LA JOLLA, Calif., Jan. 14, 2016 /PRNewswire-USNewswire/ -- The California Institute for Biomedical Research (Calibr), in collaboration with The Scripps Research Institute (TSRI), announces the publication of two papers in the Proceedings of the National Academy of Sciences (PNAS) describing the development of a "switchable" chimeric antigen receptor (sCAR)-T cell system that provides control over the activation, targeting, and anti-tumor activity of CAR-T cells. The approach uses recombinant antibody-based molecular switches to mediate the interaction between the switchable CAR-T cell and target cell. Compared with other antibody-based redirection approaches, the methods described in these papers are differentiated in that the interaction between the switchable CAR-T cell and switch is structurally defined and bio-orthogonal. This approach holds promise as a safer and more versatile alternative to conventional CAR-T cells because the switchable CAR-T cells can be turned 'on,' turned 'off,' and retargeted with high precision based on the dosing regimen of the antibody-based switch.
The authors show in mouse xenograft models of leukemia that switchable CAR-T cells retargeted with anti-CD19 switches can eliminate disease while releasing substantially lower amounts of inflammatory cytokines compared with conventional CAR-T cells. These findings suggest that the ability to control T cell activation and tumor lysis in vivo may translate to a reduced risk of cytokine release syndrome in the clinic. The authors also show that the switchable CAR-T cells in immune-competent mice can be turned off by simply discontinuing dosing of the switch – this reverses B cell aplasia in mice, offering a solution to a key chronic safety risk observed with conventional CAR-T cells. In addition, the studies demonstrate that the same switchable CAR-T cells that lyse CD19-positive cancer cells can be retargeted to CD20 or CD22, highlighting a fundamentally new approach to the unmet medical needs of patients with heterogeneous tumors and relapse due to antigen-loss escape. This represents a significant differentiation from small molecule approaches to control CAR-T cells with fixed specificity for a single target.
Beyond the potential to greatly expand the use of CAR-T cell therapy for leukemia and lymphoma, the safety and specificity profile of the switchable CAR-T platform can enable the application of CAR-T cells for solid tumors. The potential to standardize CAR-T cell therapy through this universal approach is expected to obviate the need to design and manufacture a new CAR for each antigen target. It should also substantially lower the cost and time of "bench to bedside" development, as well as provide a standardized treatment regimen which is not possible with the conventional CAR-T cell paradigm.
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SOURCE The California Institute for Biomedical Research