Chimeric Antigen Receptor-T Cells in Colorectal Cancer: Pioneering New Avenues in Solid Tumor Immunotherapy

Abstract

Colorectal cancer (CRC) remains a major global health burden, being one of the most prevalent cancers with high mortality rates. Despite advances in conventional treatment modalities, patients with metastatic CRC often face limited options and poor outcomes. Chimeric antigen receptor-T (CAR-T) cell therapy, initially successful in hematologic malignancies, presents a promising avenue for treating solid tumors, including CRC. This review explores the potential of CAR-T cell therapy in CRC by analyzing clinical trials and highlighting prominent CRC-specific targets. We discuss the challenges such as immunosuppressive microenvironment, tumor heterogeneity, and physical barriers that limit CAR-T efficacy. Emerging strategies, such as logic-gated and dual-targeting CAR-T cells, offer practical solutions to overcome these hurdles. Furthermore, we explore the combination of CAR-T cell therapy with immune checkpoint inhibitors to enhance T-cell persistence and tumor infiltration. As the field continues to evolve, CAR-T cell therapies hold significant potential for revolutionizing the treatment landscape of CRC.

FIG 1.

Overview of the CAR-T cell therapy process, highlighting the sequential steps from leukapheresis to CAR-T cell infusion. (1) T cells are isolated from the patient's peripheral blood through leukapheresis. (2) These cells are activated using anti-CD3/CD28 antibodies to stimulate their proliferation. (3) Genetic modification of the T cells is performed by inserting the CAR gene, enabling them to recognize tumor-specific antigens. (4) CAR-T cells are expanded ex vivo to achieve sufficient quantities for therapeutic use. (5) Before reinfusion, the patient undergoes lymphodepletion, typically via chemotherapy, to enhance CAR-T cell engraftment. (6) CAR-T cells are infused back into the patient, where they target and eliminate cancer cells expressing the CAR-specific antigen. CAR-T, chimeric antigen receptor-T.

FIG 2.

Barriers to effective CAR-T cell therapy in CRC. This figure outlines several key challenges impeding the efficacy of CAR-T cells in solid tumors such as CRC. (Top left) Immunosuppressive TME: the CRC microenvironment is rich in immunosuppressive cells, such as TAMs, Tregs, and MDSCs, which inhibit CAR-T cell function. (Top middle) Tumor heterogeneity: CRC tumors exhibit significant intratumoral heterogeneity, making it difficult for CAR-T cells to target all malignant clones effectively, as different subclones may express varying levels of the target antigen. (Top right) Antigen escape: tumor cells can downregulate or lose the expression of the targeted antigen, resulting in antigen escape, where CAR-T cells are no longer able to recognize and attack tumor cells. (Bottom left) Pharmacokinetics: CAR-T cell persistence and functional efficacy are influenced by pharmacokinetics, where an initial expansion phase may be followed by a decline in cell numbers and activity, limiting sustained therapeutic impact. (Bottom middle) Physical barriers: dense ECM and CAFs in the CRC tumor stroma create physical barriers that impede CAR-T cell infiltration and cytotoxic function within the tumor. (Bottom right) On-target, off-tumor effect: because of the expression of shared antigens between tumor and healthy tissues, CAR-T cells may inadvertently target normal cells, leading to off-tumor toxicity, which is a significant concern in the treatment of CRC. CAFs, cancer-associated fibroblasts; CAR-T, chimeric antigen receptor-T; CRC, colorectal cancer; ECM, extracellular matrix; MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; TME, tumor microenvironment; Tregs, regulatory T cells.

FIG 3.

Advancements in CAR-T cell therapies for CRC. This figure illustrates the various innovative CAR-T cell designs aimed at improving efficacy, specificity, and safety in the treatment of CRC. The diagram depicts several generations of CAR-T cell modifications. (1) Traditional CAR-T cells are engineered to target a single antigen on tumor cells. Although effective in hematologic malignancies, their efficacy in solid tumors is limited by antigen heterogeneity and the immunosuppressive TME. (2) Dual CAR-T cells use two distinct strategies. Tandem or bispecific CAR-T cells recognize two different tumor antigens simultaneously, enhancing their tumor specificity and reducing the chances of antigen escape. Logic-gated CAR-T cells use AND or OR gates, requiring multiple conditions (eg, the presence of two antigens) to trigger their activation, reducing the risk of off-tumor activity. (3) TME-modulating CAR-T cells include armored CAR-T cells, which secrete immune-stimulatory cytokines (eg, IL-12) to enhance their own function and reshape the TME to be more immunologically favorable. TRUCK CAR-T cells deliver cytokines directly into the TME, not only attacking the tumor but also stimulating a broader immune response within the hostile tumor environment. (4) Allogeneic CAR-T cells are derived from healthy donors, allowing for an off-the-shelf CAR-T cell product. Universal CAR-T cells within this group are engineered to avoid immune rejection and GvHD, which can occur when using donor-derived T cells. (5) Combination CAR-T cells integrate other approaches such as ICI combined with CAR-T cell therapy. Relevant clinical data, such as ORR and DCR, have been added where available, with NCT numbers included for reference to trials still lacking published results. CAR-T, chimeric antigen receptor-T; CDH17, cadherin 17; CEA, carcinoembryonic antigen; CRC, colorectal cancer; CRS, cytokine release syndrome; DCR, disease control rate; DLT, dose-limiting toxicity; EpCAM, epithelial cell adhesion molecule; GUCY2C, guanylyl cyclase C; GvHD, graft-versus-host disease; HD, high dose; HLA, human leukocyte antigen; ICANS, immune effector cell–associated neurotoxicity syndrome; ICI, immune checkpoint inhibitor; IL, interleukin; LGR5, leucine-rich repeat-containing G protein–coupled receptor 5; MSLN, mesothelin; NCT, National Clinical Trial; NKG2D, natural killer group 2 member D; ORR, overall response rate; scFv, single-chain variable fragment; SD, stable disease; TME, tumor microenvironment; TRUCK, T cells redirected for universal cytokine killing.