AML cells are heterogeneous and share protein expression with healthy HSPCs. To target AML and spare HSPC toxicity, Haubner et al. combined a sensitivity-tuned CAR for ADGRE2 (an antigen expressed poorly on HSPCs and more highly on AML) with a 4-1BB chimeric costimulatory receptor (CCR) binding CLEC12A (not expressed on HSPCs) to specifically augment CAR signaling toward ADGRE2loCLEC12A+ AML, but not CLEC12A- HPSCs. Compared to ADGRE2-alone CAR T cells, the combinatorial CAR T cells better controlled ADGRE2loCLEC12A+ AML cell lines and patient-derived xenografts in humanized mice, while minimally reducing HSPC numbers.
Contributed by Alex Najibi
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 ADGRE2(pos)CLEC12A(pos) leukemic stem cells over ADGRE2(low)CLEC12A(neg) 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-_. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue.
Author Info: (1) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York,
Author Info: (1) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (6) 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. (7) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (8) Takeda Development Center Americas, Inc., Lexington, MA 02421, USA. (9) Takeda Development Center Americas, Inc., Lexington, MA 02421, USA. (10) Department of Medicine III, University Hospital, LMU Munich, 81377 Munich, Germany. (11) 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. (12) 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. (13) 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. (14) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: m-sadelain@ski.mskcc.org.
