Cancer Immunotherapies: A Rise in Immune System Activation

What are Immunotherapies?

Immunotherapies are a new category of cancer treatments that activate the immune system. Immune checkpoints defend healthy tissues, and cancer cells exploit these checkpoints to escape from the immune system. Before immunotherapies, cancer had been fought against with chemotherapy, radiotherapy, and oncogene-associated therapy. Within this therapy, the tumor microenvironment includes the injection of molecules which protect cells from viral infections and blockage of proteins similar to T-cells. T-cells defend the immune suppressive cells or inhibition of immune suppressive cells. Immune checkpoint inhibitors have been used in studies to treat melanoma, lung cancer, and other types of cancer. One type of cancer immunotherapy that has been developed is an adoptive T-cell transfer, which is when T-cells are changed to have receptors that allow T-cells to notice cancer cells and are placed back into patients. Cancer vaccines are more of a preventative approach than an actual treatment.

Pathways in the Immune System

The immune system can sometimes become overactive and start attacking healthy cells accidentally, causing autoimmune reactions. To prevent this from happening, there are immune checkpoints throughout the immune system. These checkpoints include the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway, and the programmed cell death protein 1 (PD-1) pathway. These pathways reside on the surface of all types of T-cells and specialized cancer cells. Their ligands, the cluster of differentiation 80 and the cluster of differentiation 86 (CD80 and CD86, respectively) for CTLA-4 and programmed death ligand 1 (PD-L1) for PD-1, are on the surface of healthy cells. When the T-cell is looking out for foreign bodies that may be malicious, they hit the brakes when their CTLA-4 or PD-1 receptors encounter their ligands (on the surface of healthy cells). Immune checkpoint inhibitors allow the immune system to drive as fast as it wants to trap any invaders.

The first generation of new immunotherapies relates to antibodies that inhibit certain immune checkpoint molecules like cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein (PD-1) and its respective ligand PD-L1.

How the Immune System Functions

Cancer cells can exploit immune checkpoints by suppressing the host’s immune system, resulting in the lack of activation of the T-cells and the rest of the immune system not attacking the foreign cancer cells. The immune checkpoint pathways are a negative process since the immune system is stopping while the inhibitor inhibits this inhibitory pathway; the two negative processes cancel out and activate the immune system. The immune system eventually becomes imbalanced with immune checkpoint inhibitors like antibodies suppressing immune checkpoints. As a result, immune-related adverse events (IRAEs), or dysfunction of toxicities in the immune system, were formed mostly in the gut, skin, liver, lungs, endocrine system, and other tissues in the body. Even though there were steroids that could put the immune system back into balance, the immunosuppression caused by the blockage of PD-1/PD-L1 or CTLA-4 would be reversed.

History of Immunotherapies

Regarding the history of immunotherapy, William Coley first discovered the idea of regulators blocking certain immune checkpoints in 1891. He figured it out by injecting sarcoma patients with bacteria that copied an immune response against tumors, resulting in him noticing a connection between the cells in the immune system and enemy cells. Without the influence of cancer cells, T-cells can detect the difference between self and foreign cells. Dendritic cells help the process by presenting to T-cells what antigens are present in the body. However, with cancer cells mutating themselves, they can coat their surfaces with antigens and receptors that are considered part of the host. As a result, T-cells cannot identify that cancer cells are foreign and conduct an immune response. Cancer cells also create neoantigens so that the body’s host’s defenses can recognize that the cancer cells are not part of the body. The body’s immune system can recognize that the cancer cells are foreign but with the cancer cells gaining immunosuppressive abilities, there is no immune attack triggered against the cancer cells. Two groups led by James Allison and Jefferson Bluestone discovered the inhibitory properties of CTLA-4. CTLA-4, like other protein receptors, works by attaching to the other protein receptors on the cell surface of T-cells by competing with CD28, a costimulatory protein on the surface of T-cells that triggers the activation of T-cells, to connect to other costimulatory proteins CD80 and CD86. From this knowledge, Allison concluded that an antibody or other molecule could be used to block the interaction of immune checkpoints.

Current Treatments

Immune checkpoint inhibitors have been more commonly used for cancer treatments as time has progressed. The inhibitors that have been approved by the FDA as of now include the PD-1 inhibitors nivolumab and pembrolizumab; PD-L1 inhibitors atezolizumab, durvalumab, and avelumab; and the CTLA-4 inhibitor ipilimumab.

Thank you for reading!

-Siri Nikku



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