Clinical outcomes of chimeric antigen receptor T cell therapy in 21 patients with Relapse/Refractory Ileocecal B cell lymphoma

Clinical outcomes of chimeric antigen receptor T cell therapy in 21 patients with Relapse/Refractory Ileocecal B cell lymphoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical outcomes of chimeric antigen receptor T cell therapy in 21 patients with Relapse/Refractory Ileocecal B cell lymphoma Zeyan Shi, Xing Chen, Yue Chun, Fankai Meng, Yang Cao, Zhicheng Zhang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8776621/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To evaluate the efficacy, safety, and prognostic factors of chimeric antigen receptor-T cell (CAR-T) therapy in patients with relapsed/refractory ileocecal lymphoma and provide evidence for salvage therapy. Methods This retrospective analysis included 21 patients with ileocecal lymphoma (IC group) and 23 matched patients without ileocecal lymphoma (non-IC group) who received CAR-T therapy between June 2014 and August 2024. Baseline characteristics, genetic mutations, CAR-T cell kinetics, treatment response, overall survival (OS), and progression-free survival (PFS) were assessed. Prognostic factors were identified using Kaplan–Meier analysis, Cox regression, and least absolute shrinkage and selection operator models. Results The IC group showed a significantly lower 3-month objective response rate (57.14% vs. 86.96%, P = 0.042) and shorter median PFS (5 months vs. 27 months, P = 0.0007) than the non-IC group. CAR-T cell expansion was higher in the IC group (CD19 Cmax: 55774 vs. 3811, P = 0.014), but persistence was similar. The safety profiles of CRS and ICANS were comparable across groups (P > 0.05). Multivariate analysis revealed poor 3-month treatment response (hazard ratio [HR] = 32.075, P = 0.015) and higher pre-treatment lines (HR = 8.6, P = 0.036) as independent risk factors for PFS. Delayed B-cell recovery and low baseline lymphocyte counts were associated with poorer OS. Conclusion CAR-T therapy is feasible and safe for relapsed/refractory ileocecal lymphoma, but short-term efficacy is inferior to that in the non-IC group. High CAR-T expansion did not improve long-term outcomes. Early response assessment (3 months), baseline lymphocyte levels, and B-cell recovery are critical prognostic indicators, suggesting the need for optimised treatment timing and combination strategies to enhance efficacy. Ileocecal valve CAR-T cell therapy Lymphoma B-cell Progression-free survival Recurrence Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION The ileocecum is the most commonly affected site in primary intestinal lymphoma, accounting for approximately 20.3–39.8% of all cases [1–4 ]. The predominant pathological types include diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma [ 5 ]. Ileocecal lymphoma frequently presents with acute complications, such as abdominal pain, intestinal obstruction, perforation, or haemorrhage [ 3 ] which may necessitate emergency surgical intervention and disrupt the continuity of systemic antitumor therapy. Currently, the first-line treatment for ileocecal lymphoma primarily relies on R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy; however, therapeutic efficacy varies significantly owing to biological heterogeneity, with approximately 20–30% of patients experiencing disease relapse or progression [ 2 ]. For these patients, traditional salvage therapies, such as autologous hematopoietic stem cell transplantation (ASCT) combined with high-dose chemotherapy, have limited benefits. In recent years, chimeric antigen receptor-T cell (CAR-T) therapy has emerged as a revolutionary approach to relapsed/refractory B-cell lymphomas. Early-phase ZUMA-7 studies demonstrated a 58% complete remission rate with CAR-T therapy, which was significantly superior to the efficacy of high-dose chemotherapy combined with ASCT (complete response rate, 32%) [ 6 ]. Furthermore, CAR-T therapy has demonstrated favourable efficacy and safety in patients with relapsed/refractory primary gastrointestinal lymphomas [ 7 ]. Nevertheless, no studies have specifically addressed CAR-T therapy for ileocecal lymphomas. In this study, we focused on 21 patients with ileocecal lymphoma treated with CAR-T therapy. By integrating molecular profiling and systematically analysing the associations with overall survival (OS), progression-free survival (PFS), and treatment-related toxicities, we aimed to provide a theoretical framework for personalised CAR-T therapy in this distinct patient subgroup. METHODS Patients This retrospective, single-centre cohort study was based on the lymphoma database of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Patients with B-cell lymphoma who underwent CAR-T cell therapy between June 2014 and August 2024 were screened, and 21 patients with histologically or radiologically confirmed ileocecal lymphoma were enrolled. A propensity score-matched cohort of 23 patients without ileocecal lymphoma served as controls. Ileocecal involvement was defined as a disease affecting the ileocecal valve, terminal ileum, cecum, or appendix. All patients were staged according to the Lugano staging system. Each patient completed the following staging examinations: physical examination, plain computed tomography (CT) scan, positron emission tomography (PET)/CT, bone marrow cytology, and bone marrow biopsy. B symptoms were defined as the presence of at least one of the following: unexplained recurrent fever (temperature ≥ 38°C), night sweats, or weight loss (≥ 10% of body weight within 6 months). The last follow-up was conducted on December 30, 2025. Data Collection Baseline assessments included demographic characteristics, serological and immunological parameters, treatment-related adverse events, and radiographic findings. Treatment response was evaluated at 3 months post-CAR-T therapy using contrast-enhanced CT or PET/CT. Histology Formalin-fixed biopsy specimens were histologically classified according to the World Health Organisation (WHO) classification of haematolymphoid tumours (5th edition). Immuno-histochemical staining included Leukocyte Common Antigen (LCA, CD45) , CD20, CD19, CD22, CD3, CD5, CD10, CD30, CD45RO, CD56, Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK) , B-cell Lymphoma 2 (BCL-2) , B-cell Lymphoma 6 (BCL-6) , C-myc, and cyclin D1. Double-expressor lymphoma was defined as the co-expression of C-myc with either BCL-2 or BCL-6 on immunohistochemistry. Molecular Genetics Double-expressor cases underwent fluorescence in situ hybridisation to confirm double-hit lymphoma (C-myc with BCL-2 and/or BCL-6 rearrangements). Gene mutation profiling was performed using next-generation sequencing or polymerase chain reaction (PCR)-based methods. Therapy Procedure Of the 21 patients, 11 underwent ASCT followed by CD19/20/22 CAR-T cell therapy, with prior collection of autologous stem cells and peripheral blood mononuclear cells (PBMCs). The remaining 10 patients underwent CD19/22 CAR-T cell therapy alone following PBMC collection, and CAR-T cell products were manufactured. Bridging therapy was administered when clinically indicated during CAR-T cell manufacturing, with regimen selection guided by institutional experience, disease status, and prior treatment history. Conditioning regimens for the ASCT-CAR-T cohort included BEAM (carmustine, etoposide, cytarabine, melphalan), BEAMF (BEAM plus fludarabine), or liposomal doxorubicin combined with BEAM, whereas the CAR-T-only cohort received fludarabine and cyclophosphamide (FC). Patients subsequently received infusions of commercially available CD19 CAR-T products (Relma-cel or Axi-cel) or investigational CD19/CD22 CAR-T cells within 2–6 days post-conditioning, either as single or sequential infusions. Of the 23 patients without ileocecal lymphoma, 17 received ASCT followed by CAR-T cell therapy. The ASCT conditioning regimens included BEAM (nine cases), doxorubicin + BEAM (four cases), BEAMF (one case), and TBC (one case). Patients in the CAR-T group received the FC regimen as conditioning chemotherapy, with the infusion procedure being consistent with that of the ileocecal group. Patients with and without ileocecal lymphoma received structurally identical CAR-T cells from Senlang Bio (Hebei, China). Response Criteria Treatment response was assessed using the following WHO criteria (complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]). Initial response evaluation was performed 3 months after infusion. OS was defined as the time from CAR-T infusion to death from any cause or the last follow-up (March 7, 2025). PFS spanned from infusion to relapse, progression, death, or last follow-up. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed according to ASCT consensus criteria [ 8 ]. Statistical Analysis Categorical variables were compared using Fisher's exact test, and continuous variables were compared using the t-test. Survival curves were generated using the Kaplan_Meier method with log-rank testing. Multivariate analyses of PFS and OS were performed using the least absolute shrinkage and selection operator (LASSO) regression and logistic regression, respectively. Significant and clinically significant variables were included in the univariate analysis. Clinical characteristics and survival curves were analysed using GraphPad Prism 10.0; multivariate analyses were performed using SPSS 29.0 (SPSS Inc, Chicago, IL, USA). RESULTS Patient Characteristics Initially, 23 patients with relapsed/refractory ileocecal lymphoma confirmed by pathology or imaging were enrolled. Excluding two patients who did not undergo CAR-T cell therapy post-diagnosis, 21 patients were enrolled ( Fig. 1 ) . The clinical characteristics of the 21 patients are summarised in Table 1 . Before CAR-T therapy, patients had received a median of two lines of treatment (range: 1–5). The median age was 45 years (range: 21–71), with a male predominance (80.95%, 17/21; male-to-female ratio: 4.25:1). All cases were of B-cell origin, with DLBCL being the most common histological type (85.71%, 18/21). Of the DLBCL cases, 10 (55.56%) were non-germinal centre B-cell-like (non-GCB) subtype, and eight (44.44%) were germinal centre B-cell-like (GCB) subtype. At initial diagnosis, 15 patients (71.43%) presented with B symptoms. According to the Lugano staging system, 17 patients (80.95%) had stage IV disease at onset, including 6 with distant extranodal involvement. The most common non-gastrointestinal sites were bone marrow (three cases) and bone (two cases), followed by the central nervous system (CNS), vertebrae, and pleura (one case each). In addition, three patients (14.29%) had stage IIE disease, and one (4.76%) had stage II1 disease. Most patients had intermediate-risk International Prognostic Index scores (2–3 points). The molecular genetic characteristics are shown in Supplementary Figure S1 A (Additional File 1). Notably, 15 patients underwent genetic mutation profiling, revealing a mean of 4.8 mutations per patient (range: 1–12). Tumor Protein P53 (TP53) mutations were the most frequent alteration, detected in nine patients (60%) with ileocecal lymphoma. These frequently co-occurred with mutations in CD79B, Lysine Methyltransferase 2D (KMT2D, also known as MLL2), Tet Methylcytosine Dioxygenase 2(TET2) , and E1A Binding Protein P300(EP300). BTG Anti-Proliferation Factor 2 (BTG2) mutations were present in three patients (20%). At the initial presentation, 14 patients (66.67%) reported abdominal symptoms as their chief concern (Supplementary Figure S1 B, Additional File 1) . The most common manifestations were abdominal pain and intestinal obstruction (five cases each), followed by abdominal distension and altered bowel habits (four cases each). Four patients required surgical intervention because of intestinal complications. Table 1 Baseline characteristics of patients IC Group(n = 21) non-IC Group(n = 23) P Value Age, y, median (range) Age, n (%) ≥ 60 y 46 (16–71) 5(23.81) 49 (20–71) 4 (17.39) .716 < 60 y 16 (76. 