CAR-T cells for Colorectal Cancer: Target-selection and strategies for improved activity and safety

Abstract

Chimeric antigen receptor-T (CAR-T) cell immunotherapy is a novel method that is genetically engineered to recruit T cells against malignant disease. Administration of CAR-T cells has led to progress in hematological malignancies, and it has been proposed for solid tumors like colorectal cancer (CRC) for years. However, this method was not living up to expectations for the intrinsic challenges posed to CAR-T cells by solid tumors, which mainly due to the lacking of tumor-restricted antigens and adverse effects following treatment. New approaches are proposed to overcome the multiple challenges to alleviate the difficult situation of CAR-T cells in CRC, including engineering T cells with immune-activating molecules, regional administration of T cell, bispecific T cell engager, and combinatorial target-antigen recognition. In this review, we sum up the current stage of knowledge about target-selection, adverse events like on/off-tumor toxicity, the preclinical and clinical studies of CAR-T therapy, and the characteristics of strategies applied in CRC.

Immunotherapy-Related Publications in Colorectal Cancer: A Bibliometric Analysis

“…This approach has shown promise in hematological malignancies [ 26 , 27 ], and it has also been advocated for solid tumors. However, there are no CAR-T cell treatments currently approved for CRC despite several studies that have entered clinical trials as a result of ongoing fundamental research efforts [ 28 ].…”

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

“…Costimulatory molecules are often administered with engineered T cells, including CD28 or 4-1BB (CD137) [ 92 ]. Low efficacy due to a lack of tumor-specific antigens and adverse events after CAR-T treatment of patients with solid tumors necessitates new approaches including the addition of immune-activating molecules on CAR-T cells, regional administration, bispecific engagers, and optimization of CAR structure [ 93 ]. Very few clinical studies evaluating TCR T cells are underway, but one ongoing trial is investigating the use of TCRs that were cloned from neoepitope-targeting CD8+ cells in the patient’s blood for treatment of solid tumors [ 94 ].…”

Landscape of Immunotherapy Options for Colorectal Cancer: Current Knowledge and Future Perspectives beyond Immune Checkpoint Blockade

“…CAR-T cell therapy has also been explored in the setting of CRC. CAR-T cells can be manipulated to target a series of tumor-associated antigens (TAAs) highly expressed by CRC tumors, most notably carcinoembryonic antigen CEA [122]. A phase I clinical trial (NCT02349724) indicated that CEA CAR-T cell therapy has some efficacy in mCRC patients with CEA positive tumors, with an acceptable toxicity profile.…”