Immunotherapy – a class of treatments that uses the body’s own immune system to fight cancer – has increasingly gained widespread acceptance from leading biomedical scientists. There are various types of immunotherapeutic agents. Recently one approach to immunotherapy called “Chimeric Antigen Receptor T-Cell Therapy (CAR-T-Cell Therapy) has received a great deal of attention and is finding success in current clinical trials. CAR-T Cell Therapy entails engineering a patient’s own immune cells to recognize and attack their tumors. Investigator Ray Wong explains in greater detail below what CAR-T Cell therapy is, what the risks are, and what the future of this form of immunotherapy might look like.
How does Chimeric Antigen Receptor T-Cell therapy (CAR-T Cell therapy) work?
The current generation of CAR T cell therapies being tested in clinical trials involves a complex manufacturing process. A patient’s immune cells are first removed from their bloodstream through a process called leukapheresis. Leukapheresis typically takes 2-4 hours, where a patient is connected to a machine that separates immune cells from the blood, and the remaining components are returned to circulation. The immune cells are shipped to specialized manufacturing facilities where the T cells in the leukapheresis specimens are genetically engineered to insert specific anti-tumor receptors called chimeric antigen receptors (CAR). The T cells are simultaneously grown to large numbers over 7-10 days, then shipped back to the patient for intravenous infusion by their oncologist. CAR T cell therapy is currently combined with chemotherapy, which appears necessary to achieve full effectiveness of CAR T cells.
Photo Credit: UNC Lineberger
What are some of the limitations of CAR-T Cell therapy? Which cancers have the best response rate so far?
Other than the two week manufacturing time and high financial cost of treatment, the main limitation is that it thus far only works well in blood cancers like certain leukemias and lymphomas. There does appear to be a high cure rate in certain blood cancers, with some clinical trials reporting well over 50% complete response rates (disappearance of all disease). However, solid tumors like mesothelioma have been much more difficult to treat with CAR T cells. The current prevailing hypothesis is that CAR T cells do not efficiently penetrate solid tumors and/or are shut down by immune suppressive factors often present in solid tumors.
What are your thoughts on the future of CAR-T-Cell therapy?
Patient safety is still the top concern of CAR T cell therapy. The FDA has halted some clinic trials as recently as 2016 due to patient deaths. CAR T cells are very powerful, and can causes excessive immune reactivity resulting in a condition called “cytokine release syndrome,” which can be fatal. The interaction of CAR T cells combined with chemotherapy is still not fully understood. The FDA may want several more years of extensive clinical trials to further study safety improvements of CAR T cell therapy.
Next-generation CAR T cells may not need to be custom manufactured for each patient. Researchers are now exploring the use of a gene deletion technology called “clustered regularly interspaced short palindromic repeats” (CRISPR) in the laboratory. CRISPR might be used to convert T cells from healthy donors into universally compatible CAR T cells. In laboratory studies, CRISPR can be used to delete proteins on the surface of T cells that normally would cause them to be rejected in genetically unrelated recipients. If successful, this would allow for bulk manufacturing of “off-the-shelf” CAR T cells ready for immediate use, analogous to universally compatible Type O-negative blood. CRISPR is also being studied to delete other genes in CAR T cells that would make them more resistant to immune suppression. This might improve their effectiveness in solid cancers.