When you think of cancer treatments, chemotherapy, surgery, radiation, or even newer targeted drug therapies will likely come to mind. But some of the most exciting developments in the fight against cancer are taking place in a rapidly evolving category of treatment: immunotherapy. Immunotherapy harnesses and enhances the power of a patient’s existing immune system to attack cancer cells. One of the most promising types of immunotherapy uses adoptive cell transfer (ACT), in which tumor-reactive lymphocytes are extracted from the patient, genetically modified and cultured in the lab to large numbers, and then re-administered to the patient to help his or her immune system fight the cancer.
While all types of ACT are in their early days of development relatively speaking, one method showing great promise is chimeric antigen receptor T-cell therapy, or CAR-T. In fact, two CAR T-cell therapies were approved by the FDA in 2017: one for the treatment of children with acute lymphoblastic leukemia (ALL) and the other for adults with advanced lymphomas. The outcomes achieved for patients with B-cell malignancies are inspiring scientists to continue to explore the possibilities of this “living drug” for other hematologic malignancies and solid tumors, with more than 180 clinical trials being conducted to test CAR T-cell therapies today.
How CAR T-Cell Therapy Works
CAR T-cell therapy is designed to redirect a patient’s T cells to specifically target and destroy tumor cells. CAR T-cells are composed of a single-chain Fragment variant (scFv) derived from an antibody, fused to intracellular T cell signaling domains that trigger activation and proliferation of the T cell. T cells are extracted from the patient (or donor) and genetically modified, adapted to generate receptors on their surface called chimeric antigen receptors (CARs). CARs are engineered receptors that can graft an arbitrary specificity onto an immune effector cell like the T cell. These non-naturally occurring receptors allow the T cell to target and attack a specific marker, such as a protein or antigen that is present on tumor cells. After the T cells are modified to target the appropriate tumor markers, they are multiplied in a laboratory into the hundreds of millions. The CAR T-cells are then infused into the patient and continue to proliferate in the body to a point where they are able to seek out and affect cancer cells with the marker on their surface.
Innovations and Expanding Knowledge
As the applications for CAR-T expands, more oncology patients will have the opportunity to take advantage of meaningful treatments; that said, there are still major challenges that exist to successfully extend the use of CAR T-cell therapy to solid cancers. CAR design and T cell manufacturing are intrinsic variables that are critical determinants of overall therapy. Additionally, a number of extrinsic factors related to the tumor microenvironment can impact the ability of CAR T-cells to penetrate the tumor, retain potency within the hostile microenvironment, and overcome antigen heterogeneity of the tumor. These issues have spurred more complex CAR T-cell engineering strategies so that the cells are more equipped to expand and survive once infused into the patient.
Another way that scientists are working to develop further applications for this therapy is by identifying new target antigens. This exploration is vital because there is building evidence that a combined approach using two antigen targets could mitigate some of the inefficiencies of the original treatment, such as lack of durability and antigen loss. For example, T cells genetically modified to express CARs targeting CD19 have produced impressive results in treating patients with B-cell malignancies, but unfortunately not all responses are durable. Emerging data indicate that targeting an alternative antigen instead of or as well as CD19 could improve CAR T-cell efficacy and reduce antigen-negative relapse.
It will be also important for our industry to increase understanding of the toxicities of CAR T-cell therapy, which can include cytokine release syndrome (CRS), neurological toxicity, on-target/off-tumor recognition, anaphylaxis, and other worrisome or potentially fatal side effects. The utility of CAR T-cells for cancer treatment will ultimately depend on the feasibility of their safe administration, and being able to effectively anticipate and manage toxicities will be key to improving clinical management.
A Partner for Advanced Cancer Therapy Development
BioAgilytix has a long history of expertise in immunology and oncology, and as such has been a partner of choice to those in the industry that are making significant strides in CAR T-cell cancer treatments. As pharmaceutical and biotechnology companies continue to explore new ways to utilize this technique, BioAgilytix is ready to work as a partner that can genuinely collaborate, scientist to scientist, to produce the best results efficiently. CAR T-cell therapy will continue to grow and change, and we are excited to see the impact that this treatment innovation will make for those fighting cancer.