| First Author | Haubner S | Year | 2023 |
| Journal | Cancer Cell | Volume | 41 |
| Issue | 11 | Pages | 1871-1891.e6 |
| PubMed ID | 37802054 | Mgi Jnum | J:353111 |
| Mgi Id | MGI:7544780 | Doi | 10.1016/j.ccell.2023.09.010 |
| Citation | Haubner S, et al. (2023) Cooperative CAR targeting to selectively eliminate AML and minimize escape. Cancer Cell |
| abstractText | 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-gamma. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue. |