19) 19 (82.61) Sex, n (%) .825 Male 17 (80.95) 18 (78.26) Female 4 (19.05) 5 (21.74) Disease type, n (%) .666 DLBCL 18 (85.71) 19(82.60) BL 3 (14.29) 2 (8.70) FL 0 2 (8.70) DLBCL subtype, n (%) > .999 GCB 8 (44.44) 8 (42. 11) non-GCB 10 (55.56) 11 (57.89) B symptom, n (%) > .999 Yes 15 (71.43) 17 (73.91) No 6(28.57) 6(26.09) Staging, n (%) .540 II 4 (19.05) 0 II1 1 (4.76) II2 0 IIE 3 (14.29) III - IIIS - IV 17 (80.95) IPI, n (%) .421 0–1 3 (14.29) 2 8 (38. 10) 3 7 (33.33) 4–5 3 (14.29) ECOG, n (%) .157 0–1 14 (66.67) ≥ 2 7 (33.33) Double hit n (%) .887 Yes 2 (9.52) No 15 (71.43) Unknown 4 (19.05) LDH (U/L, Mean ± SD) 304.29 ± 215.74 .80 Treatment .211 ASCT + CAR-T 11 (52.38) CAR-T 10 (47.62) Prior treatment line, median (range) 2.00 (1–5) 3.00 (1–5) .260 Abbreviations: ASCT, Autologous Hematopoietic Stem Cell Transplantation; BL, 644 Burkitt’s lymphocytephoma; CAR-T, Chimeric Antigen Receptor T; CR, Complete remission; DLBCL, Diffuse Large B Cell lymphocytephoma; ECOG, Eastern Cooperative Oncology Group; FL, Follicular lymphocytephoma; GCB, Germinal Centre B-cell like; IC group, ileocecal group; IPI: International Prognostic Index; LDH, Lactate Dehydrogenase; non-IC group, non-ileocecal group; non-GCB, Non-Germinal Centre B-cell like; PD, Progressive Disease; PR, Partial Response; SD, Stable Disease. Objective Response Of the 21 patients in the ileocecal group ( Fig. 2 a ) , 11 (52.38%) received CAR-T therapy alone, and 10 (47.62%) received ASCT followed by CAR-T therapy. By December 30, 2025, all patients completed the 3-month response assessments ( Fig. 2 b ) . In the ileocecal subgroup, seven patients achieved CR and five achieved PR, resulting in an ORR of 57. 14% (12/21), which was significantly lower than that in the non-ileocecal group (86.96%, P = 0.042, 95% CI: 1.131–19.080). Among the responders (n = 12), the maximum response duration was 74 months; however, eight patients (five CR and three PR) experienced relapse or progression at a median of 8 months (range: 3–21). One patient achieved sustained partial remission after secondary CD19/CD22 CAR-T cell retreatment. Subgroup analysis revealed no significant differences in ORR based on the abdominal symptoms present (63.64% vs 42.86%, P = 0.397), TP53 mutation status (55.55% vs 71.43%, P > 0.999), or ASCT bridging (60% vs 66.67%, P > 0.999) (Supplementary Figure S3A-(a), B-(d), C-(g), Additional File 1) . Survival Analysis As of the final follow-up date (December 30, 2025), the median follow-up duration from the first CAR-T therapy was 21 months (range: 0–64). Seven patients died during the study period, including six due to disease progression and one due to sepsis. Two patients were lost to follow-up after treatment discontinuation owing to disease progression. Seven patients with < 1 year of follow-up were excluded from long-term survival analyses. The median 1-year PFS in the ileocecal group was 5 months (95% CI: 3–11) (Fig. 2 c) and a 3-year PFS rate of 0% (Fig. 2 d). In the non-ileocecal group, the median of 3-year PFS was 27 months (95%CI: 4-infinity). The 3-year PFS rates were significantly lower in the ileocecal group than in the non-ileocecal group (P = 0.001). The median 1-year OS in the ileocecal group was not attained ( Supplementary F igure S2 a, Additional File 1 ). The median 3-year OS rate was 10.5 months ( Supplementary F igure S2 b, Additional File 1 ). In the non-ileocecal group, the median 1-year OS was undefined, and the median 3-year OS was 27 months. No statistically significant differences in 1-year or 3-year OS were observed between the two groups (P = 0.990 and P = 0.490, respectively). Subgroup analyses revealed no significant differences in OS or PFS based on the presence of abdominal symptoms, TP53 mutation status, or prior ASCT before CAR-T therapy (Supplementary Figure S3 a -(b)(c) , b -(e)(f) , c -(h)(i), Additional File 1) . Adverse Reactions Analysis of CAR-T cell-related toxicities revealed that grade 1 CRS was the most common adverse event in the ileocecal (14/21, 66.67%) and non-ileocecal cohorts (14/23, 60.87%) ( Fig. 3 a ) , with no significant intergroup difference in CRS severity distribution (P = 0.565). Three patients in the ileocecal cohort (14.29%) developed grade 3 CRS. One patient (4.76%) with diffuse large BCL (GCB subtype) and bone marrow involvement experienced grade 4 CRS accompanied by disseminated intravascular coagulation, grade 4 ICANS, and septic shock (polymicrobial bacterial, fungal, and viral infections), and ultimately succumbed to septic shock 20 days after CAR-T cell infusion. ICANS was absent in 16 (76. 19%) and 21 patients (91.30%) in the ileocecal and non-ileocecal cohorts, respectively, with no significant difference in severity between the groups (P = 0.088) ( Fig. 3 b ) . Grade 3 ICANS occurred in three patients with ileocecal lymphoma (14.29%): one patient with DLBCL (GCB subtype) with CNS involvement exhibited concurrent grade 3 CRS, demonstrated progressive disease (PD) at the 3-month assessment, and died from disease progression 5 months post-treatment; one patient with Burkitt lymphoma exhibited PD at 3 months and discontinued therapy because of disease progression at 5 months; and one patient (4.76%) developed grade 4 ICANS. All four patients in the ileocecal cohort with severe ICANS (≥ grade 3) had concurrent CRS ≥ grade 2. Patients in the non-ileocecal cohort experienced only grade ≤ 1 ICANS. Kinetics of CAR-T Cells CAR-T cell copies in peripheral blood were quantified using digital PCR. Patients in the ileocecal group demonstrated a significantly higher median peak CD19 copy number of 55,774 (range, 69–288,940) (Fig. 4 a-d) than patients in the non-ileocecal group, who had a median of 3,811 (range, 0–199,660) (P = 0.009). Similarly, the median CD19 area under the curve (AUC)0-last in the ileocecal group was 498,977 (range, 384–1,628,799), which was also significantly higher than that in the non-ileocecal group (38978, range, 1–1,347,430) (P = 0.015). The median time to reach peak CD19 copy number was 9 days (range, 0–13) in the ileocecal group, with a median duration of 41 days (range, 0–253 days). These values did not differ significantly from the median time to peak of 7 days (range, 0–62 days) and median duration of 46 days (range, 0–226 days) observed in the non-ileocecal group. For CD22, the median peak copy number in patients with ileocecal involvement was 5,789 (range, 906–24,266) (Fig. 4 e-h), which was not significantly different from that in the non-ileocecal group (P = 0.461). The median CD22 AUC0-last was 64,789 (range, 2,895–335,266) in the ileocecal group, which was not significantly different from that in the non-ileocecal group (P = 0.821). The median time to reach peak CD22 copy number was 6 days (range, 0–15), with a median duration of 24 days (range, 0-116), and neither parameter showed a significant difference compared with the non-ileocecal group (P = 0.579; P = 0.562). CD20 copies were assessed in five patients who underwent ASCT sequentially with CAR-T therapy (Fig. 4 i-l). The median peak CD20 copy number was 4,720 (range, 526–44,737), with a median AUC0-last value of 41,206 (range, 1,490–311,940). The median time to reach peak number was 6 days (range, 0–6), and the median duration was 17 days (range, 0–120). No significant differences were observed in any of these CD20 kinetic parameters compared with the non-ileocecal group (P = 0.591; P = 0.284; P = 0.537; P = 0. 126). Multivariate Analysis Univariate Cox regression analysis of OS and PFS in patients in the ileocecal cohort identified potential prognostic factors (P < 0. 1), which were subsequently included in the multivariate analysis (Fig. 5 -a, b). Factors with P < 0.05 in multivariate Cox regression were considered independent predictors. For PFS, multivariate analysis revealed two independent predictors: 3-month post-CAR-T cell treatment response and pretreatment lines ( Supplementary Table S1 , Additional File 1 ). Due to multicollinearity (variance inflation factor > 10 for all variables) and a limited sample size, LASSO regression was employed for the multivariate analysis of OS ( Supplementary Table S2, Additional File 1 ). Regression coefficients > 0 indicated independent prognostic significance. LASSO regression identified four independent predictors of OS: 3-month post-CAR-T cell treatment response, time to B-cell lymphoma recovery, baseline absolute lymphocyte count, and cumulative PD-1 inhibitor use (Fig. 5 c, 5 d). DISCUSSION CAR-T therapy has demonstrated ground-breaking efficacy in relapsed/refractory B-cell lymphomas [ 9 – 12 ]. The 5-year follow-up data from the ZUMA trial revealed that Axicabtagene Ciloleucel achieved a CR rate of 58%, with a median OS of 25.8 months and an estimated 5-year OS rate of 42.6% [ 13 ]. However, subgroup analyses focusing on intestinal lymphomas are rare [ 14 ]. In this study, we evaluated the efficacy and safety of CAR-T therapy in 21 patients with relapsed/refractory ileocecal lymphoma, providing critical insights into therapeutic mechanisms and clinical decision-making. The ileocecal region represents the second most common site of primary gastrointestinal lymphoma (20–30%) [ 1 , 2 , 8 ], with rare T-cell or NK-cell subtypes [ 15 ]. Consistent with the literature, 85.7% of our cohort had DLBCL, and survival analysis revealed that patients with Burkitt lymphoma exhibited poorer outcomes than those with DLBCL. At initial diagnosis, 80.95% of patients presented with stage IV disease, often involving bone marrow (14.29%) or the CNS (4.76%), while 71.43% exhibited B symptoms, underscoring the aggressive clinical behaviour of ileocecal lymphoma. The mean of 2.3 prior treatment lines before CAR-T therapy highlights the propensity for chemoresistance following standard therapies. Similarly, early retrospective studies on ileocecal lymphoma reported that conventional therapies, such as surgery, radiotherapy, and chemotherapy, failed to improve long-term survival [ 16 ]. Next-generation sequencing analysis of 15 patients with ileocecal lymphoma revealed a gene mutation profile; TP53 mutations occurred at a rate of 42.86%, representing the most frequent mutation type in this cohort, consistent with that reported in ileocecal lymphoma [ 17 ]. Notably, the rate of CD79B mutations/aberrant expression in this cohort was 21.4% (3/14), which was significantly higher than the approximately 8% reported in primary gastrointestinal lymphoma [ 18 ], suggesting mutational heterogeneity between ileocecal lymphoma and lymphomas originating from other gastrointestinal sites or extranodal locations. Furthermore, TP53 mutations in this study frequently co-occurred with mutations in EP300, KMT2D, and TET2. Inactivation of these genes impairs histone acetylation and methylation as well as DNA methylation, leading to epigenetic dysregulation and subsequent blockade of B-cell differentiation [ 19 – 21 ]. Concurrently, CD79B mutations constitutively activate the B-cell receptor (BCR) signalling pathway and the downstream nuclear factor kappa beta (NF- κB) pathway [ 18 ]. This indicates that ileocecal lymphomagenesis involves the cooperative dysregulation of multiple pathways, including TP53 inactivation, epigenetic dysregulation, and aberrant BCR signalling activation. TP53 and KMT2D mutations contribute to chemotherapy resistance and poor prognosis in lymphoma [ 19 , 22 – 24 ]. potentially explaining the poor initial response to standard therapy and