Colorectal Cancer Immunotherapy: Options and Strategies

Abstract

Colorectal cancer is the third most common cancer in the world with increasing incidence and mortality rates globally. Standard treatments for colorectal cancer have always been surgery, chemotherapy and radiotherapy which may be used in combination to treat patients. However, these treatments have many side effects due to their non-specificity and cytotoxicity toward any cells including normal cells that are growing and dividing. Furthermore, many patients succumb to relapse even after a series of treatments. Thus, it is crucial to have more alternative and effective treatments to treat CRC patients. Immunotherapy is one of the new alternatives in cancer treatment. The strategy is to utilize patients' own immune systems in combating the cancer cells. Cancer immunotherapy overcomes the issue of specificity which is the major problem in chemotherapy and radiotherapy. The normal cells with no cancer antigens are not affected. The outcomes of some cancer immunotherapy have been astonishing in some cases, but some which rely on the status of patients' own immune systems are not. Those patients who responded well to cancer immunotherapy have a better prognostic and better quality of life.

Keywords: FDA; T-cells; antibodies; colorectal carcinoma; cytokines; immunotherapy; treatments.

FIGURE 1

Monoclonal antibodies in cancer. Monoclonal antibodies (mAbs) such as Cetuximab are designed to target tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) that are abundant in cancer cells surface. The signals produced by receptor activities mediated immune cells toward malignant sites thus produced immune responses that lead to cell death to eradicate the tumor.

FIGURE 2

Deactivated (A) and activated (B) T cell-based on immune checkpoint inhibitors mechanism. During resting of T cell (deactivated T cell), CTLA4 and PD1 receptors on T cell surface binds to CD80 and CD86 on the antigen-presenting cell (APC) such as dendritic cell and PDL-1 and PDL-2 on cancer cell, respectively, while T cell receptor (TCR) binds to major histocompatibility complex (MHC) with the presence of peptide. Thus, no immune response triggered to kill cancer cells. T cells will only be activated with the presence of blockade or inhibitor on CTLA4 and PD1 receptors. Hence, a CTLA4 inhibitor known as Ipilimumab and PD1 inhibitor of Nivolumab functioned to block those receptors and elicit immune response thus leading to the apoptosis of cancer cells.

FIGURE 3

CAR-T cells approach to treating cancer. T cells were firstly isolated either from the patient itself or HLA matched donor through apheresis. Next, the cells were cultured and a genetically modified chimeric antigen receptor (CAR) was inserted into it and these T cells are now known as CAR-T cells. This modification is necessary to enhance T cells’ ability to recognize tumor-associated antigens (TAAs) such as CD19 and avoid the major histocompatibility complex class I (MHC I) restriction recognition on the cancer cell. Upon binding, FAS ligand (FASL) and TNF-related apoptosis-inducing ligand (TRAIL) promotes cytotoxicity by releasing effector cytokines and lead to cancer cell apoptosis.