T Cell Receptor Stimulation Enhances the Expansion and Function of CD19 Chimeric Antigen Receptor-Expressing T Cells

Purpose: Current protocols for CD19 chimeric antigen receptor expressing T cells (CD19.CAR T cells) require recipients to tolerate pre-infusion cytoreductive chemotherapy, and the presence of sufficient target antigen on normal or malignant B cells. Experimental Design: We investigated whether additional stimulation of CD19.CAR T cells through their native receptors can substitute for cytoreductive chemotherapy, inducing expansion and functional persistence of CD19.CAR T even in patients in remission of B-cell acute lymphocytic leukemia (ALL). We infused a low-dose of CD19.CAR-modified virus-specific T cells (CD19.CAR-VST) without prior cytoreductive chemotherapy into 8 patients after allogeneic stem cell transplant. Results: Absent virus reactivation, we saw no CD19.CAR-VST expansion. By contrast, in patients with viral reactivation, up to 30,000-fold expansion of CD19.CAR-VSTs was observed, with depletion of CD19+ B-cells. Five patients remain in remission at 42-60+ months. Conclusions: Dual TCR and CAR stimulation can thus potentiate effector cell expansion and CAR-target cell killing, even when infusing low numbers of effector cells without cytoreduction.