frequent progression to relapsed/refractory disease observed in the TP53-positive patients in this cohort. Subsequent subgroup analysis demonstrated no significant impact of TP53 mutation status on the 3-month ORR, PFS, or OS, as previously reported by Porpaczy et al. [ 25 ]. TP53 mutations or deletions in patients with lymphoma led to CD19-negative antigen escape, increasing relapse rates after CD19-directed CAR-T therapy [ 26 ]. In this study, application of the sequential ‘cocktail’ therapy using dual-target (CD19/22) and triple-target (CD19/20/22) CAR-T cells substantially reduced the likelihood of tumour immune evasion through single antigen (CD19) loss, which has been shown to significantly reduce relapse rates after CAR-T therapy [ 27 ]. Furthermore, patients with ileocecal lymphoma exhibited significantly higher peak expansion levels and AUC0-last of peripheral blood CD19 CAR-T cells compared to the control group; however, the ORR at 3 months post-CAR-T therapy (55.56%) was significantly lower than that in the control group (86.96%), suggesting that while CAR-T cell expansion efficiency was superior in patients with ileocecal lymphoma, the robust expansion did not translate into durable remission, potentially due to immune factors inhibiting CAR-T cell function or accelerating CAR-T cell exhaustion in vivo. First, alterations in the gut microbiota and the immune microenvironment are significant factors in lymphomagenesis, affecting CAR-T efficacy and toxicity. Gut microbiota-derived lipopolysaccharide promotes intestinal B cell lymphoma by enhancing tumour necrosis factor-mediated NF- κB pathway - Toll Like Receptor 4 (TLR4) signalling. Short-chain fatty acids (such as butyrate) promote regulatory T cell function and inhibit lymphomagenesis, while ursolic acid A demonstrates immunomodulatory and anti-proliferative effects against lymphoma in vitro [ 28 ] Altered gut microbiota in patients with acute B-lymphoblastic leukaemia influenced CAR-T cell expansion efficiency [ 29 ]. Oral vancomycin administration modulated the gut microbiota, subsequently regulating T cell immunity and enhancing CAR-T cell expansion and treatment outcomes. Similarly, a higher abundance of specific gut microbes (such as Bifidobacterium and Clostridium) was found to correlate with milder CRS and improved treatment response during CAR-T therapy [ 30 ]. Concurrently, modulating cytokine expression within the microenvironment and targeting immunosuppressive cells were reported to enhances CAR-T cell function and improve patient outcomes [ 31 ]. We only assessed CAR-T cell expansion in peripheral blood. Further exploration is warranted to examine the correlation between CAR-T cell expansion efficiency in the ileocecal tissue and the gut microbiota/microenvironment. Gut-associated lymphoid tissue (GALT) constitutes the core of intestinal immune responses; the ileocecal GALT lamina propria is rich in Peyer's patches (PPs) [ 32 ], which exhibit concentrated distributions of B and T cells. Early research revealed that PPs efficiently adsorb the aromatic hydrocarbon carcinogen 3-methylcholanthrene, which plays a key role in inducing B-cell lymphomagenesis [ 33 ]. The mucosal epithelium of the ileocecal harbours a significantly higher density of M cells compared to other gastrointestinal areas, which mediate the active transport of external antigens from the intestinal lumen into PPs, where they are taken up by dendritic cells, playing a critical role in mucosal immune surveillance [ 34 , 35 ]. M cells secrete immunoglobulin A antibodies to neutralise pathogens and are also crucial for maintaining gut microbiota homeostasis [ 36 ]. However, the role of alterations in this structure in the toxicity and efficacy of CAR-T cell therapy for ileocecal lymphoma remains limited and warrants further investigation. Current research on CAR-T therapy for ileocecal lymphoma is limited, with only a few studies available on gastrointestinal or intestinal lymphomas. In a study of 14 patients with primary gastrointestinal DLBCL, CAR-T therapy yielded 6-month OS and PFS rates of 58.33% and 54.55%, respectively [ 37 ]. Previously, an analysis of 81 patients with intestinal lymphoma identified ileocecal involvement as an independent prognostic factor for improved OS and event-free survival, while the absence of perforation correlated with better OS [ 38 ]. In this study, all 14 patients presented with gastrointestinal symptoms, and four patients required emergency surgery, suggesting that local tissue structural destruction may exacerbate tumour aggressiveness. However, the median PFS in the ileocecal group of 5 months was significantly lower than that in the non-ileocecal group (27 months), whereas no difference in OS was observed between groups. Subgroup analysis revealed no significant difference in PFS or OS based on the presence or absence of abdominal symptoms. Concurrently, we found that surgical intervention did not improve patient survival, which deviates from the findings described in the aforementioned studies. Relapsed/refractory patients in this study with high tumour burden and distinct intestinal immunity likely experienced CAR-T cell therapy resistance or reduced persistence, resulting in rapid disease progression. Second, the aforementioned studies primarily employed conventional treatments such as surgery, radiotherapy, and chemotherapy, whereas our approach was based mainly on CAR-T and ASCT, with different treatment modalities leading to divergent outcomes. Third, the small sample size in this study may have introduced statistical bias. The lack of differences in 1-year and 3-year OS suggests that although disease progression occurred shortly after CAR-T therapy, patients still achieved expected survival through various salvage therapies, including intensive chemotherapy, PD-1 inhibitors, second CAR-T infusions, and ASCT. In the analysis of CAR-T cell therapy-related toxicities, we found that ICANS and CRS reactions were most frequently grade 0 1, respectively, in patients with ileocecal lymphoma undergoing CAR-T therapy. No statistically significant differences were observed in the incidence of any grade of toxicity reaction between the ileocecal and non-ileocecal groups, demonstrating the favourable safety of CAR-T therapy in patients with ileocecal lymphoma. One patient with ileocecal lymphoma with GCB subtype DLBCL involving bone marrow and central nervous system died due to grade 4 CRS, grade 4 ICANS, sepsis, and multi-organ failure, demonstrating that pre-transplantation disease progression and high tumour burden in the patient may exacerbate CAR-T toxicity [ 39 ]. In multivariate analysis, we identified suboptimal response at 3 months after CAR-T therapy as an independent prognostic factor for PFS and OS, suggesting that precise clinical assessment at this time point is warranted to guide prognosis and inform subsequent consolidation or maintenance therapy selection. Concurrently, we found that a higher number of lines of prior therapy was an independent prognostic factor for inferior PFS, while lower absolute lymphocyte counts pre-CAR-T, delayed B-cell recovery post-CAR-T, and fewer administrations of PD-1 inhibitors were independent prognostic factors for inferior OS. Similarly, Stock S et al. [ 31 ] reported concordant findings, demonstrating that detectable B cells and T-helper (Th) cells > 200 µ L were associated with superior OS and PFS, and reduced risks of infection and non-relapse mortality. Cherkassky et al. [ 40 ] found that PD-1 inhibitors significantly down-regulated PD-1 expression within the tumour microenvironment, thereby enhancing CAR-T cell function and improving patient survival. Notably, the 95% CIs for the aforementioned exposure factors were wide, suggesting sparse data or underlying heterogeneity. Further validation in larger cohorts is required. CONCLUSIONS Our results indicate that CAR-T therapy is a feasible and manageable salvage option for patients with relapsed/refractory ileocecal lymphoma who failed ≥ 2 prior lines of treatment. Patients with ileocecal lymphoma exhibited significantly inferior ORR and PFS compared to non-ileocecal counterparts; however, comparable OS underscores the potential of post-progression salvage therapies (such as chemotherapy, PD-1 inhibitors, or secondary CAR-T/ASCT) to mitigate early treatment failure. Optimising CAR-T cell timing (front-line application) may enhance long-term outcomes in this high-risk population. As indicated in this study, the clinical recommendation for patients with ileocecal lymphoma following CAR-T treatment is to perform an early assessment at the 3-month mark to predict PFS and OS. In addition, the administration of immunomodulatory agents (such as PD-1 inhibitors) should be considered as maintenance therapy to enhance long-term patient survival outcomes. However, the single-centre design, small sample size, and potential selection bias inherent to this study warrant validation through multicentre trials with larger cohorts. Abbreviations ALK Anaplastic Lymphoma Receptor Tyrosine Kinase ASCT Autologous hematopoietic stem cell transplantation AUC Area under the curve BCL 2—B—cell Lymphoma 2 BCL 6—B—cell Lymphoma 6 BCR B—cell receptor CAR T—Chimeric antigen receptor—T cell CD Cluster of differentiation CI Confidence interval CNS Central nervous system CR Complete response CRS Cytokine release syndrome CT Computed tomography DLBCL Diffuse large B—cell lymphoma DNA Deoxyribonucleic acid EP300 E1A Binding Protein P300, p300 FC Fludarabine and cyclophosphamide GALT Gut—associated lymphoid tissue GCB Germinal centre B—cell—like ICANS Immune effector cell—associated neurotoxicity syndrome IPI International Prognostic Index KMT2D Lysine Methyltransferase 2D, MLL2 LASSO Least absolute shrinkage and selection operator LCA Leukocyte Common Antigen, CD45 MALT Mucosa—associated lymphoid tissue NF κB—Nuclear factor kappa—B NK Natural killer ORR Objective response rate OS Overall survival PBMCs Peripheral blood mononuclear cells PCR Polymerase chain reaction PD Progressive disease PD 1—Programmed cell death protein—1 PET Positron emission tomography PFS Progression—free survival PPs Peyer’s patches PR Partial response SD Stable disease TLR4 Toll—like receptor 4 TET2 Tet Methylcytosine Dioxygenase 2 TP53 Tumor Protein P53 WHO World Health Organisation Declarations Ethics approval and consent to participate This study was approved by the ethics committees of each participating centre and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all patients included in the study. Consent to publish Not applicable Competing interests The authors have no conflicts of interest to declare. Funding This work was supported by the National Natural Science Foundation of China (82270173) and the Medical Youth Top Notch Talent Project of Hubei Province. Author Contribution XZ, ZL, and WW designed and directed the study. XC, FM, YC,and ZZ collected the clinical data and conducted the follow-up. ZS contributed to the data analysis and wrote the paper. YC edited the images in this article. All authors had full access to the primary study data and reviewed the manuscript. Acknowledgements We sincerely thank the 21 patients and their families for their participation in this study. We acknowledge the clinical teams at Tongji Hospital and Guangxi Medical University for providing patient care and data collection. Special gratitude to Wuhan Bio-Raid Biotechnology Co., Ltd. for providing investigational CD19/CD22 CAR-T cells. Technical support from the laboratory staff for molecular analyses (NGS and dPCR) is appreciated. We deeply thank Professors Xiaojian Zhu, Wang Wei, and Zhenfang Liu for their guidance. This work was supported by the National Natural Science Foundation of China (82270173) and the Medical Youth Top Notch Talent Project of Hubei Province. Availability of data and materials The data supporting the findings of this study are available from the corresponding authors upon reasonable request and are subject to institutional and ethical guidelines. References Wang GB, Xu GL, Luo GY, Shan GD, Wang ZQ, Xia JY et al (2011) Primary intestinal non-Hodgkin's lymphoma: a clinicopathologic analysis of 81 patients. 