion peaks, lack of accumulation upon repeat dosing, and no clear dose-exposure relationship, with a trend toward delayed peak concentration and relatively consistent elimination kinetics. These findings suggest that increasing cell dose may influence early distribution or trafficking dynamics without substantially prolonging systemic persistence. The lack of clear dose-exposure proportionality further highlights the complexity of cellular pharmacokinetics, which is influenced by host factors, immune clearance, and tissue distribution.\u003c/p\u003e \u003cp\u003eThe absence of detectable anti-drug antibodies suggests a low risk of classical humoral immunogenicity. However, the observed cytokine elevations, although limited by small sample size and missing data, suggest a treatment-associated innate immune activation occurs following infusion, likely reflecting NK cell activation and immune crosstalk rather than antigen-specific adaptive responses. This distinction is important for interpreting immunogenicity and safety in cell-based therapies.\u003c/p\u003e \u003cp\u003eExploratory analyses suggest that donor-recipient HLA/KIR interactions may influence clinical outcomes, with intermediate matching associated with more favorable disease control. This observation is consistent with current understanding of NK cell education and activation, in which a balance between inhibitory and activating signals is required for optimal function\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Excessive inhibitory signaling may suppress cytotoxicity, whereas excessive mismatch may limit persistence or promote premature clearance. These findings warrant further investigation in larger, biomarker-driven studies.\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. The small sample size, tumor heterogeneity, and short follow-up inherent to a phase 1 design limit definitive conclusions regarding efficacy. In addition, incomplete biomarker data restricted the ability to identify predictors of response or resistance. The absence of a control arm further limits interpretation of disease stabilization in this population.\u003c/p\u003e \u003cp\u003eFuture studies should incorporate larger, more homogeneous patient cohorts and prospective biomarker strategies, including standardized assessment of 5T4 expression and comprehensive immune profiling. Given the favorable safety profile, combination approaches with immune checkpoint inhibitors or agents that modulate the tumor microenvironment may enhance NK cell persistence and antitumor activity. Such strategies may be critical to translating disease stabilization into more durable and clinically meaningful responses.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis FIH study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee and Institutional Review Boards of National Cancer Center/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (approvals No. 2023LP00207/2023LP00208 and updated approvals No. 2024LB00345/2024LB00346).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that Z.M, N.S, and J.B are employees of Inbright (Hangzhou) Biopharmaceutical Co., which sponsored the manufacturing of the investigational product used in this study. The authors confirm that no conflicts of interest that are directly relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN.L. reports financial support for this clinical trial from Inbright (Hangzhou) Biopharmaceutical Co.. This study was also supported by the National Key Research and Development Program of China (2023YFC2508500), the National Natural Science Foundation of China (82272951 and 82272953), the National High Level Hospital Clinical Research Funding (2025-LYZX-C-A03), and the Innovation Project for Medical and Health Sciences and Technology of the Chinese Academy of Medical Sciences (2024-I2M-TS-005).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eL.S: analyzed data, wrote and revised the manuscript. P.M: performed research and collected data. Z.M, N.S, and J.B: contributed products. S.W. and N.L. conceived of or designed study; funding acquisition. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets supporting the conclusions of this article are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChu J, Gao F, Yan M et al (2022) Natural killer cells: a promising immunotherapy for cancer. J Transl Med 20(1):240. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12967-022-03437-0\u003c/span\u003e\u003cspan address=\"10.1186/s12967-022-03437-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJ\u0026oslash;rgensen LV, Christensen EB, Barnkob MB et al (2025) The clinical landscape of CAR NK cells. Exp Hematol Oncol 14(1):46\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu Y, Ho M (2025) CAR NK cell therapy for solid tumors: potential and challenges. Antib Ther 8(4):275\u0026ndash;289\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang D, Li B, Shen G et al (2025) NKG2D CAR-NK adoptive cellular immunotherapy combined with or without PD-1 blockade in the treatment of patients with metastatic colorectal cancer: an exploratory study. Cancer Immunol Immunother 74(11):341\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTuhin IJ, Zhu HJ, Monty MA et al (2025) From innate power to intelligent design: The evolution of NK cell-based cancer immunotherapy. Crit Rev Oncol Hematol 216:104972. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.critrevonc.2025.104972\u003c/span\u003e\u003cspan address=\"10.1016/j.critrevonc.2025.104972\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTerr\u0026eacute;n I, Orrantia A, Vitall\u0026eacute; J et al (2020) Modulating NK cell metabolism for cancer immunotherapy. Semin Hematol 57(4):213\u0026ndash;224. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.seminhematol.2020.10.003\u003c/span\u003e\u003cspan address=\"10.1053/j.seminhematol.2020.10.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang W, Erbe AK, Hank JA et al (2015) NK Cell-Mediated Antibody-Dependent Cellular Cytotoxicity in Cancer Immunotherapy. Front Immunol 6:368. