by Geeta Paranjape, MD
Cellular therapy is a rapidly progressing field with new clinical trials for novel products being added all the time.
Autologous and allogeneic hematopoietic stem cell transplants have been used for many hematological malignancies as treatment. The new kid on the block is CAR T-cell (Chimeric Antigen Receptor T) therapy. Development of cancer is usually attributed to the failure or exhaustion of T lymphocyte surveillance, which leads to persistence and proliferation of malignant cells and development of clinically detectable cancer.
Since the 1980s, researchers have been looking for ways to re-direct or re-educate a patient’s own T lymphocytes so they can attack cancer cells more effectively. CAR T is one form of this adoptive cell therapy. Cancer cells may express tumor associated antigen (TAA) or tumor specific antigen (TSA). The concept is to genetically modify T-cells so they express a fragment of the antibody to this TAA on their surface as a receptor. This is not a naturally-occurring antigen (hence referred to as Chimera). T-cells expressing this receptor are able to interact and kill tumor cells with no need of HLA recognition. They are also able to secrete cytokines that recruit more killing cells to the tumor. However, cytokines are a double-edged sword. They can lead to cytokine release syndrome (CRS) seen in many CAR T patients.
A patient’s own mononuclear cells (which contain lymphocytes as well as monocytes) are collected by apheresis (leukapheresis). They are transported to the manufacturing site, and are genetically modified by transfecting them with replication incompetent retrovirus or lentivirus vector carrying the genetic code for the chimeric antigen. Once transfected, the T-cells are grown and expanded to achieve a minimum number. Following the completion of all quality and sterility tests, the CAR T product is returned to the patient. The entire process takes weeks and may be a rate limiting factor for patients who are very ill. Another issue limiting access to this therapy is that some patients may have an insufficient number of T-cells for initial collection, due to previous therapies and the cancer itself.
The therapy is autologous and hence does not carry the risk of GvHD as allogeneic stem cell transplant does. And yet, it has its own risks. Patients need to receive lymphodepletion therapy in order for CAR T cells to effectively live and expand in the patient’s body. These cells can cause CRS, as well as neurotoxicity and other severe side effects. Patients with severe CRS need to be treated with an IL6 inhibitor in order to survive.
Currently, there are two products licensed by the FDA: KYMRIAH® – for B Acute Lymphoblastic Leukemia (patients up to 25 years of age) and adults with diffuse B Cell Lymphoma, and YESCARTA® for adults with diffuse B Cell Lymphoma. In both cases, patients must have refractory/relapsed disease or must have failed previous therapies. Both drugs target CD19 on B cells and, when effective, can lead to B cell aplasia needing immunoglobulin treatment.
While the results for pediatric patients with B ALL have been impressive, researchers are discovering that cancer cells get smarter and learn to “escape” CAR T-cells. Research is ongoing to find CAR T-cells that can target more than one antigen and last longer, so the anti-tumor effect will be long lasting. There are also ongoing efforts to combine different adoptive immunotherapies to achieve the best results. The focus so far has been hematological malignancies, but scientists are asking if this can be applied to solid tumors. This approach presents more challenges. Autologous T-cell use requires weeks to get the product. Can an allogeneic CAR T be developed for “off-the-shelf” use? How is GvHD avoided, if this is possible? Will this therapy ever become affordable?
Like any novel therapy, there are more questions than answers – but this is an exciting development in cell therapy.