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The adsorption from the gut and retention of 3-methylcholanthrene by Peyer's patches. Carcinogenesis 7(8):1257–1265. 10.1093/carcin/7.8.1257 Nakamura Y, Kimura S, Hase K (2018) M cell-dependent antigen uptake on follicle-associated epithelium for mucosal immune surveillance. Inflamm Regen 38:15. 10.1186/s41232-018-0072-y Vitetta L, Chen J, Clarke S (2019) The vermiform appendix: an immunological organ sustaining a microbiome inoculum. Clin Sci (Lond) 133(1):1–8. 10.1042/CS20180956 Garrett LR, Byers P, Cuchens MA, Bost KL (1991) The role of the Peyer's patch in the carcinogenesis of lymphoid cells. Int J Cancer 47(4):586–591. 10.1002/ijc.2910470421 Cortes-Bullich A, Perez A, Bachmeier C, Chavez JC, Jain MD, Locke FL et al (2021) Outcomes of CD19 Chimeric Antigen Receptor T Cell Therapy in Patients with Gastrointestinal Tract Involvement of Large B Cell Lymphoma. Transpl Cell Ther 27(9):768. 10.1016/j.jtct.2021.05.025 Jiang YL, Mu J, Cui R, Wang C, Zheng J, Wang Q et al (2024) Efficacy and side effects of anti-CD19 CAR T-cell therapy in patients with relapsed/refractory gastrointestinal lymphoma. Cancer Med 13(4):e7064. 10.1002/cam4.7064 Schubert ML, Schmitt M, Wang L, Hückelhoven-Krauss A, Neuber B, Kunz A et al (2021) Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Ann Oncol 32(1):34–48. 10.1016/j.annonc.2020.10.478 Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR et al (2016) Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest 126(8):3130–3144. 10.1172/JCI83092 Additional Declarations No competing interests reported. Supplementary Files SUPPLEMENTALAPPENDIX.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8776621","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":589159573,"identity":"7ebf07f7-346b-4736-92bc-72f564b09d21","order_by":0,"name":"Zeyan Shi","email":"","orcid":"","institution":"First Affiliated Hospital of GuangXi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zeyan","middleName":"","lastName":"Shi","suffix":""},{"id":589159574,"identity":"a98858af-3f18-4e41-9fa2-40d53dbd5ad5","order_by":1,"name":"Xing Chen","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xing","middleName":"","lastName":"Chen","suffix":""},{"id":589159575,"identity":"0ad40e16-80a6-456b-bc2c-1decc2069799","order_by":2,"name":"Yue Chun","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Chun","suffix":""},{"id":589159583,"identity":"55b4111b-fcf4-4757-8464-edefaaed8ad4","order_by":3,"name":"Fankai Meng","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fankai","middleName":"","lastName":"Meng","suffix":""},{"id":589159584,"identity":"c42a0e2d-7362-40da-98fe-366bd799f15c","order_by":4,"name":"Yang Cao","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Cao","suffix":""},{"id":589159585,"identity":"4477b29f-054c-4049-bdd7-efc47fc1071d","order_by":5,"name":"Zhicheng Zhang","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhicheng","middleName":"","lastName":"Zhang","suffix":""},{"id":589159586,"identity":"e24cc3e7-6e64-496d-83af-21991a475ba1","order_by":6,"name":"Zhenfang Liu","email":"","orcid":"","institution":"First Affiliated Hospital of GuangXi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhenfang","middleName":"","lastName":"Liu","suffix":""},{"id":589159587,"identity":"d09c51a0-f4a9-4688-bed5-25be3d313e4c","order_by":7,"name":"Wang Wei","email":"","orcid":"","institution":"Tongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wang","middleName":"","lastName":"Wei","suffix":""},{"id":589159589,"identity":"0b2db558-fe5a-4e85-9f81-8eb7d4dcb305","order_by":8,"name":"Xiaojian Zhu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYDACCSBOYGBgZmNgYHwMFTMgWguzMZRPhBYoYJMmSov87B4ziQc1Nux87GePVRe21dUxsDdvk2CouYNTC+OcM8YGCcfSmNl48tJuz2w7LMHAc6xMguHYM5xamCVyDB8ksB0G+iXH7DZv2wEJBokcMwnGhsM4tbBJ5BgcSPgH1ML/xqyYt61OgkH+DX4tPCBbEtuAWoCGM/O2MQNt4cGvRUIirdggsQ/oF4k3xtI85w5LtvGkFVskHMOtRX5G8jbJH99skuX7cww/85TV8fOzH95440MNbi0wkIzwHYhIIKiBgcGOCDWjYBSMglEwUgEA6QpFAr+jOCIAAAAASUVORK5CYII=","orcid":"","institution":"Tongji Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xiaojian","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2026-02-03 13:41:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8776621/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8776621/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102462862,"identity":"6d3f0a01-ff96-4568-8c42-06080f119932","added_by":"auto","created_at":"2026-02-12 01:11:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":227531,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart. Flowchart illustrates the enrollment of 21 ileocecal patients primarily treated with CAR-T therapy in this retrospective study. Extranodal organsinvolves in non-ileocecal lymphoma, including the bone marrow, stomach, kidneys, spleen, chest wall, breasts, colon, pancreas, lungs, and adrenal glands. ASCT: Autologous Hematopoietic Stem Cell Transplantation; CAR-T: Chimeric AntigenReceptor T cell therapy\u003c/p\u003e","description":"","filename":"Fig1.flowchart.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8776621/v1/25afe9b2947197ad9c5a6b09.jpg"},{"id":102462865,"identity":"dde0c72e-bc04-4ba9-959a-39aa6b218a74","added_by":"auto","created_at":"2026-02-12 01:11:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":7799678,"visible":true,"origin":"","legend":"\u003cp\u003eObject response of patients in the ileocecal cohort. a. Treatment responseand survival timeline. This swimmer plot depicts the temporal evolution of diseasestatus and treatment responses. The grid line of zero represents the time point of thefirst CAR-T or ASCT+CAR-T treatment. b. Three-month therapeutic responses. c. 1-year PFS; d: 3-year PFS. CR: Complete remission; non-IC: non-ileocecal; ORR: Objective Response Rate (CR+PR); PD: Progressive Disease; PR: Partial Response; SD: Stable Disease; PFS: Progression-Free Survival\u003c/p\u003e","description":"","filename":"Fig2Objectresponses.png","url":"https://assets-eu.researchsquare.com/files/rs-8776621/v1/e5eb164507c0fb6e38a69616.png"},{"id":102746172,"identity":"f64bd13d-e830-4431-8ee2-0c096a185a7c","added_by":"auto","created_at":"2026-02-16 08:55:59","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1787189,"visible":true,"origin":"","legend":"\u003cp\u003eAdverse events following CAR-T therapy. (a) CRS. (b) ICANS. The x-axis represents toxicity grades, and the y-axis indicates the number of affected patients, 669 with red and blue bars denoting IC and non-IC groups, respectively. In the IC cohort, 24 toxicity events were recorded: one patient (P18) received ASCT followed by CAR-T retreatment after relapse; one (P16) underwent ASCT+CAR-T post-progression; and one (P19) received two CAR-T courses followed byASCT+CAR-T. The non-IC cohort reported 25 toxicity events, including two patients who received secondary CAR-T therapy after ASCT+CAR-T failure. CRS: cytokine release syndrome; IC cohort: ileocecal cohort; ICANS: Immune EffectorCell-Associated Neurotoxicity Syndrome\u003c/p\u003e","description":"","filename":"Fig3AdverseeventsfollowingCARTtherapy..png","url":"https://assets-eu.researchsquare.com/files/rs-8776621/v1/d675718a178b4b553c4ddb4d.png"},{"id":102462866,"identity":"2bedd0b7-26ce-4fe5-937b-79551b4fc1b8","added_by":"auto","created_at":"2026-02-12 01:11:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":13532827,"visible":true,"origin":"","legend":"\u003cp\u003eKinetics of CAR-T Cells. a. CD19-targeted kinetics: (a) CD19 Cmax; (b) CD19 AUC0-last; (c) CD19 Tmax; (d) CD19 T0-last. b. CD22-targeted kinetics: (e) CD22679 Cmax; (f) CD22 AUC0-last; (g) CD22 Tmax; (h) CD22 T0-last. C. CD20-targeted kinetics: (i) CD20 Cmax; (j) CD20 AUC0-last; (k) CD20 Tmax; (l) CD20 T0-last. Data are presentedas median with interquartile range. Intergroup comparisons were performed usingMann-Whitney U tests. AUC: Area Under the Curve; AUC0-last: The area under thecurve from the time point of CAR-T infusion to the time point when the last quantitative detection of copies was performed; Cmax: detectable peak copy numbers; T0-last: duration of detectable copies; Tmax: time to peak copy number\u003c/p\u003e","description":"","filename":"Fig4KeniticsofCARTcells.png","url":"https://assets-eu.researchsquare.com/files/rs-8776621/v1/31cc230a76201b2000c178fa.png"},{"id":102462868,"identity":"5f933c99-e536-4b1e-88c5-d149b7f7a58e","added_by":"auto","created_at":"2026-02-12 01:11:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":16237246,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate and multivariate analysis. a. Univariate analysis of OS;b. Univariate analysis of PFS; c. The trend graph depicting the LASSO coefficient ofOS in relation to the variation of Lambda. d. The statistical graph of the LASSO regression coefficients of the OS. CD3+CD4+ T cells, Total T cells, serum ferritin, LDH and lymphocyte count were all included in the final test results before CAR-Ttreatment. CRS: cytokine release syndrome; ICANS: immune effector cell-associatedneurotoxicity syndrome; IPI: International Prognostic Index; LASSO: Least AbsoluteShrinkage and Selection Operator; LDH: lactate dehydrogenase; PD-1 inhibitor usage: The frequency of using PD1 inhibitors after CAR-T therapy; sFn: serum ferritin\u003c/p\u003e","description":"","filename":"Fig5Univariateandmultivariateanalysis.png","url":"https://assets-eu.researchsquare.com/files/rs-8776621/v1/5035d6be75da52974ef30b3b.png"},{"id":109252309,"identity":"73e3361f-ec64-43c8-ab99-1906cc4cddd3","added_by":"auto","created_at":"2026-05-14 09:24:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":39494837,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8776621/v1/f9c50666-8089-41f0-a994-f8eeeab5f47c.pdf"},{"id":102462867,"identity":"c1c6642a-3a33-4b35-a4ef-499dd683a70c","added_by":"auto","created_at":"2026-02-12 01:11:52","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2529865,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTALAPPENDIX.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8776621/v1/48a93823cd01838c0315c851.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical outcomes of chimeric antigen receptor T cell therapy in 21 patients with Relapse/Refractory Ileocecal B cell lymphoma","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe ileocecum is the most commonly affected site in primary intestinal lymphoma, accounting for approximately 20.3\u0026ndash;39.8% of all cases [1\u0026ndash;4 ]. The predominant pathological types include diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue (MALT) lymphoma [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Ileocecal lymphoma frequently presents with acute complications, such as abdominal pain, intestinal obstruction, perforation, or haemorrhage [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] which may necessitate emergency surgical intervention and disrupt the continuity of systemic antitumor therapy. Currently, the first-line treatment for ileocecal lymphoma primarily relies on R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy; however, therapeutic efficacy varies significantly owing to biological heterogeneity, with approximately 20\u0026ndash;30% of patients experiencing disease relapse or progression [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For these patients, traditional salvage therapies, such as autologous hematopoietic stem cell transplantation (ASCT) combined with high-dose chemotherapy, have limited benefits.