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fimmu.2015.00368\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2015.00368\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStern PL, Harrop R (2017) 5T4 oncofoetal antigen: an attractive target for immune intervention in cancer. Cancer Immunol Immunother 66(4):415\u0026ndash;426. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00262-016-1917-3\u003c/span\u003e\u003cspan address=\"10.1007/s00262-016-1917-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang R, Lai Q, Tang L et al (2018) A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models. Am J Cancer Res 8(4):610\u0026ndash;623\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMehta RS, Rezvani K (2016) Can we make a better match or mismatch with KIR genotyping? Hematol Am Soc Hematol Educ Program 2016(1):106\u0026ndash;118. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/asheducation-2016.1.106\u003c/span\u003e\u003cspan address=\"10.1182/asheducation-2016.1.106\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnfossi N, Andr\u0026eacute; P, Guia S, Immunity et al (2006) ;25(2):331\u0026ndash;342. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.immuni.2006.06.013\u003c/span\u003e\u003cspan address=\"10.1016/j.immuni.2006.06.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Subject demographic and baseline characteristics\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"628\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of patients, %\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e62 (20\u0026ndash;75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e57.3 (15.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e8 (42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e11 (57.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eECOG score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e18 (94.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor site\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eLungs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eMediastinum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eColon\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e3 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eLymph nodes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e9 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003ePeritoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eNeck\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e7 (20.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePathological type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eAdenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e9 (47.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eMucinous adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e2 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e7 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLatest TNM stage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e17 (89.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of previous lines\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e1~2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e7 (43.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003e\u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e9 (56.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 48.2484%;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 51.7516%;\"\u003e\n \u003cp\u003e3.25 (1.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eECOG, Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003eTable 2. Summary of treatment-emergent adverse events\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"443\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\u003cbr clear=\"all\"\u003e \u0026nbsp;\u003cp\u003e\u003cstrong\u003eAdverse Event\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny grade n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade \u0026ge;3 n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\n \u003cp\u003eCytokine elevation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e8 (42.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\n \u003cp\u003eInfusion-related reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e6 (31.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\n \u003cp\u003ePyrexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e4 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\n \u003cp\u003eCytokine release syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e2 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\n \u003cp\u003eGastrointestinal hemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\n \u003cp\u003eOxygen saturation decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 41.3093%;\"\u003e\n \u003cp\u003eChills\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.0226%;\"\u003e\n \u003cp\u003e1 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28.6682%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable 3. Exploratory analysis of donor-recipient HLA/KIR matching, dose level, and disease control\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"564\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHLA/KIR matching score\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDose (live cells)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of patients (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEfficacy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDisease control rate, n (%) [95% CI]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 99px;\"\u003e\n \u003cp\u003e0~1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e3.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e5.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e7.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e9.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e12.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eTotal\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e1\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePD\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e100 (0.0, 97.5)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1~2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e3.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e5.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e7.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e9.