1458 Efficacy and immunomodulatory of Claudin18.2-specific IL-7/XCL1 armored CAR-T cells in digestive tract cancers

<h3>Background</h3> Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated efficacy in hematological malignancies but faces challenges in solid tumors due to the suppressive tumor microenvironment (TME), tumor heterogeneity, and insufficient CAR-T cell expansion and persistence.¹ To address these, we developed CAR-T cells that produce IL-7 and XCL1 to augment T cell and conventional type I dendritic cells (cDC1s) accumulation in tumor tissues. Specifically, we genetically modified CAR-T cells to target Claudin18.2, an antigen that is considered a promising target in digestive tract cancers(DTCs). These engineered cells, which we named RD07, demonstrated the safety and efficacy in treating DTCs in preclinical studies. <h3>Methods</h3> This was a single-arm, open-label, dose-escalation study(http://www.chictr.org.cn, ChiCTR2000038650). All of the patients underwent lymphodepletion consisting of cyclophosphamide, fludarabine or nab-paclitaxel before RD07 infusion at a dose of 0.1–2×10⁷ cells/kg body weight. The objective of this study was to evaluate the safety and efficacy of RD07. Single-cell RNA sequencing (scRNA-seq) and spatial landscape analysis were utilized to evaluate the TME. <h3>Results</h3> As of July 1, 2023, a total of 12 DTCs patients who had received ≥2 prior lines of therapy and ECOG performance status score of 0–2 were enrolled (table 1), apheresed and finished RD07 infusion. 4 patients received multiple infusions. With a median follow-up of 203 days (range, 12–466), grade 3–4 AEs were mainly hematologic toxicity caused by preconditioning therapy. Eight patients experienced G1 CRS, and no ICANS was observed. Two patients had G2 gastrointestinal hemorrhage. No treatment-related deaths occurred. The overall response rate (ORR) and disease control rate (DCR) for the 10 evaluable patients were 20.0% and 80.0%, respectively. Among the 6 patients with GC/GEJ with medium to high CLDN18.2 expression, the ORR was 33.3%, and the DCR was 100%. Seven patients experienced tumor shrinkage (figure 1). The median PFS and OS were 148 days and 327 days, respectively. All patients experienced CAR-T cell expansion following RD07 infusion, with a median duration of 10 (range, 10–54) days for CAR-T cell persistence in peripheral blood after the first infusion. Finally, single-cell RNA sequencing and spatial landscape analysis of patients’ tumor tissues revealed that the anti-tumor ability and activation of endogenous immune cells within the TME of RD07. <h3>Conclusions</h3> Collectively, our data indicate the efficacy and safety of RD07, and demonstrate the ability of anti-tumor and remodeling the TME, which could serve as an innovative CAR-T cell therapy for the treatment of DTCs and possibly other solid tumors. <h3>Trial Registration</h3> www.chictr.org.cn, ChiCTR2000038650. <h3>Reference</h3> O’Rourke DM, MP Nasrallah, A Desai, <i>et al.</i> A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. <i>Sci Transl Med</i>, 2017;<b>9</b>(399). <h3>Ethics Approval</h3> This study was reviewed and approved by the Ethics Committee of PKU-Nanjing Joint Institute of Translational Medicine, Raygen Health Molecular Medicine Technology Co., Ltd (IACYC-2022-014). <h3>Consent</h3> Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.