CAR T Cells: Immunotherapy’s Rise in Healthcare

Surgery, radiotherapy, and chemotherapy — the three traditional pillars of cancer treatment. They have served cancer patients well for very long. As time goes on, however, improvement of these treatments is necessary. Researchers look for treatments that are more specific, effective, and less toxic. The new millennium has brought many new immunotherapies, which modify and enhance the body’s own defenses to accomplish the task most effectively [1]. One of these, CAR T cell therapy, has been particularly promising, demonstrating its potential to become a mainstream treatment for a variety of diseases.

CAR T cell therapy uses the body’s own T cells to attack cancer. T cells can recognize and eliminate foreign particles or problematic cells and are essential to the immune system. During CAR T cell therapy, T cells are extracted from the body and genetically modified to produce a certain surface receptor that can easily recognize cancerous cells [1]. These receptors are known as chimeric antigen receptors, or CARs. These modified T cells are allowed to multiply and then are reintroduced into the patient body, where they identify and destroy cancer cells [1].

Early trials using CAR T cells demonstrated success in patients with advanced blood cancers, such as acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). One phase 2 trial resulted in an 81% remission rate within three months [2]. In 2017, the successes of these trials prompted the Food and Drug Administration (FDA) to approve a CAR T cell therapy for ALL in children. The same year, the FDA approved a second CAR T cell therapy for adults with B cell lymphoma [2]. With the approval of :, a treatment for multiple myeloma, in March 2021, there are now five approved CAR T cell therapies [3]. Indeed, this field of research has made great progress in recent years.

In addition to the efficacy of the treatment, the cost of the therapy has also been studied. Though CAR T cell therapy is quite expensive, even for a cancer treatment, the effectiveness of the treatment could lead to increased value. However, this would depend on the long-term effectiveness of CAR T cell therapy, which is not clearly known yet [4]. Another large factor is the cost of the hospitalization of patients receiving CAR T cell therapy. CAR T cell therapy is usually administered in the inpatient setting, when the patient is hospitalized, which drives costs up. Researchers and clinicians are currently looking for ways to transition to outpatient delivery, allowing for a less expensive treatment [5].

With its successes in leukemia, lymphoma, and myeloma, researchers have been looking to expand CAR T cell therapy beyond the blood cancers. Logically, researchers would look toward solid tumors. In fact, much research on the feasibility and efficacy of CAR T cell therapy on solid cancers including breast, pancreatic, gastric, ovarian, prostate, liver, and renal cancer has already begun [6]. Specifically, early investigations have shown that CAR T cell therapy is particularly promising for ovarian, breast, and prostate cancer. For ovarian cancer, advances in immunotherapies are especially important due to high rates of recurrence after treatment using chemotherapy or surgery [6]. However, CAR T cells face challenges with solid tumors. They have a more difficult time accessing densely packed solid cancers than blood cancers, and there is an immune-suppressive microenvironment surrounding these tumors [6]. Despite these obstacles, there is potential that various CAR T cell therapies will be approved for solid cancers in the coming years.

So what about other diseases? It would initially appear that CAR T cell therapy may only be effective against cancer, and that only oncologists are interested in this novel therapy. Yet, as early as the 1990s, modified T cells were considered as a possible treatment for HIV. At the time, after some experimentation, the method was deemed infeasible [7]. However, now with better understanding of CAR T cells, the idea is once again being proposed. The therapy now appears realistic, though it hinges on the resistance of CAR T cells themselves to HIV infection. It has been hypothesized that gene editing can produce the necessary protection, though it is still unclear if this is feasible at a large scale [7].

Similar studies are being carried out for autoimmune diseases. The modern treatments for autoimmune diseases are largely insufficient, so researchers have looked to other treatments. One hypothesized treatment involves the modification of the CARs into chimeric autoantibody receptors (CAARs), which reprograms the T cells to target certain autoimmune cells [7]. Despite not having achieved results yet, the theoretical viability of CAR T cell therapies means this research into expanding CAR T cell therapies beyond cancers is still promising.

Starting as a hypothetical treatment in the 2000s, the speed of the development of CAR T cell therapy has proven to be an encouraging sign in the development of new cancer treatments. Initially a leukemia treatment, there are now approved CAR T cell therapies for many blood cancers. By exploring its use against solid cancers, the combination of clinical efficacy and cost effectiveness may render more traditional, destructive treatments unnecessary. The use of this therapy against infectious and autoimmune diseases is still in its early days, but the prospect is enticing. With every year, great progress is made, and it would not be surprising if these novel ideas become reality in the near future.

References:

1. Kalos, M., Levine, B. L., Porter, D. L., Katz, S., Grupp, S. A., Bagg, A., & June, C. H. (2011). T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Science translational medicine, 3(95), 95ra73. https://doi.org/10.1126/scitranslmed.3002842

2. Schultz, L., & Mackall, C. (2019). Driving CAR T cell translation forward. Science translational medicine, 11(481), eaaw2127. https://doi.org/10.1126/scitranslmed.aaw2127

3. U.S. Food and Drug Administration. (2021, March 27). FDA Approves First Cell-Based Gene Therapy for Adult Patients with Multiple Myeloma [Press release]. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-multiple-myeloma

4. Lin, J. K., Lerman, B. J., Barnes, J. I., Boursiquot, B. C., Tan, Y. J., Robinson, A., Davis, K. L., Owens, D. K., & Goldhaber-Fiebert, J. D. (2018). Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Pediatric B-Cell Acute Lymphoblastic Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 36(32), 3192–3202. https://doi.org/10.1200/JCO.2018.79.0642

5. Lyman, G. H., Nguyen, A., Snyder, S., Gitlin, M., & Chung, K. C. (2020). Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma. JAMA network open, 3(4), e202072. https://doi.org/10.1001/jamanetworkopen.2020.2072

6. Marofi, F., Motavalli, R., Safonov, V.A. et al. CAR T cells in solid tumors: challenges and opportunities. Stem Cell Res Ther 12, 81 (2021). https://doi.org/10.1186/s13287-020-02128-1

7. Maldini, C.R., Ellis, G. & Riley, J.L. CAR T cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol 18, 605–616 (2018). https://doi.org/10.1038/s41577-018-0042-2