Harnessing the CD2 axis to broaden and enhance the efficacy of CAR T-cell therapies
Abstract
Abstract Patients with T-cell lymphomas and leukemias have overall poor outcomes because of the lack of targeted and effective treatments, particularly in the relapsed and refractory settings. The development of chimeric antigen receptor (CAR) T cells against T-cell neoplasms is limited by a lack of discriminating T-cell antigens that allow for effective antitumor responses while preventing CAR T-cell fratricide. We hypothesized that targeting CD2, a pan–T-cell antigen, with anti-CD2 CAR T cells engineered to lack CD2 expression (CART2) would improve manufacturability and preclinical efficacy. Optimized CD2-knockout CART2 cells, generated using CRISPR-Cas9, eradicated primary patient-derived CD2+ hematological neoplasms in vitro and in vivo, secreted effector cytokines, and exhibited adequate proliferative capacity. Nevertheless, CD2 has a key costimulatory function, and its deletion could lead to CAR T-cell dysfunction. Therefore, we tested the role of the CD2:CD58 axis in CAR T cells, using the anti-CD19 CART models. We demonstrate that CD2 loss attenuates CART19 efficacy by reducing avidity for tumor antigen, costimulation, and ultimately in vivo activity. Analogously, we show that tumor CD58 loss reduces CART19 efficacy. To overcome this issue, we developed a novel programmed cell death protein 1 (PD-1):CD2 switch receptor that rescues intracellular CD2 signaling, particularly when programmed death-ligand 1 is engaged, thereby improving in vivo outcomes. Collectively, we studied the role of CD2 both as a target for CAR T-cell therapy and as a critical costimulatory protein, whose signaling can be rescued using the PD-1:CD2 switch receptor. This receptor can be incorporated into CAR T cells and provides an effective strategy to overcome CD2-signaling deficiencies.
Article Details
Authors (42)
Alberto Carturan
Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia
Mathew G. Angelos
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Puneeth Guruprasad
Ruchi P. Patel
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Raymone Pajarillo
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Andrew Lee
David Espie
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Yunlin Zhang
Yi-Hao Chiang
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Wei Xie
Jesse L. Rodriguez
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Jaryse Harris
6Division of Hematopathology, University of Pennsylvania, Philadelphia, PA
Pooja Devi
Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia
Olabisi I. Afolayan-Oloye
6Division of Hematopathology, University of Pennsylvania, Philadelphia, PA
Jason Xu
Jonathan H. Sussman
Omar Elghawy
2Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA
Austin Yang
7Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA
Adam Barsouk
2Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA
Jong Hyun Cho
Carolyn E. Shaw
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Ekta Singh
Ositadimma Ugwuanyi
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Luca Paruzzo
Federico Stella
Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia
Shan Liu
Siena Nason
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Antonio Imparato
Antonia Rotolo
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Jean Lemoine
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
David M. Barrett
Avery Posey
1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA
Alain H. Rook
10Department of Dermatology, University of Pennsylvania, Philadelphia, PA
Vinodh Pillai
Adam Bagg
6Division of Hematopathology, University of Pennsylvania, Philadelphia, PA
Stefano A. Pileri
12Division of Hematopathology, Istituto Europeo di Oncologia, Milan, Italy
Dongfang Liu
Kai Tan
Stephen J. Schuster
Lymphoma Program, Abramson Cancer Center, Division of Hematology Oncology, Department of Medicine, University of Pennsylvania
David T. Teachey
Patrizia Porazzi
Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia
Marco Ruella