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

Figure 1

Schematic diagram of chimeric antigen receptor-T cell construction and preparation. Chimeric antigen receptor (CAR)-T therapy involves isolating T cells from the patient’s blood, genetically engineering them to express CARs, and expanding the modified cells in vitro. After lymphodepleting therapy, the engineered CAR-T cells are infused back into the patient, where they recognize and eliminate tumor cells. PBMC: Peripheral blood mononuclear cell; CAR: Chimeric antigen receptor; scFv: Single-chain variable fragments; VL: Variable region of light chain; VH: Variable region of heavy chain. (Created with BioRender.com).

Figure 2

Schematic diagram of tumor-infiltrating lymphocytes construction and preparation. The process includes tumor digestion and tumor-infiltrating lymphocyte (TIL) isolation, interleukin (IL)-2-mediated culture and expansion, tumor antigen recognition assessment via enzyme linked immune spot assay, and rapid expansion using activating antibodies or magnetic beads. Expanded TILs are cryopreserved and transferred to treatment centers. Before infusion, patients receive lymphodepleting chemotherapy, followed by IL-2 administration to stimulate TIL proliferation and activation. TIL: Tumor-infiltrating lymphocyte; IL: Interleukin; ELISPOT: Enzyme-linked immune spot assay; CD: Cluster of differentiation. (Created with BioRender.com).

Figure 3

Schematic diagram of T-cell receptor-T cell construction and preparation. T-cell receptor (TCR)-T cell therapy involves genetically modifying T cells to express tumor-specific TCRs, enhancing immune recognition of tumor antigens presented by human leukocyte antigen (HLA) molecules. The process includes tumor and blood sample collection, antigen identification via proteomics and sequencing, T cell stimulation and selection using HLA-I tetramer staining, TCR gene sequencing and cloning, and lentiviral transfection to generate engineered TCR-T cells. These cells are expanded and reinfused into the patient to specifically target and eliminate tumor cells. TCR: T-cell receptor; IFN: Interferon; TNF: Tumor necrosis factor; APC: Antigen-presenting cell; PBMC: Peripheral blood mononuclear cell. (Created with BioRender.com).

Figure 4

Challenges in adoptive cell therapy for colorectal cancer. Schematic diagram of the challenges in adoptive cell therapy for colorectal cancer, including immune evasion, immunosuppressive tumor microenvironment, insufficient immune cell infiltration, antigen heterogeneity, off-target effects, cytokine release syndrome, and immune effector cell-associated neurotoxicity syndrome. TME: Tumor microenvironment; CRS: Cytokine release syndrome; ICANS: Immune effector cell-associated neurotoxicity syndrome. (Created with BioRender.com).