GUCY2C‐Directed CAR‐T Cell Therapy for Upper‐GI Cancers

Abstract

Gastrointestinal (GI) cancers have dismal 5-year survival rates (19% in esophagus, 30% in stomach, 9% in pancreas, 65% in colorectal) and account for 20% of all cancer-related deaths. Development of safe and effective therapies is limited, and the impact of groundbreaking immunotherapies has been only minor for GI cancers. The intestinal epithelial protein, guanylyl cyclase C (GUCY2C) is found in nearly all primary and metastatic colorectal cancers and about 65% of pancreatic, gastric, and esophageal cancers. Disruption of epithelial tight junctions, cell polarity, and apical localization of GUCY2C makes it a desired target for systemic agents in tumor tissues while leaving normal tissues unaffected. Indeed, we have safely translated GUCY2C-targeted vaccines into clinical trials to prevent GI cancer recurrence in early-stage patients. CAR-T cell therapy employs bulk T cells of unknown specificity obtained from patients, engineered to express chimeric antigen-specific receptors (CARs), and administered to the patient to mediate remarkable antitumor effects for advanced hematologic cancers. We have generated GUCY2C-directed CAR-T cells which produce effector cytokines and lyse colorectal cancer cell lines. The joint safety and antitumor efficacy of GUCY2C-specific CAR-T cells were demonstrated in mice receiving CAR-T cells directed towards mouse GUCY2C. Here, we established patient-derived xenograft (PDX) models in mice by surgical implantation of GI cancer specimens and a clinical manufacturing process to explore the efficacy of GUCY2C-directed CAR-T cells that can be translated to GI cancer patients. While GUCY2C was present in nearly all colorectal cancer specimens collected by surgical resection, it was present in only 33% of gastroesophageal resection samples. Interestingly, those upper GI patients with detectable GUCY2C were treatment-naïve, while neoadjuvant-treated patients lacked viable tumor, revealing neoadjuvant therapy as a significant barrier to upper GI cancer model generation (neoadjuvant chemoradiation is uncommon in colon cancer patients). In contrast, 66% of gastroesophageal specimens collected by endoscopic biopsy in treatment-naïve patients express GUCY2C and >50% successfully formed PDX models. Gastroesophageal adenocarcinoma PDX models were histologically similar to their matched primary tumors and retained GUCY2C expression. Importantly, GUCY2C-directed CAR-T cells controlled GI cancer PDX growth, maintaining a >12-fold reduction in tumor volume compared to control and in some cases produced complete tumor elimination. In the context of previously established safety in mouse models, these studies support future translation of GUCY2C CAR-T cell therapy to patients with advanced upper-GI cancers.