Cell Therapy for Colorectal Cancer: The Promise of Chimeric Antigen Receptor (CAR)-T Cells

Abstract

Colorectal cancer (CRC) is a global public health problem as it is the third most prevalent and the second most lethal cancer worldwide. Major efforts are underway to understand its molecular pathways as well as to define the tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs) or neoantigens, in order to develop an effective treatment. Cell therapies are currently gaining importance, and more specifically chimeric antigen receptor (CAR)-T cell therapy, in which genetically modified T cells are redirected against the tumour antigen of interest. This immunotherapy has emerged as one of the most promising advances in cancer treatment, having successfully demonstrated its efficacy in haematological malignancies. However, in solid tumours, such as colon cancer, it is proving difficult to achieve the same results due to the shortage of TSAs, on-target off-tumour effects, low CAR-T cell infiltration and the immunosuppressive microenvironment. To address these challenges in CRC, new approaches are proposed, including combined therapies, the regional administration of CAR-T cells and more complex CAR structures, among others. This review comprehensively summarises the current landscape of CAR-T cell therapy in CRC from the potential tumour targets to the preclinical studies and clinical trials, as well as the limitations and future perspectives of this novel antitumour strategy.

Recent findings on chimeric antigen receptor (CAR)-engineered immune cell therapy in solid tumors and hematological malignancies

“…Colorectal cancer (CRC) refers to colon and rectal epithelial tissue cancers that primarily affect the elderly and have a poor prognosis [ 153 ]. Various promising CAR T-cell-based therapeutic targets have been proposed in preclinical models for CRC, including CEA, EGFR, MUC1, NKG2DL, HER2, and CD133 with many therapeutic strategies [ 154 , 155 ]. Hedge et al published one of the first human studies utilizing first-generation retrovirally transduced CAR T-cells targeting tumor-associated glycoprotein (TAG)-72 in metastatic CRC.…”

Cardiotoxicity of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Pathophysiology, Clinical Implications, and Echocardiographic Assessment

“…Therefore, the chimeric antigen receptor is transferred in T cells, refined, and cryopreserved until patient administration. CAR-T therapy has shown dramatic results against hematologic and solid disorders, with a 70–90% response rate in relapsed/refractory conditions [ 1 , 7 , 8 , 11 ]. However, early trials suggested that the tremendous cytokine release might have profound clinical implications.…”

“…With the introduction of this treatment, concerns about cardiotoxicity were progressively evaluated. From the mechanistic point of view, the cytokine cascade and signaling mechanisms leading to inflammatory activation are known [ 4 , 5 , 6 , 7 , 8 ], but a better understanding of the macroscopic counterpart is warranted. Cardiac events might result in prolonged hospitalization, life-threatening adverse events, or even death.…”

How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes

“…While classic chemotherapeutic treatment regimens predominantly target the proliferation and survival of tumor cells directly, more recent immunotherapeutic approaches instead aim at supporting anticancer immunity by modulating the tumor microenvironment. Thus, the principle of immunotherapy is primarily to increase the number of tumor-infiltrating and tumor antigen-specific cytotoxic T lymphocytes (e.g., by adaptive cell transfer [ 18 , 19 ] or by optimized recruitment of systemic effector cells) and to increase their cytolytic activity (e.g., by checkpoint inhibitors [ 11 ] or by inhibition of immunosuppressive components). However, a large proportion of CRC patients show only a rather disappointing response to monotherapy with clinically established PD-1 checkpoint inhibitors [ 11 ].…”