Cell-Based Therapies in GI Cancers: Current Landscape and Future Directions

Area of Science:

• Oncology
• Immunotherapy
• Gastroenterology

Background:

• Cell-based therapies are established for hematologic malignancies and show promise in solid tumors like melanoma.
• Evidence for cell-based therapy success in gastrointestinal (GI) cancers is emerging.
• CLDN18.2 is a promising target for gastric cancer (GC) due to its specific expression.

Purpose of the Study:

• To review the current status and future potential of cell-based therapies for GI cancers.
• To highlight challenges and opportunities in developing targeted cell therapies for GI malignancies.
• To discuss next-generation approaches and alternative cell types for GI cancer treatment.

Main Methods:

• Review of existing literature on cell-based therapies in oncology, focusing on GI cancers.
• Analysis of challenges including tumor microenvironment, target heterogeneity, and toxicity.
• Exploration of emerging cell therapy strategies like next-generation CAR-T, macrophage, and NK cell therapies.

Main Results:

• Chimeric antigen receptor T-cell (CAR-T) therapies targeting CLDN18.2 have shown initial tumor shrinkage in GC patients.
• Durable responses remain infrequent due to CAR-T exhaustion and target molecule heterogeneity.
• On-target, off-tumor toxicities are a concern for therapies targeting tissue-associated antigens.

Conclusions:

• Next-generation CARs are being developed to overcome resistance mechanisms.
• Adoptive macrophage and natural killer (NK) cell therapies offer potential efficacy and off-the-shelf production.
• Advanced neoantigen prediction and T-cell activation strategies could advance TIL and T-cell receptor-T therapies in GI cancers, potentially transforming treatment landscapes.