By Martina McGrath, MD
September 13, 2017
Each individual is estimated to have around 4 x 1011 T cells, comprising many millions of T cell clones,1 each randomly produced in the thymus with a unique T cell receptor (TCR) specific for a given antigen. This massive diversity in T cell repertoire gives our immune systems the capacity to protect against the incredible array of bacteria, viruses and fungi that assail us on a constant basis.
Over the past few decades, the central role of T cells in controlling cancers has been recognized and is now being exploited therapeutically with remarkable success. Like infected cells, cancer cells undergo changes from their normal, resting state. These changes typically label the cancer cells as targets for destruction by the immune system. However, many tumors can work around this—they are a little Darwinian—and can mutate and find ways to either evade or control the immune response, to ensure their own survival. Many of the huge breakthroughs in cancer therapeutics in recent years have targeted this specific feature. Novel anticancer agents can block the ability of tumors to evade the immune response, essentially turning the patients’ own immune system on the cancer to eradicate it, similar to how an infection is overcome.
However, a truly personalized approach would be to prime the patients’ immune system to directly target their own cancer cells. One such approach is to develop T cells specific for antigens within the patients’ specific cancer—with the aim of maximizing anticancer efficacy and reducing serious off-target effects. In recent weeks, the FDA has approved Chimeric Antigen Receptor T cell therapy (CAR-T) for the treatment of refractory or relapsed B cell-precursor acute lymphoblastic leukemia. What are CAR-T cells and how do they work?
The product approved by the FDA is Kymriah, made by Novartis.2 This product is made from T cells, harvested from the patient and then genetically engineered in the lab, to express a TCR specific for CD19, which is expressed on all B cells. The engineered T cells also undergo further manipulation to increase their capacity to survive and proliferate once returned to the patient. Kymriah, made from the individuals’ own T cells, is then ready to be re-infused into the patient. On infusion, CAR-T cells proliferate and kill malignant B cells, clearing the cancer. As they can easily migrate to sites of disease including the bone marrow, lymph nodes, and central nervous system, CAR-T cells appear to be highly effective in clearing these niches of malignant cells. Due to their prolonged survival, CAR-T cells maintain surveillance against disease relapse in the longer term.
In 2014, Meade et al reported a Phase I/II study of patients with highly refractory B cell ALL who were treated with CAR-T cells.3 Of these 30 patients felt to have incurable disease, 90% were in complete remission by one month after infusion of CAR-T cells. Seven patients died after disease relapse or progression, giving a six-month overall survival rate of 78%. The authors quoted a response rate to standard therapy of around 25% in similar patient cohorts. In this study, sustained remissions up to two years were seen. Other studies have documented the persistence of CAR-T cells for up to four years following infusion, with a prolonged antitumor effect.4
Kymriah is associated with severe adverse events and prolonged immunosuppression. Technical issues mean that in around 9% of cases, it is not possible to generate these engineered T cells from the patients’ own cells. Treatment is associated with high rates of IL-6 mediated cytokine-release syndrome, which can be very severe.2 However, its approval represents an exciting technological advance in medicine—the ability to generate an individualized cellular therapy to treat a previously incurable disease. The future applications of this type of technology appear endless.
- Jenkins M.K., Chu H.H., McLachlan J.B., Moon J.J. On the composition of the preimmune repertoire of T cells specific for peptide-major histocompatibility complex ligands. Ann. Rev. Immunol. 2009;28:275–294.
- https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdf. Accessed 09/12/17.
- Maude S.L, Frey N., et al. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. N Engl J Med 2014; 371:1507-151
- Porter D.L., Hwang W. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Science Translational Medicine 02 Sep 2015 : 303ra139
Dr. Martina McGrath is an Instructor in Medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine, at Brigham and Women’s Hospital, both in Boston. Dr. McGrath is the Medical Editor for the Trends in Medicine blog.