-By Kelly Haskins
According to the National Cancer Institute, it is estimated that over 1.5 million new cases of cancer will be diagnosed in 2018 in the United States alone. Worldwide, cancer is the leading cause of death, with 8 million cancer related deaths in 2012 (1). Cancer arises from dysregulated cell growth, where cells copy themselves at rates much faster than normal. Generally, this dysregulation is due to mutations, or errors, in the sequence of genes controlling replication and cell death, resulting in an uncontrolled increase in cells that begin to invade other bodily tissues. Unfortunately, despite improvements in our understanding of cancer biology, the incidence of cancer shows no signs of decreasing, and it is estimated that by the year 2030, the number of new cases of cancer per year will top 23 million (1). Despite the predicted increase in the incidence of cancer, recent scientific advances have led to more promising treatments for some types of cancer, including CAR T cells.
Progress in cancer treatment options
Although great strides have been made in improving how cancer is treated, the current therapies are often not effective in achieving complete and lasting remission, so cancer comes back even after the original tumor is treated. The earliest treatment for cancer was surgical removal of solid tumors. However, removal of a tumor is rarely curative, due to metastasis, or spread, of cancerous cells to other sites in the body, and cancerous tumors often reoccur. Treatments aimed at the killing of cancerous cells, such as radiation therapy using localized beams of energy, which results in DNA damage and cell death, and chemotherapy, which uses chemical agents to prevent cells from replicating, are not tumor specific and result in detrimental side effects. More recent therapies, including CAR T cells, have tried to mimic the way in which the body naturally tries to eliminate cancerous or dysfunctional cells through the immune system.
The role of the immune system as a guard against cancer
The immune system plays a vital role in maintaining health within the human body. Cellular mutations are not uncommon. However, immune cells can ordinarily recognize and kill altered or mutated cells before further mutations can occur and cancer can develop. The immune system needs to maintain a balance between too much activation, which can result in autoimmunity, where the immune system begins to attack and kill normal, healthy cells, and not enough activation, which can allow cancer to progress. Cancer cells can adapt in ways that allow them to either escape recognition by the immune system, or avoid being killed by the immune system. One way they do that is by producing signals or recruiting other cells that suppress the immune system. Currently, a number of treatments, often referred to as checkpoint inhibitors, attempt to block this suppression to induce immune cells to once again target cancerous cells.
CAR T cells: the next generation of cancer therapeutics
Chimeric antigen receptor, or CAR T, cells are the most recent step in harnessing the immune system to treat cancer. This treatment involves genetic modification of T cells, a type of white blood cell that is known to play an important role in killing cancerous cells. All CAR T cell therapies currently approved by the FDA make use of T cells taken from the patient. These cells circulate in the blood normally and they can be isolated through a process similar to a blood draw. Once the T cells have been isolated, they are genetically engineered to express a receptor (the CAR) that will recognize a specific antigen, a molecule found only on cancer cells. The modified CAR-expressing T cells are then returned to the patient and will become activated to destroy cancerous cells through recognition of the antigen. CAR T cells have shown impressive results in patients with certain types of leukemia and lymphoma, with effective killing of cancerous cells in over 80% of patients in numerous trials (2-5).
Challenges Remain for CAR T cell therapies
Despite the promising results that have been observed in patients thus far, CAR T cells are not yet a cure-all for cancer. A number of challenges remain that may hamper the success of CAR T cell treatments, including the incidence of severe side effects. One method by which CAR T cells kill cancerous cells is the release of chemicals called cytokines. While the release of cytokines is important for CAR T cell activity, the production of large amounts of cytokines leads to cytokine-release syndrome, or CRS, which can in some cases lead to neurotoxicity, or damage and potential loss of cells that transmit and process signals in the brain. Additionally, some patients may develop an allergic reaction to the genetically engineered receptor expressed by CAR T cells. Scientists are working to develop “suicide switches,” or methods to rapidly kill or remove CAR T cells from the circulation in the event of severe adverse reactions. This is a goal of the next generation of CAR T cells to help improve the safety of this therapy.
Although CAR T cells have been very effective in treating so called “liquid tumors,” like leukemia and lymphoma that circulate in the blood, the efficacy of CAR T cells to treat solid tumors is significantly reduced. This is because targeting of solid tumors involves a number of additional challenges. Unlike “liquid tumors” that are easily accessible to CAR T cells moving throughout the body, solid tumors often reside in locations that are not directly accessible to the cells in circulating blood. This means that methods to enable CAR T cells to get to the tumor must be built into the treatment. Additionally, the activity of CAR T cells can be affected by the immune suppressive cells that tumors often recruit, meaning that even if they get to the tumor, they may not become activated to kill cancerous cells. The combination of CAR T cells with therapeutic treatments that inhibit the suppressive effect of tumors on immune cells, such as the checkpoint inhibitors, have shown some promise.
Conclusions
CAR T cells have provided significant improvements in the treatment outcomes of patients with some types of leukemia and lymphoma. However, a long road remains for effective treatment of patients with solid tumors, and the potential for significant side effects remains a challenge of CAR T cell therapy. While CAR T cells serve as a notable advance in the race against cancer, the end is not yet in sight.
Resources for further reading
References
1) https://www.cancer.gov/about-cancer/understanding/statistics
2) Brentjens, R. J. et al. (2013) CD19-targeted T cell rapidly induce molecular remission in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med, 5(177), 38.
3) Kochenderger, J. N., & Rosenberg, S. A. (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol, 10(5), 267-76.
4) Maude, S.L. et al. (2014). Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. NEJM, 371, 1507-1517.
5) Gardner, R. A., et al. (2017). Intent to treat leukemia remission by CD19CAR T cells of defined formulation and dose in children and young adults. Blood.