Cooperative CAR targeting to selectively eliminate AML and minimize escape Journal Article
| Authors: | Haubner, S.; Mansilla-Soto, J.; Nataraj, S.; Kogel, F.; Chang, Q.; de Stanchina, E.; Lopez, M.; Ng, M. R.; Fraser, K.; Subklewe, M.; Park, J. H.; Wang, X.; Rivière, I.; Sadelain, M. |
| Article Title: | Cooperative CAR targeting to selectively eliminate AML and minimize escape |
| 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 ADGRE2posCLEC12Apos leukemic stem cells over ADGRE2lowCLEC12Aneg 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. © 2023 The Author(s) |
| Keywords: | leukemia, myeloid, acute; t lymphocyte; t-lymphocytes; mouse; animal; metabolism; animals; mice; cell line, tumor; tumor cell line; hematopoietic stem cells; chimeric antigen receptor; hematopoietic stem cell; adoptive immunotherapy; immunotherapy, adoptive; lectins, c-type; lectin; hematotoxicity; combinatorial targeting; acute myeloid leukemia; lectin receptor; receptors, mitogen; humans; human; car t cell therapy; cooperative car; icaht; if-better gate; off-target toxicity; on-target toxicity; clec12a protein, human |
| Journal Title: | Cancer Cell |
| Volume: | 41 |
| Issue: | 11 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2023-11-13 |
| Start Page: | 1871 |
| End Page: | 1891.e6 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2023.09.010 |
| PUBMED: | 37802054 |
| PROVIDER: | scopus |
| PMCID: | PMC11006543 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Michel Sadelain -- Source: Scopus |
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