Adoptive cell therapy in colorectal cancer: Advances in chimeric antigen receptor T cells

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide and remains a major treatment challenge, particularly in advanced and metastatic stages. Current standard treatments have limited efficacy, underscoring the urgent need for innovative strategies. Adoptive cell therapy (ACT), which involves in vitro expansion or genetic engineering of immune cells, is a promising approach to bolster anti-tumor immune responses. Key ACT modalities include chimeric antigen receptor (CAR) T cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-engineered T cells. CAR-T cell therapy has shown success in hematological malignancies but faces significant challenges in solid tumors like CRC. These challenges include antigen heterogeneity, an immunosuppressive tumor microenvironment, on-target off-tumor toxicity, among other factors. To address these limitations, combinatorial approaches, such as immune checkpoint inhibitors, cytokines, and advanced gene-editing tools like CRISPR/Cas9, are being actively explored. These strategies aim to enhance CAR-T cell specificity, improve resistance to immunosuppressive signals, and optimize in vivo functionality. This review summarizes ACT approaches for CRC, with a focus on CAR-T therapy. It briefly introduces TILs and TCR-T cells, while emphasizing the major challenges faced by CAR-T therapy in solid tumors and discusses potential strategies to improve therapeutic outcomes.

Keywords: Colorectal cancer; Adoptive cell therapy; Immunotherapy; Chimeric antigen receptor T cells; Tumor-infiltrating lymphocytes; T-cell receptor-engineered T cells

Core Tip: This review discusses adoptive cell therapy approaches for colorectal cancer (CRC), emphasizing chimeric antigen receptor (CAR) T cell therapy. Despite its success in hematological malignancies, CAR-T therapy faces challenges in solid tumors like CRC, including antigen heterogeneity, tumor microenvironment immunosuppression, and on-target off-tumor toxicity. In this review, we explore combinatorial strategies, such as immune checkpoint inhibitors and CRISPR/Cas9 gene editing, to overcome these challenges and enhance CAR-T cell specificity, resistance to immunosuppressive signals, and in vivo functionality.