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e12.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eTotal\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e5\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSD\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e40 (5.3, 85.3)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 99px;\"\u003e\n \u003cp\u003e2~3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e3.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e5.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e7.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e9.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003eSD, PD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e12.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eTotal\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e7\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eSD\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e71.4 (29.0, 96.3)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"6\" style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e3.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e5.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e7.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e9.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e12.0 \u0026times;10⁹\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 99px;\"\u003e\n \u003cp\u003ePD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd nowrap=\"\" style=\"width: 169px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eTotal\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e3\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ePD\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 169px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0 (0.0, 70.8)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eHLA, human leukocyte antigen; KIR, killer cell immunoglobulin-like receptor; BOR, best overall response; SD, stable disease; PD, progressive disease; DCR, disease control rate; CI, confidence interval.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"IBR854, 5T4 antigen, Allogeneic NK cell therapy, Solid tumors, First-in-human trial","lastPublishedDoi":"10.21203/rs.3.rs-9597110/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9597110/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePatients with unresectable locally advanced or metastatic solid tumors have limited therapeutic options. Antibody-guided allogeneic natural killer (NK) cell therapy represents a novel immunotherapeutic strategy to enhance tumor targeting and cytotoxicity by coupling NK cells with tumor-specific antibodies targeting antigens such as 5T4.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary efficacy of IBR854, a non-viral, non-genetically modified, 5T4 antibody-coupled allogeneic NK cell therapy, in patients with advanced solid tumors.\u003c/p\u003e\u003ch2\u003ePatients and Methods\u003c/h2\u003e \u003cp\u003eThis open-label, first-in-human phase 1 dose-escalation study enrolled 19 patients with unresectable locally advanced or metastatic solid tumors across five dose cohorts (3.0\u0026times;10⁹ to 12.0\u0026times;10⁹ cells per dose). Patients received intravenous IBR854 in a 3\u0026thinsp;+\u0026thinsp;3 escalation design. Safety, dose-limiting toxicities, adverse events, pharmacokinetics, anti-drug antibodies, and antitumor activity (RECIST v1.1) were assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNo dose-limiting toxicities were observed. The most common treatment-emergent adverse events were elevated interleukin levels (42.1%), infusion-related reactions (31.6%), and fever (21.1%). No anti-drug antibodies were detected. The disease control rate was 43.8%. Median progression-free survival was 43 days. Pharmacokinetic analysis based on transgene copy number showed a dose-dependent prolongation of T\u003csub\u003emax\u003c/sub\u003e (0.867\u0026ndash;3.433 h), with a relatively consistent half-life (1.390\u0026ndash;2.648 h).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIBR854 demonstrated an acceptable safety and tolerability profile and achieved disease stabilization in a subset of heavily pretreated patients with advanced solid tumors. These findings support further clinical development of 5T4-targeted antibody-coupled allogeneic NK cell therapy.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eThis study was registered at ClinicalTrials.gov (registration number: NCT06001684).\u003c/p\u003e","manuscriptTitle":"Safety and feasibility of 5T4 antibody-coupled allogeneic NK cell therapy for solid tumors: A first-in-human phase 1 trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-15 17:46:37","doi":"10.21203/rs.3.rs-9597110/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-05-06T08:19:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-05T02:15:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-05T02:14:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Immunology, Immunotherapy","date":"2026-05-03T03:06:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-immunology-immunotherapy","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ciim","sideBox":"Learn more about [Cancer Immunology, Immunotherapy](http://link.springer.com/journal/262)","snPcode":"262","submissionUrl":"https://submission.nature.com/new-submission/262/3","title":"Cancer Immunology, Immunotherapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"08f2d2f1-2444-492a-b335-49caeb2aa36d","owner":[],"postedDate":"May 15th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewersInvited","content":"35","date":"2026-05-06T08:19:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-05T02:15:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-05T02:14:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cancer Immunology, Immunotherapy","date":"2026-05-03T03:06:22+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T17:46:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-15 17:46:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9597110","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9597110","identity":"rs-9597110","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}