S80. Prolongation of T cell response by OX40 co-signalling CARS

Adoptive therapy of cancer with genetically redirected T cells showed spectacular efficacy in recent trials. A body of pre-clinical and clinical data indicate that young effector and central memory T cells perform superior in a primary anti-tumor response; repetitive antigen engagement, however, drives T cell maturation to terminally differentiated cells associated with the loss of CCR7 which enables T cells to persist in peripheral tissues. Chimeric antigen receptor (CAR) engineered CCR7 T cells more efficiently accumulated at the tumor site, secreted more IFN-g, expressed higher amounts of cytotoxic molecules and showed superior tumor cell lysis compared to the younger CCR7 cells. CCR7 T cells, however, were more prone to spontaneous and activation induced cell death which could be counteracted by simultaneous CD28 and OX40 (CD134) costimulation. Consequently, the combined CD28-z-OX40 signaling CAR rescued CCR7 T cells from apoptosis which then produced more efficient anti-tumor efficacy than CCR7 T cells redirected by the same CAR. In contrast, cytokine induced killer (CIK) cells, predominantly consisting of terminally differentiated CD8CD56 cells, accelerated terminal maturation of CD56 CIK cells producing high frequencies in activation induced cell death (AICD) and reduced anti-tumor efficiency when stimulated by the CD28-z-OX40 CAR compared to the CD28-z CAR. Translated into therapeutic strategies, T cell therapy will benefit from combined CD28-z-OX40 stimulation in the long-term by rescuing continuously generated CCR7 T cells for an anti-tumor attack. CAR redirected CIK cells benefit from CD28 co-stimulation; “super-costimulation” by the CD28-z-OX40 CAR, however, performed less in anti-tumor efficacy due to increased AICD.