System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ppublish 48 citations

PubMed: 37802054 DOI: 10.1016/j.ccell.2023.09.010

Cooperative CAR targeting to selectively eliminate AML and minimize escape.

Cancer Cell 41(11):1871-1891.e6

Authors: Sascha Haubner, Jorge Mansilla-Soto, Sarah Nataraj, Friederike Kogel, Qing Chang, Elisa de Stanchina, Michael Lopez, Mei Rosa Ng, Kathryn Fraser, Marion Subklewe, Jae H Park, Xiuyan Wang, Isabelle Rivière, Michel Sadelain

Affiliations

  • Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Takeda Development Center Americas, Inc. Lexington, MA 02421, USA.
  • Department of Medicine III, University Hospital, LMU Munich, 81377 Munich, Germany.
  • Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Abstract

Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2CLEC12A leukemic stem cells over ADGRE2CLEC12A normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.

MeSH

Stem Cells, Therapeutics, Microscopy, Electron, Scanning Transmission, T-Lymphocytes, Leukemia, Myeloid, Acute

Cited by