\u003c/p\u003e \u003cp\u003eIn recent years, chimeric antigen receptor-T cell (CAR-T) therapy has emerged as a revolutionary approach to relapsed/refractory B-cell lymphomas. Early-phase ZUMA-7 studies demonstrated a 58% complete remission rate with CAR-T therapy, which was significantly superior to the efficacy of high-dose chemotherapy combined with ASCT (complete response rate, 32%) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Furthermore, CAR-T therapy has demonstrated favourable efficacy and safety in patients with relapsed/refractory primary gastrointestinal lymphomas [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Nevertheless, no studies have specifically addressed CAR-T therapy for ileocecal lymphomas. In this study, we focused on 21 patients with ileocecal lymphoma treated with CAR-T therapy. By integrating molecular profiling and systematically analysing the associations with overall survival (OS), progression-free survival (PFS), and treatment-related toxicities, we aimed to provide a theoretical framework for personalised CAR-T therapy in this distinct patient subgroup.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis retrospective, single-centre cohort study was based on the lymphoma database of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Patients with B-cell lymphoma who underwent CAR-T cell therapy between June 2014 and August 2024 were screened, and 21 patients with histologically or radiologically confirmed ileocecal lymphoma were enrolled. A propensity score-matched cohort of 23 patients without ileocecal lymphoma served as controls. Ileocecal involvement was defined as a disease affecting the ileocecal valve, terminal ileum, cecum, or appendix. All patients were staged according to the Lugano staging system. Each patient completed the following staging examinations: physical examination, plain computed tomography (CT) scan, positron emission tomography (PET)/CT, bone marrow cytology, and bone marrow biopsy. B symptoms were defined as the presence of at least one of the following: unexplained recurrent fever (temperature\u0026thinsp;\u0026ge;\u0026thinsp;38\u0026deg;C), night sweats, or weight loss (\u0026ge;\u0026thinsp;10% of body weight within 6 months). The last follow-up was conducted on December 30, 2025.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eBaseline assessments included demographic characteristics, serological and immunological parameters, treatment-related adverse events, and radiographic findings. Treatment response was evaluated at 3 months post-CAR-T therapy using contrast-enhanced CT or PET/CT.\u003c/p\u003e\n\u003ch3\u003eHistology\u003c/h3\u003e\n\u003cp\u003eFormalin-fixed biopsy specimens were histologically classified according to the World Health Organisation (WHO) classification of haematolymphoid tumours (5th edition). Immuno-histochemical staining included \u003cem\u003eLeukocyte Common Antigen (LCA, CD45)\u003c/em\u003e, CD20, CD19, CD22, CD3, CD5, CD10, CD30, CD45RO, CD56, \u003cem\u003eAnaplastic Lymphoma Receptor Tyrosine Kinase (ALK)\u003c/em\u003e, \u003cem\u003eB-cell Lymphoma 2 (BCL-2)\u003c/em\u003e, \u003cem\u003eB-cell Lymphoma 6 (BCL-6)\u003c/em\u003e, C-myc, and cyclin D1. Double-expressor lymphoma was defined as the co-expression of C-myc with either BCL-2 or BCL-6 on immunohistochemistry.\u003c/p\u003e\n\u003ch3\u003eMolecular Genetics\u003c/h3\u003e\n\u003cp\u003eDouble-expressor cases underwent fluorescence in situ hybridisation to confirm double-hit lymphoma (C-myc with BCL-2 and/or BCL-6 rearrangements). Gene mutation profiling was performed using next-generation sequencing or polymerase chain reaction (PCR)-based methods.\u003c/p\u003e\n\u003ch3\u003eTherapy Procedure\u003c/h3\u003e\n\u003cp\u003eOf the 21 patients, 11 underwent ASCT followed by CD19/20/22 CAR-T cell therapy, with prior collection of autologous stem cells and peripheral blood mononuclear cells (PBMCs). The remaining 10 patients underwent CD19/22 CAR-T cell therapy alone following PBMC collection, and CAR-T cell products were manufactured. Bridging therapy was administered when clinically indicated during CAR-T cell manufacturing, with regimen selection guided by institutional experience, disease status, and prior treatment history. Conditioning regimens for the ASCT-CAR-T cohort included BEAM (carmustine, etoposide, cytarabine, melphalan), BEAMF (BEAM plus fludarabine), or liposomal doxorubicin combined with BEAM, whereas the CAR-T-only cohort received fludarabine and cyclophosphamide (FC). Patients subsequently received infusions of commercially available CD19 CAR-T products (Relma-cel or Axi-cel) or investigational CD19/CD22 CAR-T cells within 2\u0026ndash;6 days post-conditioning, either as single or sequential infusions. Of the 23 patients without ileocecal lymphoma, 17 received ASCT followed by CAR-T cell therapy. The ASCT conditioning regimens included BEAM (nine cases), doxorubicin\u0026thinsp;+\u0026thinsp;BEAM (four cases), BEAMF (one case), and TBC (one case). Patients in the CAR-T group received the FC regimen as conditioning chemotherapy, with the infusion procedure being consistent with that of the ileocecal group. Patients with and without ileocecal lymphoma received structurally identical CAR-T cells from Senlang Bio (Hebei, China).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eResponse Criteria\u003c/h2\u003e \u003cp\u003eTreatment response was assessed using the following WHO criteria (complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]). Initial response evaluation was performed 3 months after infusion. OS was defined as the time from CAR-T infusion to death from any cause or the last follow-up (March 7, 2025). PFS spanned from infusion to relapse, progression, death, or last follow-up. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed according to ASCT consensus criteria [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were compared using Fisher's exact test, and continuous variables were compared using the t-test. Survival curves were generated using the Kaplan_Meier method with log-rank testing. Multivariate analyses of PFS and OS were performed using the least absolute shrinkage and selection operator (LASSO) regression and logistic regression, respectively. Significant and clinically significant variables were included in the univariate analysis. Clinical characteristics and survival curves were analysed using GraphPad Prism 10.0; multivariate analyses were performed using SPSS 29.0 (SPSS Inc, Chicago, IL, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePatient Characteristics\u003c/h2\u003e \u003cp\u003eInitially, 23 patients with relapsed/refractory ileocecal lymphoma confirmed by pathology or imaging were enrolled. Excluding two patients who did not undergo CAR-T cell therapy post-diagnosis, 21 patients were enrolled \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The clinical characteristics of the 21 patients are summarised in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Before CAR-T therapy, patients had received a median of two lines of treatment (range: 1\u0026ndash;5). The median age was 45 years (range: 21\u0026ndash;71), with a male predominance (80.95%, 17/21; male-to-female ratio: 4.25:1). All cases were of B-cell origin, with DLBCL being the most common histological type (85.71%, 18/21). Of the DLBCL cases, 10 (55.56%) were non-germinal centre B-cell-like (non-GCB) subtype, and eight (44.44%) were germinal centre B-cell-like (GCB) subtype. At initial diagnosis, 15 patients (71.43%) presented with B symptoms. According to the Lugano staging system, 17 patients (80.95%) had stage IV disease at onset, including 6 with distant extranodal involvement. The most common non-gastrointestinal sites were bone marrow (three cases) and bone (two cases), followed by the central nervous system (CNS), vertebrae, and pleura (one case each). In addition, three patients (14.29%) had stage IIE disease, and one (4.76%) had stage II1 disease. Most patients had intermediate-risk International Prognostic Index scores (2\u0026ndash;3 points). The molecular genetic characteristics are shown in \u003cb\u003eSupplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eA (Additional File 1).\u003c/b\u003e Notably, 15 patients underwent genetic mutation profiling, revealing a mean of 4.8 mutations per patient (range: 1\u0026ndash;12). \u003cem\u003eTumor Protein P53 (TP53)\u003c/em\u003e mutations were the most frequent alteration, detected in nine patients (60%) with ileocecal lymphoma. These frequently co-occurred with mutations in CD79B, \u003cem\u003eLysine Methyltransferase 2D (KMT2D, also known as MLL2), Tet Methylcytosine Dioxygenase 2(TET2)\u003c/em\u003e, and \u003cem\u003eE1A Binding Protein P300(EP300). BTG Anti-Proliferation Factor 2 (BTG2)\u003c/em\u003e mutations were present in three patients (20%). At the initial presentation, 14 patients (66.67%) reported abdominal symptoms as their chief concern \u003cb\u003e(Supplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eB, Additional File 1)\u003c/b\u003e. The most common manifestations were abdominal pain and intestinal obstruction (five cases each), followed by abdominal distension and altered bowel habits (four cases each). Four patients required surgical intervention because of intestinal complications.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIC Group(n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003enon-IC Group(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, y, median (range)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eAge, n (%)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;60 y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (16\u0026ndash;71)\u003c/p\u003e \u003cp\u003e5(23.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (20\u0026ndash;71)\u003c/p\u003e \u003cp\u003e4 (17.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.716\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;60 y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (76. 19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (82.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.825\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (80.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (78.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (19.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (21.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease type, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.666\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDLBCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (85.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(82.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (14.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDLBCL subtype, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;.999\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (44.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (42. 11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enon-GCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (55.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (57.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eB symptom, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026gt;\u0026thinsp;.999\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (71.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (73.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(28.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(26.