T cell therapies have shown remarkable clinical efficacy in bone marrow and organ transplantation, cancer immunotherapy, viral infections, and auto-immune diseases. However, T cell are also involved in deleterious side effects. For instance, administration of engineered T cells can damage the normal tissues due to on-target/off-tumor effects. Physiological regulation of T cell activation is achieved by several mechanisms including immune inhibitory receptors such as CTLA4 and PD1, which play pivotal roles in reducing or terminating T cell responses. Inhibitory receptors can be up-regulated during T cell priming to taper immune responses or basally expressed to regulate activation thresholds. A safety CAR (sCAR) contains an extracellular scFv fused to inhibitory domains that prevent the activity of CAR-T cells.
For example, mice deficient of the inhibitory domain CTLA-4 exhibit massive T cell activation and proliferation and eventually succumb to severe systemic autoimmune disease with infiltration of activated T cells. Moreover, loss of PD-1, another inhibitory signaling domain specifically expressed on activated T cells, induces progressive arthritis and accelerates insulitis in nonobese diabetic (NOD) mice. Thus, modulation of the inhibitory signaling domain CTLA-4 or PD-1 during T cell stimulation can selectively divert off-target immunotherapy responses.
Safety chimeric antigen receptor models and concepts
Nature Reviews Cancer. 2016.
Creative Biolabs possesses the most exquisite service platform for CAR-T cell therapy. With efforts from numerous researches and years of experience, we have developed a variety of effective methods to improve the safety for CAR-T cell therapy. Safety CAR can regulate the activity of T cells, and inhibit the secretion of cytokine and off-tumor effect, further improve the safety of CAR-T cell therapy. Creative Biolabs provides the most advanced safety CAR construction service for customers all over the world.
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