To improve the quality of CAR immune synapse, Chockley et al. modified a CAR construct with a domain binding PDZ (structural proteins involved in cell–cell junctions; CAR.PDZ) derived from CRTAM, an internal scaffolding protein with known activity in NK and T cells. Compared to normal CAR NK cells, CAR.PDZ-NK cells showed improved target-binding avidity, signaling (i.e., calcium burst and synaptic pZAP70 accumulation), effector cytokine production, in vitro cytolytic capacity, and efficacy in mouse models of osteosarcoma and lung adenocarcinoma. CAR.PDZ-T cells also demonstrated superior synaptic signaling and antitumor efficacy relative to CAR T cells.
Contributed by Alex Najibi
ABSTRACT: Chimeric antigen receptor (CAR) technologies have been clinically implemented for the treatment of hematological malignancies; however, solid tumors remain resilient to CAR therapeutics. Natural killer (NK) cells may provide an optimal class of immune cells for CAR-based approaches due to their inherent anti-tumor functionality. In this study, we sought to tune CAR immune synapses by adding an intracellular scaffolding protein binding site to the CAR. We employ a PDZ binding motif (PDZbm) that enables additional scaffolding crosslinks that enhance synapse formation and NK CAR cell polarization. Combined effects of this CAR design result in increased effector cell functionality in vitro and in vivo. Additionally, we used T cells and observed similar global enhancements in effector function. Synapse-tuned CAR immune cells exhibit amplified synaptic strength, number and abundance of secreted cytokines, enhanced killing of tumor cells and prolonged survival in numerous different tumor models, including solid tumors.
Author Info: (1) Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA. peter.chockley@stjude.org. (2) Department of Bone Marro
Author Info: (1) Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA. peter.chockley@stjude.org. (2) Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA. (3) Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA. (4) Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA. Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN, USA. (5) Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.
