Patel et al. used the CRISPR-Cas9 system to ablate expression of the TCR-associated T cell inhibitory receptor CD5 from CAR T cells of several specificities and TCR-redirected T cells. CD5 KO boosted T cell signaling, activation, and cytotoxic pathways, and enhanced the persistence, expansion, and antitumor effects of CAR T cells transferred into mouse models of hematological and solid cancers, surpassing PD-1 KO CAR T cell efficacy. TCGA database analysis showed better outcomes for patients with lower CD5/CD3ε-expressing pretreatment tumor biopsies. In a small NHL study, response to therapy correlated with lower CD5 RNA expression levels in the CAR T cell product.
Contributed by Paula Hochman
ABSTRACT: Most patients treated with US Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cells eventually experience disease progression. Furthermore, CAR T cells have not been curative against solid cancers and several hematological malignancies such as T cell lymphomas, which have very poor prognoses. One of the main barriers to the clinical success of adoptive T cell immunotherapies is CAR T cell dysfunction and lack of expansion and/or persistence after infusion. In this study, we found that CD5 inhibits CAR T cell activation and that knockout (KO) of CD5 using CRISPR-Cas9 enhances the antitumor effect of CAR T cells in multiple hematological and solid cancer models. Mechanistically, CD5 KO drives increased T cell effector function with enhanced cytotoxicity, in vivo expansion, and persistence, without apparent toxicity in preclinical models. These findings indicate that CD5 is a critical inhibitor of T cell function and a potential clinical target for enhancing T cell therapies.
Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphi
Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (2) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (3) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (4) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, MacKay Memorial Hospital, Taipei, Taiwan. (5) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (6) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (7) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (8) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (9) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (10) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (11) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (12) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Republic of Korea. (13) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. (14) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (15) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (16) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (17) viTToria Biotherapeutics, Philadelphia, PA, USA. (18) viTToria Biotherapeutics, Philadelphia, PA, USA. (19) viTToria Biotherapeutics, Philadelphia, PA, USA. (20) viTToria Biotherapeutics, Philadelphia, PA, USA. (21) viTToria Biotherapeutics, Philadelphia, PA, USA. (22) viTToria Biotherapeutics, Philadelphia, PA, USA. (23) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (24) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA. (25) Department of Pathology and Laboratory Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA. (26) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (27) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (28) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (29) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (30) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (31) Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (32) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (33) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (34) Vaccine and Immunotherapy Center, Wistar Institute, Philadelphia, PA, USA. (35) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (36) Department of Dermatology, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA. (37) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (38) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (39) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Oncology, Children's Hospital of Philadelphia, PA, USA. (40) Division of Oncology, Children's Hospital of Philadelphia, PA, USA. (41) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (42) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA. (43) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (44) Division of Haematopathology, Istituto Europeo di Oncologia IRCCS, Italy. (45) Division of Hemato-pathology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (46) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (47) Department of Dermatology, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA. (48) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (49) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (50) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (51) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. Division of Hematology and Oncology, Hospital of University of Pennsylvania, Philadelphia, PA, USA. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
