A Crash Course on Immunotherapy

Illustrated by Angela Chen

Our immune system has amazing capabilities. From macrophages that ‘eat’ microbes to plasma cells which produce specific antibodies, numerous cell types work in conjunction to eliminate pathogens from the body. Equipped to target a wide range of foreign threats, the immune system’s T cells are especially powerful and adaptable, even able to recognize internal danger as well. The capabilities of the human immune system can be leveraged to target cancers, leading to the advent of a new form of cancer treatment: immunotherapy.

The immune system can be broken down into innate and adaptive components. The innate immune system protects the body non-specifically, for example using the skin as a physical barrier or cells like macrophages to engulf pathogens. (10) The adaptive immune system, however, targets specific pathogens using two main types of cells: B cells and T cells. B cells produce proteins called antibodies that bind to and neutralize foreign antigens, which are molecules produced by the pathogen. On the other hand, certain types of T cells recognize foreign antigens directly and destroy cells which carry them. (9) The two main aspects of immunotherapy involve activating existing anti-tumor T cells and engineering novel T cells to target cancer-specific antigens. 

The first major aspect of immunotherapy involves immune checkpoint blockade. Regulatory checkpoints are necessary as a form of checks and balances, to ensure that harmful overstimulation of the immune system doesn’t occur. Activation of T cells therefore involves competing inhibitory and stimulatory signals. (4) Immune checkpoint blockade uses the selective targeting of T cell proteins which suppress T cell activity using antibodies, allowing these cells to more effectively target cancer cells. The most prominent targetable receptors are cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). (3)

CTLA-4 is a cell surface protein which inhibits T cell proliferation and activation. (3) Early experiments showed that blocking CTLA-4 with an antibody in animals led to a promising decrease in tumor size. (4) Initial results of similar studies in humans pointed to improved cancer outcome, yet blocking CTLA-4 led to a wide range of inflammatory side effects. (5, 6) Most importantly, an anti-CTLA-4 antibody was found to have a significant positive effect on survival when compared to standard chemotherapy. (7) Blockade of CTLA-4 can be powerful, although the potential risks are significant.

Like CTLA-4, PD-1 is a protein on the surface of T cells which is responsible for T cell inhibition by binding to the receptor PD-L1 on the surface of tumor cells (3). After T cells recognize a tumor antigen, signaling molecules called cytokines are produced. (3) Cancer cells respond to this by increasing expression of PD-L1, which then suppresses the T cell response. (3) Because of this complex and specific pathway, blockade of PD-1 results in less toxicity and greater specificity for anti-tumor T cells, which minimizes damage to other cells in the body. (8) Since 2006, numerous anti-PD-1 antibodies have been developed for various human cancers, with relatively high response rates and low toxicities (3). 

Additionally, cancer cells express a wide range of targetable cell surface markers. Genome sequencing studies have identified tumor-specific antigens expressed across individuals and cancers. (1) Engineering T cells to express receptors for these antigens is a key goal of immunotherapy, with the two main models being T cell receptor (TCR) and chimeric antigen receptor (CAR) T cells. 

TCRs bind to foreign peptides presented to them either by other immune cells or tumor cells. T cells expressing novel TCRs can be used to target cancer-associated antigens, such as the B cell protein CD19 in certain subtypes of lymphoma. (11) The main problem with this method is the risk of targeting proteins that are shared between tumor cells and normal, healthy cells. Past studies utilizing TCRs have shown damaging side effects because of the targeting of normal cells, although the toxicity level can be low depending on the antigen targeted. (11)

CARs are composed of various antigen-binding domains from antibodies, TCRs, and other immune cell receptors. (11) Cancer cells often lose the tools necessary to present their antigens to T cells, since this allows them to evade the immune system. A major advantage of CAR T cells is that they can recognize cancer antigens regardless of whether the cancer cells have lost the tools necessary to be recognized by the immune system. (11) In 2011, CAR T cells targeting CD19, a protein highly expressed in B cell-associated cancers, showed successful results. (11) This target was especially effective in relapsed leukemia patients.

However, CAR T therapies have inherent problems. The first major problem is tumor evasion. In tumor evasion, the population of tumor cells can evolve to survive the therapy. For example, in the anti-CD19 studies, some tumor cells lost the part of the CD19 protein which the CAR T cells targeted. (11) Relapse was correlated with this loss, showing that the effectiveness of CAR T can be limited by the natural evolution of tumor cells. (11) Additionally, CAR T therapies can be extremely toxic. CAR T therapies targeting the ERBB2/HER2 protein, a receptor overexpressed in several different kinds of cancer, led to the fatality of the first patient tested. This toxicity was caused by the presence of normal cells expressing ERBB2 in the lung (11) A therapy targeting carbonic anhydrase 9 (CAIX), a protein frequently overexpressed in renal cell carcinoma, led to similar toxicities due to expression of the protein in normal cells. (11) Finding proteins uniquely expressed on cancer cells, and not on normal cells, would allow for the specific targeting of tumor cells by CAR T.

Additionally, mutations in tumor cells can produce mutant proteins expressed on the cell surface, known as neoantigens. Neoantigens are patient-specific, since they result from tumor-specific mutations. (2) Identifying neoantigens therefore relies on DNA and RNA sequencing of individual tumors. Once the protein-coding segments of the tumor genome are sequenced, mutations that lead to new protein sequences are identified. These sequences are then filtered for their ability to be presented to T cells and identified by them. (2) The major challenges in neoantigen identification are the massive amounts of DNA data, and how to best filter it, as well as large numbers of false negative results. However, once the pipeline for identifying neoantigens becomes streamlined, patient-specific neoantigens can be targeted alongside standard immunotherapy. Examples of treatment strategies include synthetic DNA, RNA or protein vaccines that can target neoantigens, or introducing T cells specific for these neoantigens into the patient’s system. (2) Neoantigens are powerful because they are tumor specific, and therefore allow for more personalized treatments.

The human body is remarkably adaptable. Its tools are able to respond to new environments effectively and efficiently. The immune system is the epitome of this, with T cells able to fend against never before seen pathogens and B cells able to produce antibodies specifically targeting foreign molecules. Harnessing these tools to fight against cancer is showing promising results, whether targeting immune regulatory molecules or engineering cells to target a specific antigen. Immunotherapy carries inherent problems with it, including the inability to distinguish normal cells from cancer. As current research seeks to find more and more cancer-specific mutations, however, the scope of possible immunotherapies will only increase. Treatments can be tailored specifically to each patient based on the unique mutations they have. Through immunotherapy, a new era of personalized cancer treatment is on the horizon.

Edited by: Jessika Baral

Illustrated by: Angela Chen

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