CAR T Cell Therapy: Engineering the Immune System to Fight Cancer

By Michelle Bloom, PhD

In my previous article, Immunotherapy: Harnessing the Power of Our Own Cells to Treat Cancer, I introduced the concept of immunotherapy. These targeted therapies utilize aspects of our immune system to discriminate between cancerous and non-cancerous cells to target and kill cancer. In that article, I also introduced the two main branches of the immune system, innate and adaptive, which use different mechanisms to discern the protein uniforms that identify the cells that comprise our bodies versus the cells that form pathogens. This article will explore a revolutionary new type of immunotherapy that takes advantage of our adaptive immune system to fight cancer, called CAR T cell therapy.

The adaptive immune system, similar to Navy SEAL special forces, takes time to train and mount highly specialized attacks against pathogens in our bodies. The two classes of cells that comprise the adaptive immune system are B cells and T cells. In my article about immunotherapy, I explained how B cells attack pathogens by producing antibodies that are sent throughout the body with the job of targeting specific proteins from the pathogens. The proteins that comprise the protein uniforms on pathogens that are targeted by antibodies are called antigens. T cells, similarly, can detect these pathogenic protein uniforms but use a different mechanism called antigen receptors. Antigen receptors are specialized proteins that sit on the surface of the T cell and detect pathogens by interacting with antigens through the detection domain of the receptor. Antigen receptors also contain a second domain that activates T cells to seek out the pathogens with the corresponding proteins.

As a result of gene rearrangements, millions of unique antigen receptors can be created that each have the capacity to interact with different proteins. These different versions of antigen receptors allow for the highly specialized responses of T cells. In contrast to the ability of antibodies secreted from B cells and sent throughout the body to target pathogens, antigen receptors are permanently attached to T cells. They also cannot directly detect proteins on pathogens. Similar to the way a mother bird chews up food before giving it to her chick, T cells first become activated by detecting pathogen proteins that have been chewed up by other immune cells. The cancer vaccine, sipuleucel-T, which I described in my previous article, utilizes another type of immune cell, dendritic cells, to train T cells to identify and kill cancer cells through this same method.

A new, groundbreaking type of cancer therapy also takes advantage of the ability of T cells to seek out and kill specific cells, but eliminates the step in which other immune cells have to chew up and present pathogenic proteins to the T cell. This therapy is called Chimeric Antigen Receptor (CAR) T cell therapy. You might be familiar with chimeras from literature and mythology in which creatures are made up of the parts of multiple animals. In the context of antigen receptors, however, chimeras are created from sections of antibodies, T cell antigen receptors, and other proteins from the immune system that activate T cells. Rather than consisting of the pathogen-detection domain of the antigen receptor that can only recognize the digested fragments of the target proteins, CARs contain the detection domain of an antibody. Utilizing this part of the antibody allows the CAR to identify unprocessed pathogen proteins. While CARs maintain activation domains from antigen receptors that tell T cells to kill pathogens, they also contain parts of other proteins to help maintain the activated state of T cells. CARs, therefore, can become highly attuned to interact with any single protein in the body. Scientists, consequently, can engineer them to target proteins found on the surface of cancer cells.

Unlike many other treatments, which involve administering a drug created in the laboratory, CAR T cell therapy involves genetic engineering of cells in the laboratory. T cells are harvested directly from the patient and then activated in the laboratory through a process that mimics the activation process that occurs in the body. Simultaneously, DNA that codes for the CAR is introduced to the cells, allowing the cells to synthesize the CAR protein. Once the T cells are activated, they are reintroduced to the patient, after which the cells can disseminate throughout the body, detecting and killing the cancerous cells.

While there are hundreds of therapies currently in clinical trials, CAR T cell therapy is in its infancy and only two therapies have been approved by the FDA. The first therapy, Kymirah, was approved in August, 2017, with approval of the second, Yescarta, quickly following in October, 2017. Kymirah is approved for the treatment of acute lymphoblastic lymphoma (ALL), while Yescarta is approved for the treatment of large-B-cell lymphomas. Although these therapies have proven successful for treating debilitating and otherwise unresponsive cancers, there is still much to be developed in the field of CAR T cell therapies.

One innovative feature of CAR T cell therapies is that the cells are engineered to remain active much longer than T cells generally do in the body. This quality has led to some serious side-effects, including cytokine release syndrome (a systemic response that results from an overabundance of activated immune cells), which can be life threatening. Another hurdle in creating widely effective CAR T cell therapies is targeting them toward solid tumors. Both ALL and large-B-cell lymphoma are cancers of the blood, or so called “liquid cancers.” Other cancers, such as breast cancer and prostate cancer, however, form solid tumors, which pose difficulty for the CAR T cell system.

Targeting a solid tumor like breast cancer or prostate cancer is like infiltrating a fortress; in order to attack the cells within a solid tumor, T cells must be able to infiltrate the tumor. The protein uniforms of solid tumors are harder for T cells to access than liquid cancers, which do not form masses. The availability of detectable proteins on the tumor impedes the ability for the T cells to permeate it. The microenvironment in and around a solid tumor, which often contain low levels of oxygen and nutrients, also made it difficult for T cells to survive. Because cancer cells adopt unique properties that normal cells do not have, they are able to grow despite these harsh conditions in environments in which normal cells could not survive. These factors, together, lower the efficacy of CAR T cell therapy on solid-tumor cancers. As scientists work to optimize these therapies and overcome these issues, however, more CAR T cell therapies are likely to be developed and approved for the treatment of many additional types of cancers.

CAR T cell therapy is only one type of adoptive cell therapy in which cells are transferred to a patient in order to treat disease. This process involves harvesting a patient’s own cells, then genetically modifying and activating them so they have the ability to detect and kill cancer cells. Training the cells of a patient to kill her/his cancer has the extraordinary potential to lower the risk of incompatibility that comes with transplants. Using one’s own cells as a therapy also opens up the possibility that the targeted T cells can prevent cancer from recurring because the cells remain in the body for an extended period of time. While these therapies are still relatively new, and their capacity to cure and prevent cancers has not yet been achieved, they have the potential to treat a myriad of diseases, including otherwise untreatable cancers.