CARs are recombinant protein molecules that cause cell activation upon encountering the target antigen. The antigen-recognition domain of a CAR is usually derived from monoclonal antibody sequences. Cell therapies being used or in development for treating cancer or autoimmune diseases use T cells or regulatory T cells (Tregs) respectively. CAR-T cells are engineered T cells and CAR-Treg cells are engineered Tregs.
T cells modified with a chimeric antigen receptor (CAR), called CAR-T cells, are designed to find and kill cancer cells that carry the protein recognized by the receptor. This region interacts with tumor cell surface proteins and signaling motifs in the intracellular portion of the CAR ensure cell activation. The interaction occurs in a major histocompatibility complex (MHC)-unrestricted manner.This means the interaction does not require MHC compatibility between effector and target cell. This is important because tumors often lose MHC expression as a mechanism of evading detection by endogenous T cells.
To generate CAR-T cells for therapy a CAR-encoding DNA cassette is transduced by retroviral delivery into patient peripheral blood leukocytes from a cancer patient. Transduced cells are expanded and reinfused back into the patient. The introduced DNA sequences for the tumor associated antigens are ideally only expressed on tumor cells.
The first CAR-T treatment was approved by the FDA in 2017 and there are several in clinical trials. CAR-T has been successful in treating hematological malignancies. US FDA approved CAR-T therapies include CD19-targeting CAR-T cells, tisagenlecleucel (Kymriah-Novartis) in leukemia and lymphoma and axicabtagene ciloleucel (Yescarta – Kite) in lymphoma. Challenges to CAR-T including toxicity due to attacking non-cancer cells, "clonal escape" due to diversity of cancer cells, dosing, immunosuppression (turning off) of the T-cells, and T-cell apoptosis (cell death).
Treating solid tumors with CAR-T faces challenges including a lack of truly tumor-specific target antigens. The immunosuppressiveness of the tumor microenvironment (TME) of solid tumors also prevents effective anti-tumor immune responses. Components of the immunosuppressive TME contains includes physical barriers, such as a dense extracellular matrix; dysfunctional epithelial cells; metabolic checkpoints, such as hypoxia and immunological barriers, such as immunosuppressive cytokines/molecules and immunosuppressive immune cells.
Allogeneic or universal cell therapy products, also called off-the-shelf cell therapy products would allow a broader implementation of these cell therapies. One method being researched is to derive natural killer (NK) cells from induced pluripotent stem cells (iPS) cells and engineer iPS cell-derived NK cells to target and kill cancer cell similarly to CAR-T cells.
Improved tumor recognition and specificity has been shown by incorporating the synNotch transcriptional receptor which creates a two antigen tumor recognition circuit. One antigen binds synNotch and primes CAR expression and a second antigen binds CAR to activate the T cell. This system is being used by Cell Design Labs to develop CAR-T therapies.
