Introduction: Gastrointestinal (GI) cancers remain a significant challenge in oncology, with conventional therapies often yielding limited success in advanced cases. Recent advances in cellular therapies, particularly chimeric antigen receptor T-cell (CAR-T) therapy, have shown promise in targeting GI malignancies. Dr. Kohei Shitara delves into the latest advancements, challenges, and future perspectives of these innovative therapies.CAR-T Therapy in GI Cancers
Adoptive T-cell therapies, including CAR-T, TCR-T, and tumor-infiltrating lymphocyte (TIL) therapies, are being explored for their potential to improve outcomes in GI cancers. CAR-T therapy, which involves engineering T cells to recognize tumor-associated antigens, has demonstrated success in hematologic malignancies but faces challenges in solid tumors like GI cancers due to tumor heterogeneity and the immunosuppressive tumor microenvironment.
CLDN18.2-Targeted CAR-T Therapy (CT041, Satri-cel)
A promising development in CAR-T therapy for GI cancers is the CLDN18.2-targeted approach. CLDN18.2, an adhesion molecule highly expressed in gastric and pancreatic cancers, has become a viable target. A Phase 1 clinical trial evaluating CT041 (Satri-cel) demonstrated an objective response rate (ORR) of 39% across all patients, with a higher ORR of 55% in gastric cancer and 20% in pancreatic ductal adenocarcinoma (PDAC). Median progression-free survival (mPFS) was reported at 4.4 months for all patients and 5.8 months specifically in gastric cancer cases (N=59).
The study also showed that the median persistence of CAR-T cells was 4 weeks, compared to only 2 days in a second infusion. Toxicity profiles indicated that cytokine release syndrome (CRS) of grade 1-2 occurred in 97% of cases, but no grade 3 events were reported. Additionally, gastrointestinal toxicities such as nausea (67%) and vomiting (53%) were observed. The trial also noted that CAR-T cells were detected in ascites and pleural effusion, confirming distribution beyond the bloodstream.
Challenges and Advances in CAR-T Therapy for Solid Tumors
Despite promising results, CAR-T therapy in GI cancers faces multiple challenges. On-target, off-tumor toxicity is a concern as many tumor-associated antigens are also present in normal tissues, increasing the risk of adverse effects. Intratumoral heterogeneity results in variability in antigen expression, leading to resistance. Additionally, the immunosuppressive tumor microenvironment impairs CAR-T cell efficacy.
Several strategies are being investigated to overcome these obstacles. Armored CAR-T cells such as the GPC3-specific TGFβRIIDN CAR-T (C-CAR031) aim to counteract immunosuppression and have demonstrated increased T-cell persistence. Prime CAR-T (TAK-102), which expresses IL-7 and CCL19, enhances T-cell infiltration into solid tumors and extends cellular persistence. Multi-targeting CAR-T cells are being developed to address tumor antigen heterogeneity and reduce antigen escape. Hypoxia-responsive CAR-T cells are being evaluated for their ability to target tumor cells in low-oxygen environments, with intraperitoneal infusion showing improved tumor control compared to intravenous administration. In vivo CAR-T engineering is an emerging approach aimed at streamlining the production process and improving accessibility.
Beyond CAR-T: Alternative Cellular Therapies
Given the limitations of CAR-T therapy, alternative cellular approaches are being explored for GI cancers. CAR-M, or macrophage therapy, targets HER2+ cancers, with CT-0508 utilizing macrophages to enhance tumor clearance. Invariant Natural Killer T (iNKT) cells such as AgenT-797 are being tested as allogeneic therapies with promising preclinical results. Tumor-infiltrating lymphocyte (TIL) therapy is being investigated in clinical trials for GI malignancies, showing durable responses in subsets of patients. TCR-T cell therapy, which targets tumor-specific peptides presented by MHC molecules, is currently being evaluated in Phase 2 trials for colorectal cancer (CRC), with interim results indicating disease control in 40% of treated patients.
Future Perspectives
As clinical trials advance, CAR-T therapy is expected to play an increasingly significant role in treating GI cancers. Key areas of focus include optimizing safety, improving persistence, and broadening applicability to a wider range of solid tumors. Strategies such as modifying CAR constructs, utilizing combination therapies with immune checkpoint inhibitors, and leveraging gene editing to enhance T-cell function are actively being explored. While challenges remain, ongoing innovations suggest that cellular therapy could become a viable treatment option for patients with refractory GI cancers.
Conclusion
CAR-T therapy represents a paradigm shift in GI cancer treatment, with CLDN18.2-targeted approaches showing particular promise. Despite significant hurdles, advancements in multi-targeting strategies, armored CAR-T cells, and alternative cellular therapies are paving the way for improved patient outcomes. The future of GI cancer treatment may increasingly rely on personalized cellular therapies, offering hope for more effective and durable responses. Continued clinical evaluation and refinement of these therapies will be essential in establishing them as standard treatments for GI cancers.
