Nanoparticles that act as an “ON and OFF” switch to improve the safety and effectiveness of CAR-T cancer therapy

The biggest bottle neck in Chimeric antigen receptor T-Cell (CAR-T cell) therapy is the 21 days it takes to expand the patient’s T cells before re-infusion into the patient’s blood. For many end-stage cancer patients the 21 day wait-period is a death sentence. We propose to explore a 3-part CAR-T cell therapy with only a 2 day wait time before start of therapy.  Secondly, current state-of-the art in CAR-T cell technology is only effective against bloodborne malignancies (e.g. acute lymphoblastic leukemia). CAR-T cell clinical trials against solid malignancies has resulted in poor to fatal results. Reasons for the poor performance has been off-target activation, Tumor lysis syndrome (TLS), Cytokine release syndrome (CRS) and persistent “ON” state of cytotoxic CAR-T cells. Recent literature on the switchable CAR-T cell (sCAR-T-cell) system proposed by two research teams uses a small-molecule switch that has bispecific binding domains directed to the tumor and the sCAR-T cells to redirect the sCAR-T cells to the tumor site. However, at the ideal switch concentration no amelioration of the signs related to both CRS and TLS were observed in comparison to the suicide gene auto-destruct CAR T-cell strategy, with a daily or every other day administration. We propose to explore a non-genetic, quick off switch for the gCAR-T cells in order to reduce off target activation, CRS and TLS.