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStaging, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.540\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (19.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eII1\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eII2\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eIIE\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (14.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIIIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (80.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIPI, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.421\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (14.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (38. 10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (14.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.157\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (66.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (33.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDouble hit n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.887\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (9.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (71.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (19.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLDH (U/L, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e304.29\u0026thinsp;\u0026plusmn;\u0026thinsp;215.74\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.80\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTreatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.211\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASCT\u0026thinsp;+\u0026thinsp;CAR-T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (52.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAR-T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (47.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrior treatment line, median (range)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2.00 (1\u0026ndash;5)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e3.00 (1\u0026ndash;5)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e.260\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: ASCT, Autologous Hematopoietic Stem Cell Transplantation; BL, 644 Burkitt\u0026rsquo;s lymphocytephoma; CAR-T, Chimeric Antigen Receptor T; CR, Complete remission; DLBCL, Diffuse Large B Cell lymphocytephoma; ECOG, Eastern Cooperative Oncology Group; FL, Follicular lymphocytephoma; GCB, Germinal Centre B-cell like; IC group, ileocecal group; IPI: International Prognostic Index; LDH, Lactate Dehydrogenase; non-IC group, non-ileocecal group; non-GCB, Non-Germinal Centre B-cell like; PD, Progressive Disease; PR, Partial Response; SD, Stable Disease.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eObjective Response\u003c/h2\u003e \u003cp\u003eOf the 21 patients in the ileocecal group \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea\u003cb\u003e)\u003c/b\u003e, 11 (52.38%) received CAR-T therapy alone, and 10 (47.62%) received ASCT followed by CAR-T therapy. By December 30, 2025, all patients completed the 3-month response assessments \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb\u003cb\u003e)\u003c/b\u003e. In the ileocecal subgroup, seven patients achieved CR and five achieved PR, resulting in an ORR of 57. 14% (12/21), which was significantly lower than that in the non-ileocecal group (86.96%, P\u0026thinsp;=\u0026thinsp;0.042, 95% CI: 1.131\u0026ndash;19.080). Among the responders (n\u0026thinsp;=\u0026thinsp;12), the maximum response duration was 74 months; however, eight patients (five CR and three PR) experienced relapse or progression at a median of 8 months (range: 3\u0026ndash;21). One patient achieved sustained partial remission after secondary CD19/CD22 CAR-T cell retreatment. Subgroup analysis revealed no significant differences in ORR based on the abdominal symptoms present (63.64% vs 42.86%, P\u0026thinsp;=\u0026thinsp;0.397), TP53 mutation status (55.55% vs 71.43%, P\u0026thinsp;\u0026gt;\u0026thinsp;0.999), or ASCT bridging (60% vs 66.67%, P\u0026thinsp;\u0026gt;\u0026thinsp;0.999) \u003cb\u003e(Supplementary Figure S3A-(a), B-(d), C-(g), Additional File 1)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSurvival Analysis\u003c/h2\u003e \u003cp\u003eAs of the final follow-up date (December 30, 2025), the median follow-up duration from the first CAR-T therapy was 21 months (range: 0\u0026ndash;64). Seven patients died during the study period, including six due to disease progression and one due to sepsis. Two patients were lost to follow-up after treatment discontinuation owing to disease progression. Seven patients with \u0026lt;\u0026thinsp;1 year of follow-up were excluded from long-term survival analyses. The median 1-year PFS in the ileocecal group was 5 months (95% CI: 3\u0026ndash;11) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec) and a 3-year PFS rate of 0% (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). In the non-ileocecal group, the median of 3-year PFS was 27 months (95%CI: 4-infinity). The 3-year PFS rates were significantly lower in the ileocecal group than in the non-ileocecal group (P\u0026thinsp;=\u0026thinsp;0.001). The median 1-year OS in the ileocecal group was not attained (\u003cb\u003eSupplementary\u003c/b\u003e F\u003cb\u003eigure S2\u003c/b\u003ea, \u003cb\u003eAdditional File 1\u003c/b\u003e). The median 3-year OS rate was 10.5 months (\u003cb\u003eSupplementary\u003c/b\u003e F\u003cb\u003eigure S2\u003c/b\u003eb, \u003cb\u003eAdditional File 1\u003c/b\u003e). In the non-ileocecal group, the median 1-year OS was undefined, and the median 3-year OS was 27 months. No statistically significant differences in 1-year or 3-year OS were observed between the two groups (P\u0026thinsp;=\u0026thinsp;0.990 and P\u0026thinsp;=\u0026thinsp;0.490, respectively). Subgroup analyses revealed no significant differences in OS or PFS based on the presence of abdominal symptoms, TP53 mutation status, or prior ASCT before CAR-T therapy \u003cb\u003e(Supplementary Figure S3\u003c/b\u003ea\u003cb\u003e-(b)(c)\u003c/b\u003e, b\u003cb\u003e-(e)(f)\u003c/b\u003e, c\u003cb\u003e-(h)(i), Additional File 1)\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAdverse Reactions\u003c/h2\u003e \u003cp\u003eAnalysis of CAR-T cell-related toxicities revealed that grade 1 CRS was the most common adverse event in the ileocecal (14/21, 66.67%) and non-ileocecal cohorts (14/23, 60.87%) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea\u003cb\u003e)\u003c/b\u003e, with no significant intergroup difference in CRS severity distribution (P\u0026thinsp;=\u0026thinsp;0.565). Three patients in the ileocecal cohort (14.29%) developed grade 3 CRS. One patient (4.76%) with diffuse large BCL (GCB subtype) and bone marrow involvement experienced grade 4 CRS accompanied by disseminated intravascular coagulation, grade 4 ICANS, and septic shock (polymicrobial bacterial, fungal, and viral infections), and ultimately succumbed to septic shock 20 days after CAR-T cell infusion. ICANS was absent in 16 (76. 19%) and 21 patients (91.30%) in the ileocecal and non-ileocecal cohorts, respectively, with no significant difference in severity between the groups (P\u0026thinsp;=\u0026thinsp;0.088) \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb\u003cb\u003e)\u003c/b\u003e. Grade 3 ICANS occurred in three patients with ileocecal lymphoma (14.29%): one patient with DLBCL (GCB subtype) with CNS involvement exhibited concurrent grade 3 CRS, demonstrated progressive disease (PD) at the 3-month assessment, and died from disease progression 5 months post-treatment; one patient with Burkitt lymphoma exhibited PD at 3 months and discontinued therapy because of disease progression at 5 months; and one patient (4.76%) developed grade 4 ICANS. All four patients in the ileocecal cohort with severe ICANS (\u0026ge;\u0026thinsp;grade 3) had concurrent CRS\u0026thinsp;\u0026ge;\u0026thinsp;grade 2. Patients in the non-ileocecal cohort experienced only grade\u0026thinsp;\u0026le;\u0026thinsp;1 ICANS.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eKinetics of CAR-T Cells\u003c/h2\u003e \u003cp\u003eCAR-T cell copies in peripheral blood were quantified using digital PCR. Patients in the ileocecal group demonstrated a significantly higher median peak CD19 copy number of 55,774 (range, 69\u0026ndash;288,940) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea-d) than patients in the non-ileocecal group, who had a median of 3,811 (range, 0\u0026ndash;199,660) (P\u0026thinsp;=\u0026thinsp;0.009). Similarly, the median CD19 area under the curve (AUC)0-last in the ileocecal group was 498,977 (range, 384\u0026ndash;1,628,799), which was also significantly higher than that in the non-ileocecal group (38978, range, 1\u0026ndash;1,347,430) (P\u0026thinsp;=\u0026thinsp;0.015). The median time to reach peak CD19 copy number was 9 days (range, 0\u0026ndash;13) in the ileocecal group, with a median duration of 41 days (range, 0\u0026ndash;253 days). These values did not differ significantly from the median time to peak of 7 days (range, 0\u0026ndash;62 days) and median duration of 46 days (range, 0\u0026ndash;226 days) observed in the non-ileocecal group. For CD22, the median peak copy number in patients with ileocecal involvement was 5,789 (range, 906\u0026ndash;24,266) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ee-h), which was not significantly different from that in the non-ileocecal group (P\u0026thinsp;=\u0026thinsp;0.461). The median CD22 AUC0-last was 64,789 (range, 2,895\u0026ndash;335,266) in the ileocecal group, which was not significantly different from that in the non-ileocecal group (P\u0026thinsp;=\u0026thinsp;0.821). The median time to reach peak CD22 copy number was 6 days (range, 0\u0026ndash;15), with a median duration of 24 days (range, 0-116), and neither parameter showed a significant difference compared with the non-ileocecal group (P\u0026thinsp;=\u0026thinsp;0.579; P\u0026thinsp;=\u0026thinsp;0.562). CD20 copies were assessed in five patients who underwent ASCT sequentially with CAR-T therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ei-l). The median peak CD20 copy number was 4,720 (range, 526\u0026ndash;44,737), with a median AUC0-last value of 41,206 (range, 1,490\u0026ndash;311,940). The median time to reach peak number was 6 days (range, 0\u0026ndash;6), and the median duration was 17 days (range, 0\u0026ndash;120). No significant differences were observed in any of these CD20 kinetic parameters compared with the non-ileocecal group (P\u0026thinsp;=\u0026thinsp;0.591; P\u0026thinsp;=\u0026thinsp;0.284; P\u0026thinsp;=\u0026thinsp;0.537; P\u0026thinsp;=\u0026thinsp;0. 126).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eMultivariate Analysis\u003c/h2\u003e \u003cp\u003eUnivariate Cox regression analysis of OS and PFS in patients in the ileocecal cohort identified potential prognostic factors (P\u0026thinsp;\u0026lt;\u0026thinsp;0. 1), which were subsequently included in the multivariate analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e-a, b). Factors with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 in multivariate Cox regression were considered independent predictors. For PFS, multivariate analysis revealed two independent predictors: 3-month post-CAR-T cell treatment response and pretreatment lines (\u003cb\u003eSupplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e, Additional File 1\u003c/b\u003e). Due to multicollinearity (variance inflation factor\u0026thinsp;\u0026gt;\u0026thinsp;10 for all variables) and a limited sample size, LASSO regression was employed for the multivariate analysis of OS (\u003cb\u003eSupplementary Table S2, Additional File 1\u003c/b\u003e). Regression coefficients\u0026thinsp;\u0026gt;\u0026thinsp;0 indicated independent prognostic significance. LASSO regression identified four independent predictors of OS: 3-month post-CAR-T cell treatment response, time to B-cell lymphoma recovery, baseline absolute lymphocyte count, and cumulative PD-1 inhibitor use (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec, \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ed).