Porazzi and Nason et al. showed that EZH2 inhibition sensitizes a broad spectrum of tumors to diverse adoptive T cell immunotherapies. EZH2 inhibition enhanced tumor immunogenicity and modulated inflammation and apoptosis pathways, leading to improved tumor–CAR T cell interactions and antitumor efficacy. EZH2 inhibition/KO in CART19 did not improve tumor killing, nor compromise its antitumor effect. Tumor inhibition of both EZH1 and EZH2 further enhanced CAR T cell activation, expansion, and infiltration, leading to improved antitumor efficacy across diverse liquid and solid cancer models.
Contributed by Shishir Pant
ABSTRACT: Tumor resistance to chimeric antigen receptor T cell (CAR-T) and, in general, to adoptive cell immunotherapies (ACTs) is a major challenge in the clinic. We hypothesized that inhibiting the tumor drivers' methyltransferases EZH2 and EZH1 could enhance ACT by rewiring cancer cells to a more immunogenic state. In human B cell lymphoma, EZH2 inhibition (tazemetostat) improved the efficacy of anti-CD19 CAR-T by enhancing activation, expansion, and tumor infiltration. Mechanistically, tazemetostat-treated tumors showed upregulation of genes related to adhesion, B cell activation, and inflammatory responses, and increased avidity to CAR-T. Furthermore, tazemetostat improved CAR- and TCR-engineered T cell efficacy in multiple liquid (myeloma and acute myeloid leukemia) and solid (sarcoma, ovarian, and prostate) cancers. Lastly, combined EZH1/EZH2 inhibition (valemetostat) further boosted CAR-T efficacy and expansion in multiple cancers. This study shows that EZH1/2 inhibition reprograms tumors to a more immunogenic state and potentiates ACT in preclinical models of both liquid and solid cancers.
Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphi
Author Info: (1) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the 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-Oncology, Hospital of the 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-Oncology, Hospital of the 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-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (5) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (6) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the 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-Oncology, Hospital of the 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-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (9) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the 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-Oncology, Hospital of the 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-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; School of Medicine, Universit degli Studi di Milano, Milan, Italy. (12) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (13) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (14) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (15) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (16) Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. (17) Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. (18) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (19) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. (20) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (21) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. (22) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (23) Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. (24) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (25) Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (26) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (27) Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Division of Hematology-Oncology, Hospital of the 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-Oncology, Hospital of the 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-Oncology, Hospital of the 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-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: mruella@upenn.edu.
