Immuno-oncology represents the new wave of personalized medicine. Scientists at the University of Kansas have developed an innovative approach to activate intracellular signaling pathways that enhance T cell activation, expansion, and differentiation.
Chimeric antigen receptors (CARs) are engineered T cell receptors (TCRs) that are grafted onto T cells obtained from cancer patients. The newly modified T cells are reintroduced into the patient. Because the T cell receptor is engineered to include an antibody that specifically matches the patient's cancer, the newly introduced T cells are able to recognize and kill the cancer cells. There is potential for CAR-T therapy to treat cancer, however, there are significant side effects. In order to improve the safety profile of these therapies, KU researchers incorporated engineered CAR into the endogenous T cell receptor (TCR) complex - resulting in tighter control and regulation.
CAR-T therapy may change the treatment of cancer in a profound way and there have been a considerable number of successes in this field. Individualized cancer therapy offers the potential for significant improvement in outcomes.
The present technology involves fusion of a single chain antibody (scFv) fragment with the constant region of one TCR chain and exogenous expression of a truncated form of the other TCR chain. Combining these two TCR chains results in robust expression and functional conformation of the complex. Engagement of the engineered TCR complex with tumor antigen allows for more precise activation and signaling kinetics; thereby promoting more efficient tumor destruction as compared to monomeric CARs. The scFv region can be tailored to recognize multiple tumor antigens and immunomodulatory molecules.
The approach is broadly applicable, highly successful in patients on trial, and likely to work in combination with a number of current cancer therapies.
The technology overcomes some significant challenges of current CAR-T therapies: (1) engineered T cells are constitutively active, resulting in exhaustion and inability to respond to repeated or sustained exposure; (2) CAR-expressing T cells fail to expand and persist as memory cells; and (3) cytokine release syndrome that results from rapid and robust activation of CAR-expressing T cells.