Controllable CAR-T cell Therapy
David T Rodgers1, Magdalena Mazagova1, Eric N. Hampton1, Sophie Viaud1, Eduardo Laborda1 Christopher Ackerman1, Meredith Weglarz1, Ashley K Woods1, Peter G Schultz1,2, Travis S Young1*
1Biology Department, California Institute for Biomedical Research, La Jolla, CA 92037; Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037
The past decade has witnessed the remarkable successes of chimeric antigen receptor T (CAR-T) cell therapy for hematological malignancies. To improve the control of CAR-T cells with the goal of overcoming associated toxicities and tumor resistance mechanisms, we have designed a switchable CAR-T cell platform using antibody-based molecular switches. Compared with previous methods of controlling CAR-T cells, this platform is bio-orthogonal and provides complete tunability of the CAR-T cell response for any given target. This can allow dose-titration of CAR-T cell activation to prevent cytokine release syndrome and act as a safety switch to turn off activity in the case of an adverse event. This level of control is particularly important in the treatment of solid tumors where tunability is expected allow titration to a safe therapeutic index for tumor antigens that are shared with normal tissues. Further, the universal design of this platform allows a single CAR-T cell to be retargeted simultaneously or iteratively to multiple antigens which can be useful in preventing antigen-loss relapse and treating heterogeneous disease. Ultimately combination of this “switchable” platform with allogeneic approaches is expected to expand application and greatly decease the cost of therapy. Here we report new results on this platform in demonstrating recall of the switchable CAR-T cells in vivo to tackle antigen loss relapse mutations and to reversibly induce B cell aplasia in immunocompetent mouse models in the context of CD19-targeting. In addition we report the humanization of both the switchable CAR and antibody-based CD19 switch in preparation for a first-in-human clinical trial for relapsed ALL.