What is the role of immunotherapy drugs in treating colorectal (colon and rectal) cancers?

Cancer immunotherapy aims to enhance immune system effectiveness so that malignant cells are identified and destroyed. Previously, metastatic colorectal cancers (mCRC) were considered nonimmunogenic , meaning the immune system could not adequately target colorectal cancer cells. However, substantial research showing that extensive infiltration of colon cancer tissue by T cells, important immune system components—medically called tumor-infiltrating lymphocytes (TIL)—contributes to better survival suggested that the immune system might play a role in colorectal cancer.

Tumor-specific substances composed of proteins are called tumor antigens . Recent studies indicate that immune responses against tumor antigens contribute positively to survival. However, tumor-associated antigens found in large quantities in colorectal cancer cells also occur in normal cells. Immune suppression preventing attacks on the body’s own antigens may therefore also inhibit responses against cancer cells.

In hereditary colorectal cancer (Lynch syndrome), one or more DNA repair genes are mutated. Nonhereditary colorectal cancers, medically termed sporadic , also show mutations in these genes in 15-20 percent of cases. A characteristic genetic feature is a very large number of DNA replication errors (mismatch) and high genomic instability (microsatellite instability) .

Tumors with defective DNA repair systems have greater numbers of mutations than other tumors. Immune responses are more effective against the neoantigens resulting from these mutations. The body recognizes these antigens as foreign and tumor-associated.

The immune system attacking tumor cells

The stages required for the immune system to attack tumor cells are:

1. Recognition of the tumor
2. Presentation of tumor antigens to T cells, the immune system’s fighting cells
3. Activation of T cells
4. T cells attacking tumor cells

Our body has immune checkpoints to prevent autoimmunity (the immune system attacking normal body cells) and harmful inflammation. In malignant tumors, these checkpoints allow tumors to evade immunity and become aggressive. For example, the best-known immune checkpoint in metastatic colorectal cancer is PD1 (Programmed cell Death receptor 1). PD-1 activity is very high in T cells. When the immune system recognizes a tumor cell, PD-1 binds PDL-1, which may occur on the tumor cell surface, rendering the T cell inactive. Thus, no immune response develops against the tumor.

Defective DNA repair (MisMatch Repair (MMR) deficiency) in mCRC has prompted many studies suggesting that immunotherapiesmay be effective. According to these studies:

• In 2016, a phase-2 study presented at the American Society of Clinical Oncology (ASCO) meeting reported that, in mCRC patients with extensive genomic instability called MSI, the immune checkpoint inhibitor pembrolizumab produced a 50 percent treatment response and 89 percent disease control. No significant response occurred in colorectal cancers without MSI. Interestingly, LS patients responded less to immunotherapy than other MSI-positive patients.
• Another study at the same meeting found positive preliminary responses in MSI-positive mCRC patients receiving another immune checkpoint inhibitor, nivolumab.

In conclusion, New-generation immunotherapies called immune checkpoint inhibitors are candidates to become part of standard treatment for metastatic colorectal cancers with microsatellite instability resulting from MMR deficiency. However, most patients with metastatic colorectal cancer have microsatellite-stable cancers; future research will clarify why immunotherapies fail to produce the desired results in these patients.