CAR T-Cell Therapy: Clinical Development and Regulatory Pathways in Gastrointestinal and Neuroendocrine Carcinomas

A new investigational therapy for advanced gastrointestinal cancers, CHM-2101, has been granted Fast Track Designation by the US Food and Drug Administration (FDA), highlighting its potential to address a significant unmet medical need. Developed by Chimeric Therapeutics, CHM-2101 is an autologous chimeric antigen receptor (CAR) T-cell therapy that targets Cadherin 17 (CDH17), a biomarker linked to poor prognosis and metastatic progression in common gastrointestinal tumors. These malignancies, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs), often prove resistant to standard treatments once they spread, leaving patients with limited therapeutic options.

CHM-2101 is a novel, third-generation CAR T-cell therapy originating from research conducted by Xianxin Hua, MD, PhD, at the University of Pennsylvania. Early preclinical work funded by the Neuroendocrine Tumor Research Foundation (NETRF) demonstrated striking results: in 2022, Hua and colleagues published data in Nature Cancer showing complete eradication of tumors in mouse models across seven cancer types. This foundational work set the stage for advancing CDH17 CAR T-cell therapy into human trials.

The FDA’s decision to grant Fast Track Designation was based on its assessment of CHM-2101’s potential to improve outcomes for patients with GEP-NETs who have progressed after at least one line of therapy in advanced or metastatic settings. Fast Track status is reserved for therapies that treat serious conditions and fill an unmet medical need, offering sponsors benefits such as more frequent meetings and written communication with the FDA, and the possibility of Accelerated Approval, Priority Review, or Rolling Biologics License Application (BLA) submission.

This designation represents a critical step forward for patients with advanced neuroendocrine and gastrointestinal cancers. CDH17 is highly expressed in these tumors and plays a role in promoting metastasis. Targeting this molecule with engineered T cells may disrupt tumor growth in ways conventional therapies cannot, offering a new mechanism to combat disease progression.

The investigational therapy is now being evaluated in a Phase 1/2 clinical trial (NCT06055439), a two-stage study designed to determine an optimal dose for Phase 2 and to assess safety and preliminary efficacy, including objective response rates. The trial is enrolling patients with advanced colorectal cancer, gastric cancer, and intestinal NETs who have relapsed or are refractory to standard treatments. The Phase 1 portion will enroll up to 15 patients to establish dose levels before expanding into indication-specific Phase 2 cohorts. So far, five patients have received treatment. The study is underway at multiple leading centers, including the University of Pennsylvania, University of Chicago, Sarah Cannon Research Institute, and Emory University’s Winship Cancer Center.

The development of CHM-2101 underscores the impact of long-term investment in foundational research. NETRF has supported the exploration of CDH17 CAR T-cell technology at the University of Pennsylvania since 2014. This sustained commitment has now translated into a clinical-stage program with the potential to transform care for patients facing particularly aggressive gastrointestinal malignancies.

With this regulatory milestone, Chimeric Therapeutics anticipates increased engagement with the FDA, supporting efficient progression through the clinical development pipeline. For patients and clinicians managing advanced gastrointestinal cancers, CHM-2101 represents a new avenue of investigation that may one day expand the arsenal of effective therapies against these challenging diseases.