Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma.

Abstract

2509 Background: As a promising approach for some cancers, chimeric antigen receptor T cell therapy has limited success in solid tumors. Claudin18.2 (CLDN 18.2) is a stomach-specific isoform of Claudin-18, and highly expressed in gastric and pancreatic adenocarcinoma, the advanced form of both of which have urgent unmet medical needs. We previously developed and demonstrated ability of CLDN 18.2-specific CAR (CAR-CLDN18.2) T cells to eradicate CLDN 18.2-positive gastric cancer xenografts without obvious on-target off-tumor toxicity (Huang J. JNCI 2018). Methods: In this single-arm, open-label, first-in-human phase I pilot study (NCT03159819) to investigate the safety and explore the efficacy of the autologous CAR-CLDN18.2 T cells, patients with confirmed CLDN 18.2 positive advanced gastric or pancreatic adenocarcinoma aged 18 to 70 years received 1 or more cycles of CAR-CLDN18.2 T cell infusion(s) after lymphodepletion pretreatment (fludarabine and cyclophosphamide, with or without nab-paclitaxel) until disease progression or presence of intolerable toxicity. Adverse Event (AE) grade categorization is according to CTCAE 4.0, and tumor response was assessed per RECIST 1.1. Results: As of November 30th, 2018, 12 subjects with metastatic adenocarcinoma (7 gastric and 5 pancreatic) were treated with 1–5 cycles (total of 0.5 - 55 X 108) of CAR-positive T cells infusions. There were no serious adverse events, treatment-related death or severe neurotoxicity occurred in the study. No grade 4 AEs except for decreased lymphocytes, neutrophils and white blood cells. All cytokine release syndromes observed were grade 1 or 2. Among the 11 evaluable subjects, 1 achieved a complete response (gastric adenocarcinoma), 3 had partial responses (2 gastric adenocarcinomas and 1 pancreatic adenocarcinoma), 5 had stable disease and 2 had progression of disease. The total objective response rate was 33.3%, with median PFS of 130 days estimated using Kaplan-Meier method [95% CI (38, 230)]. Conclusions: This clinical study indicated that CAR-CLDN18.2 T cell therapy were safe and well tolerated and may have promising therapeutic efficacy in patients with advanced gastric and pancreatic adenocarcinoma. Clinical trial information: NCT03159819.

Precision medicine for human cancers with Notch signaling dysregulation (Review)

“…anti-claudin-18.2 cAR-Ts that showed an ORR of 36% (4/11) in patients with gastric or pancreatic cancer (195) are cutting-edge biologics in early-stage clinical trials. Adcs and cAR-Ts (Tables II and III) could alter the therapeutic scheme for refractory solid tumors, especially peritoneal dissemination from diffuse-type gastric cancer, ovarian cancer and pancreatic cancer.…”

Chimeric Antigen Receptor-Glypican-3 T-Cell Therapy for Advanced Hepatocellular Carcinoma: Results of Phase I Trials

“…In recent years, chimeric antigen receptor (CAR) T-cell therapy has achieved significant efficacy in the treatment of hematologic malignancies (22)(23)(24)(25)(26). Although a breakthrough in disease control using CAR T-cell therapy for solid tumors has yet to be achieved, researchers have observed encouraging antitumor activity in earlyphase clinical trials of therapies targeting IL13Ra2 (27), mesothelin (28), and claudin18.2 (29,30), suggesting the feasibility of CAR T-cell therapy for solid tumors.…”

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

“…Moreover, combination of lymphodepletion with cyclophosphamide and fludarabine resulted in better CAR T-cell expansion [92,118], higher serum CAR-T peak [119,120], but increased toxicity [90,119]. The recent data from the American Society of Clinical Oncology support these observations [47][48][49][50][51], as higher treatment efficacy was achieved with pre-infusion lymphodepletion. The factors significant for CAR T-cell therapy efficacy are summarized in Figure 2.…”