Dr Shitara on Satri-Cel in Advanced Gastric/GEJ Adenocarcinoma and Pancreatic Cancer

“The study clearly suggested the activity of CAR T-cell therapy even for GI cancer, but you can still improve outcomes in terms of duration or how to change nonresponders to responders. One biomarker analysis from the same group showed the infiltration of progenitor-like exhausted T cells in responders, and more fibroblasts and epithelial-to-mesenchymal transition signatures in nonresponders. Maybe we need to combine [satri-cel] with other agents to improve its durability or change the tumor microenvironment by the depletion of immunosuppressive cells.”

Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East, discussed updated findings from an open-label, multicenter phase 1b/2 trial evaluating satricabtagene autoleucel (satri-cel, CT041), an autologous CAR T-cell therapy, in patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma and pancreatic cancer.

This study is one of the first to systematically assess the efficacy, safety, and pharmacokinetics of CAR T-cell therapy in solid tumors of the gastrointestinal (GI) tract. The trial demonstrated that satri-cel exhibited antitumor activity in heavily pretreated patients with gastric/GEJ adenocarcinoma and pancreatic cancer, supporting the feasibility of this approach in GI malignancies. However, Shitara noted that outcomes remain heterogeneous, with some patients achieving meaningful responses and others deriving limited benefit. Biomarker analyses provided mechanistic insight: responders demonstrated higher infiltration of progenitor-like exhausted T cells within the tumor microenvironment, whereas nonresponders were characterized by fibroblast enrichment and epithelial-to-mesenchymal transition signatures. These findings underscore the role of the tumor microenvironment in modulating CAR T-cell therapy efficacy and point to a need for rational combination strategies.

To enhance durability and broaden responses, several investigational approaches are under evaluation. Novel CAR T constructs, such as armored CAR T cells engineered with a dominant-negative TGF-β receptor, aim to overcome inhibitory signaling within the tumor milieu and have shown encouraging signals in hepatocellular carcinoma. Similarly, CAR T platforms incorporating cytokines, such as interleukin-15, have demonstrated deeper tumor reductions compared with conventional CAR T constructs. Alternative administration strategies, including intraperitoneal delivery, are also being explored to improve the therapeutic index and mitigate systemic toxicity.

Beyond product design, Shitara emphasized challenges associated with autologous therapy manufacturing in solid tumors. The complexity and time-intensive nature of individualized production may limit broad applicability. Allogeneic CAR T-cell therapies represent one potential solution, enabling off-the-shelf use, though graft-vs-host disease remains a safety concern despite evidence of manageable toxicity in early lymphoma trials. Emerging in vivo CAR T technologies, which rely on viral or nonviral vectors to generate CAR T cells directly within patients, may further simplify production and expand access.

Although still in early development, satri-cel and next-generation CAR T strategies highlight the promise of cellular therapies in GI oncology. Shitara concluded that although widespread clinical adoption is not imminent, the next 3 to 4 years may clarify the role of CAR T-cell therapy in improving outcomes for patients with advanced gastric/GEJ adenocarcinoma and pancreatic cancer.