Monoclonal antibodies and chimeric antigen receptor (CAR) T cells in the treatment of colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Besides common therapeutic approaches, such as surgery, chemotherapy, and radiotherapy, novel therapeutic approaches, including immunotherapy, have been an advent in CRC treatment. The immunotherapy approaches try to elicit patients` immune responses against tumor cells to eradicate the tumor. Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells are two branches of cancer immunotherapy. MAbs demonstrate the great ability to completely recognize cancer cell-surface receptors and blockade proliferative or inhibitory pathways. On the other hand, T cell activation by genetically engineered CAR receptor via the TCR/CD3 and costimulatory domains can induce potent immune responses against specific tumor-associated antigens (TAAs). Both of these approaches have beneficial anti-tumor effects on CRC. Herein, we review the different mAbs against various pathways and their applications in clinical trials, the different types of CAR-T cells, various specific CAR-T cells against TAAs, and their clinical use in CRC treatment.

The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy

“…Another form of ACT, chimeric antigen receptor (CAR) T cell therapy, has recently been introduced into early clinical trials for the treatment of CRC [132]. CAR T cells are also designed to target specific antigens associated with cancer cells to induce cell death [133]. For this purpose, T cells are extracted from the patients' blood, then they are genetically engineered to express chimeric immunoreceptors (CAR) and re-introduced to recognize and eliminate cancer cells more efficiently.…”

Advances and new frontiers for immunotherapy in colorectal cancer: Setting the stage for neoadjuvant success?

“…Other potential targets undergoing clinical studies include EGFR (HER-2) (ClinicalTrials.gov: NCT03542799, NCT03740256, and NCT04660929), mesothelin (ClinicalTrials.gov: NCT04503980), guanylyl cyclase C (GUCY2C), and mucin 1 (MUC1), with most of the studies still in an animal model or early phase of clinical trials. 80 CAR-T cell-targeting neoantigen can overcome off-target actions and minimize side effects, as the strategy can target antigens that are exclusively expressed on the surface of that patient's tumor cells (ClinicalTrials.gov: NCT03970382). Major challenges in the application of CAR cells in solid tumors include physical barriers surrounding cancer cells leading to insufficient infiltration, immunosuppressive TME, and barriers on logistics and cost of the treatment.…”

Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?

“…Besides, numerous molecular markers and receptors such as VEGF, EGFR, insulin-like growth factor-1 receptor (IGF-1R), human epidermal growth factor receptor-2 (HER2), integrins, mucin 5AC (MUC5AC), death receptor-5 (DR5), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD1) are overexpressed in the CRCME (35)(36)(37)(38)(39)(40)(41)(42)(43). Hence, immunotherapy targeting these molecules could be a promising therapeutic candidate for CRC treatment (18). Various immunotherapy methods, including monoclonal antibodies (mAbs), immune-checkpoint inhibitors (ICIs), adoptive T cell therapy (ACT), and cancer vaccines, are currently used in CRC (44).…”

“…Mutations in MMR, POLE, and KRAS, along with mutations in BRAF, NRAS, and other genes, cause high heterogeneity in the treatment response hindering CRC treatment ( 16 , 17 ). Therefore, the development of new effective treatment strategies for CRC seems necessary ( 18 ).…”