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eCAR-T therapy has demonstrated ground-breaking efficacy in relapsed/refractory B-cell lymphomas [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The 5-year follow-up data from the ZUMA trial revealed that Axicabtagene Ciloleucel achieved a CR rate of 58%, with a median OS of 25.8 months and an estimated 5-year OS rate of 42.6% [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, subgroup analyses focusing on intestinal lymphomas are rare [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In this study, we evaluated the efficacy and safety of CAR-T therapy in 21 patients with relapsed/refractory ileocecal lymphoma, providing critical insights into therapeutic mechanisms and clinical decision-making. The ileocecal region represents the second most common site of primary gastrointestinal lymphoma (20\u0026ndash;30%) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], with rare T-cell or NK-cell subtypes [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Consistent with the literature, 85.7% of our cohort had DLBCL, and survival analysis revealed that patients with Burkitt lymphoma exhibited poorer outcomes than those with DLBCL. At initial diagnosis, 80.95% of patients presented with stage IV disease, often involving bone marrow (14.29%) or the CNS (4.76%), while 71.43% exhibited B symptoms, underscoring the aggressive clinical behaviour of ileocecal lymphoma. The mean of 2.3 prior treatment lines before CAR-T therapy highlights the propensity for chemoresistance following standard therapies. Similarly, early retrospective studies on ileocecal lymphoma reported that conventional therapies, such as surgery, radiotherapy, and chemotherapy, failed to improve long-term survival [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNext-generation sequencing analysis of 15 patients with ileocecal lymphoma revealed a gene mutation profile; TP53 mutations occurred at a rate of 42.86%, representing the most frequent mutation type in this cohort, consistent with that reported in ileocecal lymphoma [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Notably, the rate of CD79B mutations/aberrant expression in this cohort was 21.4% (3/14), which was significantly higher than the approximately 8% reported in primary gastrointestinal lymphoma [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], suggesting mutational heterogeneity between ileocecal lymphoma and lymphomas originating from other gastrointestinal sites or extranodal locations. Furthermore, TP53 mutations in this study frequently co-occurred with mutations in EP300, KMT2D, and TET2. Inactivation of these genes impairs histone acetylation and methylation as well as DNA methylation, leading to epigenetic dysregulation and subsequent blockade of B-cell differentiation [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Concurrently, CD79B mutations constitutively activate the B-cell receptor (BCR) signalling pathway and the downstream nuclear factor kappa beta (NF- κB) pathway [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This indicates that ileocecal lymphomagenesis involves the cooperative dysregulation of multiple pathways, including TP53 inactivation, epigenetic dysregulation, and aberrant BCR signalling activation. TP53 and KMT2D mutations contribute to chemotherapy resistance and poor prognosis in lymphoma [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. potentially explaining the poor initial response to standard therapy and frequent progression to relapsed/refractory disease observed in the TP53-positive patients in this cohort. Subsequent subgroup analysis demonstrated no significant impact of TP53 mutation status on the 3-month ORR, PFS, or OS, as previously reported by Porpaczy et al. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. TP53 mutations or deletions in patients with lymphoma led to CD19-negative antigen escape, increasing relapse rates after CD19-directed CAR-T therapy [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In this study, application of the sequential \u0026lsquo;cocktail\u0026rsquo; therapy using dual-target (CD19/22) and triple-target (CD19/20/22) CAR-T cells substantially reduced the likelihood of tumour immune evasion through single antigen (CD19) loss, which has been shown to significantly reduce relapse rates after CAR-T therapy [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, patients with ileocecal lymphoma exhibited significantly higher peak expansion levels and AUC0-last of peripheral blood CD19 CAR-T cells compared to the control group; however, the ORR at 3 months post-CAR-T therapy (55.56%) was significantly lower than that in the control group (86.96%), suggesting that while CAR-T cell expansion efficiency was superior in patients with ileocecal lymphoma, the robust expansion did not translate into durable remission, potentially due to immune factors inhibiting CAR-T cell function or accelerating CAR-T cell exhaustion in vivo.\u003c/p\u003e \u003cp\u003eFirst, alterations in the gut microbiota and the immune microenvironment are significant factors in lymphomagenesis, affecting CAR-T efficacy and toxicity. Gut microbiota-derived lipopolysaccharide promotes intestinal B cell lymphoma by enhancing tumour necrosis factor-mediated \u003cem\u003eNF- κB\u003c/em\u003e pathway - \u003cem\u003eToll Like Receptor 4 (TLR4)\u003c/em\u003e signalling. Short-chain fatty acids (such as butyrate) promote regulatory T cell function and inhibit lymphomagenesis, while ursolic acid A demonstrates immunomodulatory and anti-proliferative effects against lymphoma in vitro [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Altered gut microbiota in patients with acute B-lymphoblastic leukaemia influenced CAR-T cell expansion efficiency [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Oral vancomycin administration modulated the gut microbiota, subsequently regulating T cell immunity and enhancing CAR-T cell expansion and treatment outcomes. Similarly, a higher abundance of specific gut microbes (such as Bifidobacterium and Clostridium) was found to correlate with milder CRS and improved treatment response during CAR-T therapy [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Concurrently, modulating cytokine expression within the microenvironment and targeting immunosuppressive cells were reported to enhances CAR-T cell function and improve patient outcomes [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. We only assessed CAR-T cell expansion in peripheral blood. Further exploration is warranted to examine the correlation between CAR-T cell expansion efficiency in the ileocecal tissue and the gut microbiota/microenvironment. Gut-associated lymphoid tissue (GALT) constitutes the core of intestinal immune responses; the ileocecal GALT lamina propria is rich in Peyer's patches (PPs) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], which exhibit concentrated distributions of B and T cells. Early research revealed that PPs efficiently adsorb the aromatic hydrocarbon carcinogen 3-methylcholanthrene, which plays a key role in inducing B-cell lymphomagenesis [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The mucosal epithelium of the ileocecal harbours a significantly higher density of M cells compared to other gastrointestinal areas, which mediate the active transport of external antigens from the intestinal lumen into PPs, where they are taken up by dendritic cells, playing a critical role in mucosal immune surveillance [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. M cells secrete immunoglobulin A antibodies to neutralise pathogens and are also crucial for maintaining gut microbiota homeostasis [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. However, the role of alterations in this structure in the toxicity and efficacy of CAR-T cell therapy for ileocecal lymphoma remains limited and warrants further investigation. Current research on CAR-T therapy for ileocecal lymphoma is limited, with only a few studies available on gastrointestinal or intestinal lymphomas. In a study of 14 patients with primary gastrointestinal DLBCL, CAR-T therapy yielded 6-month OS and PFS rates of 58.33% and 54.55%, respectively [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Previously, an analysis of 81 patients with intestinal lymphoma identified ileocecal involvement as an independent prognostic factor for improved OS and event-free survival, while the absence of perforation correlated with better OS [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In this study, all 14 patients presented with gastrointestinal symptoms, and four patients required emergency surgery, suggesting that local tissue structural destruction may exacerbate tumour aggressiveness. However, the median PFS in the ileocecal group of 5 months was significantly lower than that in the non-ileocecal group (27 months), whereas no difference in OS was observed between groups. Subgroup analysis revealed no significant difference in PFS or OS based on the presence or absence of abdominal symptoms. Concurrently, we found that surgical intervention did not improve patient survival, which deviates from the findings described in the aforementioned studies. Relapsed/refractory patients in this study with high tumour burden and distinct intestinal immunity likely experienced CAR-T cell therapy resistance or reduced persistence, resulting in rapid disease progression.\u003c/p\u003e \u003cp\u003eSecond, the aforementioned studies primarily employed conventional treatments such as surgery, radiotherapy, and chemotherapy, whereas our approach was based mainly on CAR-T and ASCT, with different treatment modalities leading to divergent outcomes.\u003c/p\u003e \u003cp\u003eThird, the small sample size in this study may have introduced statistical bias. The lack of differences in 1-year and 3-year OS suggests that although disease progression occurred shortly after CAR-T therapy, patients still achieved expected survival through various salvage therapies, including intensive chemotherapy, PD-1 inhibitors, second CAR-T infusions, and ASCT. In the analysis of CAR-T cell therapy-related toxicities, we found that ICANS and CRS reactions were most frequently grade 0 1, respectively, in patients with ileocecal lymphoma undergoing CAR-T therapy. No statistically significant differences were observed in the incidence of any grade of toxicity reaction between the ileocecal and non-ileocecal groups, demonstrating the favourable safety of CAR-T therapy in patients with ileocecal lymphoma. One patient with ileocecal lymphoma with GCB subtype DLBCL involving bone marrow and central nervous system died due to grade 4 CRS, grade 4 ICANS, sepsis, and multi-organ failure, demonstrating that pre-transplantation disease progression and high tumour burden in the patient may exacerbate CAR-T toxicity [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn multivariate analysis, we identified suboptimal response at 3 months after CAR-T therapy as an independent prognostic factor for PFS and OS, suggesting that precise clinical assessment at this time point is warranted to guide prognosis and inform subsequent consolidation or maintenance therapy selection. Concurrently, we found that a higher number of lines of prior therapy was an independent prognostic factor for inferior PFS, while lower absolute lymphocyte counts pre-CAR-T, delayed B-cell recovery post-CAR-T, and fewer administrations of PD-1 inhibitors were independent prognostic factors for inferior OS. Similarly, Stock S et al. [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] reported concordant findings, demonstrating that detectable B cells and T-helper (Th) cells\u0026thinsp;\u0026gt;\u0026thinsp;200 \u0026micro; L were associated with superior OS and PFS, and reduced risks of infection and non-relapse mortality. Cherkassky et al. [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] found that PD-1 inhibitors significantly down-regulated PD-1 expression within the tumour microenvironment, thereby enhancing CAR-T cell function and improving patient survival. Notably, the 95% CIs for the aforementioned exposure factors were wide, suggesting sparse data or underlying heterogeneity. Further validation in larger cohorts is required.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eOur results indicate that CAR-T therapy is a feasible and manageable salvage option for patients with relapsed/refractory ileocecal lymphoma who failed\u0026thinsp;\u0026ge;\u0026thinsp;2 prior lines of treatment. Patients with ileocecal lymphoma exhibited significantly inferior ORR and PFS compared to non-ileocecal counterparts; however, comparable OS underscores the potential of post-progression salvage therapies (such as chemotherapy, PD-1 inhibitors, or secondary CAR-T/ASCT) to mitigate early treatment failure. Optimising CAR-T cell timing (front-line application) may enhance long-term outcomes in this high-risk population. As indicated in this study, the clinical recommendation for patients with ileocecal lymphoma following CAR-T treatment is to perform an early assessment at the 3-month mark to predict PFS and OS. In addition, the administration of immunomodulatory agents (such as PD-1 inhibitors) should be considered as maintenance therapy to enhance long-term patient survival outcomes. However, the single-centre design, small sample size, and potential selection bias inherent to this study warrant validation through multicentre trials with larger cohorts.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAnaplastic Lymphoma Receptor Tyrosine Kinase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAutologous hematopoietic stem cell transplantation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eArea under the curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e2\u0026mdash;B\u0026mdash;cell Lymphoma 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e6\u0026mdash;B\u0026mdash;cell Lymphoma 6\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eB\u0026mdash;cell receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eT\u0026mdash;Chimeric antigen receptor\u0026mdash;T cell\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCluster of differentiation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCentral nervous system\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComplete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCytokine release syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eComputed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDLBCL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiffuse large B\u0026mdash;cell lymphoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDNA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDeoxyribonucleic acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEP300\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eE1A Binding Protein P300, p300\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFludarabine and cyclophosphamide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGALT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGut\u0026mdash;associated lymphoid tissue\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGCB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGerminal centre B\u0026mdash;cell\u0026mdash;like\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICANS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eImmune effector cell\u0026mdash;associated neurotoxicity syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIPI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Prognostic Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eKMT2D\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLysine Methyltransferase 2D, MLL2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLASSO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLeast absolute shrinkage and selection operator\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLeukocyte Common Antigen, CD45\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMALT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMucosa\u0026mdash;associated lymphoid tissue\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eκB\u0026mdash;Nuclear factor kappa\u0026mdash;B\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNatural killer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eObjective response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePBMCs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePeripheral blood mononuclear cells\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolymerase chain reaction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgressive disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e1\u0026mdash;Programmed cell death protein\u0026mdash;1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePET\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePositron emission tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgression\u0026mdash;free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePeyer\u0026rsquo;s patches\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePartial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTLR4\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eToll\u0026mdash;like receptor 4\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTET2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTet Methylcytosine Dioxygenase 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTP53\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTumor Protein P53\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWHO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWorld Health Organisation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003e This study was approved by the ethics committees of each participating centre and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all patients included in the study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to publish\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Natural Science Foundation of China (82270173) and the Medical Youth Top Notch Talent Project of Hubei Province.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eXZ, ZL, and WW designed and directed the study. XC, FM, YC,and ZZ collected the clinical data and conducted the follow-up. ZS contributed to the data analysis and wrote the paper. YC edited the images in this article. All authors had full access to the primary study data and reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe sincerely thank the 21 patients and their families for their participation in this study. We acknowledge the clinical teams at Tongji Hospital and Guangxi Medical University for providing patient care and data collection. Special gratitude to Wuhan Bio-Raid Biotechnology Co., Ltd. for providing investigational CD19/CD22 CAR-T cells. Technical support from the laboratory staff for molecular analyses (NGS and dPCR) is appreciated. We deeply thank Professors Xiaojian Zhu, Wang Wei, and Zhenfang Liu for their guidance. This work was supported by the National Natural Science Foundation of China (82270173) and the Medical Youth Top Notch Talent Project of Hubei Province.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003e The data supporting the findings of this study are available from the corresponding authors upon reasonable request and are subject to institutional and ethical guidelines.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang GB, Xu GL, Luo GY, Shan GD, Wang ZQ, Xia JY et al (2011) Primary intestinal non-Hodgkin's lymphoma: a clinicopathologic analysis of 81 patients. 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J Clin Invest 126(8):3130\u0026ndash;3144. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1172/JCI83092\u003c/span\u003e\u003cspan address=\"10.1172/JCI83092\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ileocecal valve, CAR-T cell therapy, Lymphoma, B-cell, Progression-free survival, Recurrence","lastPublishedDoi":"10.21203/rs.3.rs-8776621/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8776621/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo evaluate the efficacy, safety, and prognostic factors of chimeric antigen receptor-T cell (CAR-T) therapy in patients with relapsed/refractory ileocecal lymphoma and provide evidence for salvage therapy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis retrospective analysis included 21 patients with ileocecal lymphoma (IC group) and 23 matched patients without ileocecal lymphoma (non-IC group) who received CAR-T therapy between June 2014 and August 2024. Baseline characteristics, genetic mutations, CAR-T cell kinetics, treatment response, overall survival (OS), and progression-free survival (PFS) were assessed. Prognostic factors were identified using Kaplan\u0026ndash;Meier analysis, Cox regression, and least absolute shrinkage and selection operator models.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe IC group showed a significantly lower 3-month objective response rate (57.14% vs. 86.96%, P\u0026thinsp;=\u0026thinsp;0.042) and shorter median PFS (5 months vs. 27 months, P\u0026thinsp;=\u0026thinsp;0.0007) than the non-IC group. CAR-T cell expansion was higher in the IC group (CD19 Cmax: 55774 vs. 3811, P\u0026thinsp;=\u0026thinsp;0.014), but persistence was similar. The safety profiles of CRS and ICANS were comparable across groups (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Multivariate analysis revealed poor 3-month treatment response (hazard ratio [HR]\u0026thinsp;=\u0026thinsp;32.075, P\u0026thinsp;=\u0026thinsp;0.015) and higher pre-treatment lines (HR\u0026thinsp;=\u0026thinsp;8.6, P\u0026thinsp;=\u0026thinsp;0.036) as independent risk factors for PFS. Delayed B-cell recovery and low baseline lymphocyte counts were associated with poorer OS.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eCAR-T therapy is feasible and safe for relapsed/refractory ileocecal lymphoma, but short-term efficacy is inferior to that in the non-IC group. High CAR-T expansion did not improve long-term outcomes. Early response assessment (3 months), baseline lymphocyte levels, and B-cell recovery are critical prognostic indicators, suggesting the need for optimised treatment timing and combination strategies to enhance efficacy.\u003c/p\u003e","manuscriptTitle":"Clinical outcomes of chimeric antigen receptor T cell therapy in 21 patients with Relapse/Refractory Ileocecal B cell lymphoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-12 01:11:47","doi":"10.21203/rs.3.rs-8776621/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"41372c13-e62e-42a7-8f66-0bf153b66f48","owner":[],"postedDate":"February 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-02T21:54:01+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-12 01:11:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8776621","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8776621","identity":"rs-8776621","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}