Development of CAR T cells Targeting a Surface RNA Binding Protein for the Treatment of Acute Leukemias
Developing chimeric antigen receptor (CAR) T cells for acute myeloid leukemia (AML) has been challenging due to a lack of known AML-associated antigens that spare normal hematopoietic precursor cells. Here we reasoned that donor autoantibodies from AML recipients cured following allogeneic transplant and responsible for graft-versus-leukemia effect could be engineered to create effective CAR-T cells. We generated CAR-T cells against one such antigen - U5 snRNP200, an RNA helicase localized to the AML cell surface and absent from normal hematopoietic precursors. Anti-U5 snRNP200 CAR-T cells were effective in human and syngeneic models of AML as well as B-cell acute lymphoblastic leukemia (B-ALL), a setting where surface U5 snRNP200 is also present. Armoring CAR-T cells with IL-18 led to antigen gain on AML, durable remission, and protection from AML rechallenge. These data thereby identify a CAR-T cell platform which addresses prior limitations in tumor-selectivity and safety for patients with acute leukemias.
Authors
- Nina Fox
- Tamar Y. Feinberg (ORCID: https://orcid.org/0000-0003-2897-036X)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Alyssa D Fronk
- Maxim I. Maron (ORCID: https://orcid.org/0000-0001-7809-5888)
- Brianna Gipson (ORCID: https://orcid.org/0009-0005-5837-8676)
- Joshua T. Weinreb (ORCID: https://orcid.org/0000-0002-2832-7369)
- P Zhang
- Susan DeWolf (ORCID: https://orcid.org/0000-0002-2754-3537)
- Ileana C. Miranda (ORCID: https://orcid.org/0000-0003-3168-0515)
- Robert Stanley (ORCID: https://orcid.org/0000-0002-2308-6914)
- M S Lee
- Anthony F. Daniyan (ORCID: https://orcid.org/0009-0002-2742-2281)
- Bingyi Chen (ORCID: https://orcid.org/0000-0001-9525-2021)
- Kenyon Weis
- Andrew L. Kung (ORCID: https://orcid.org/0000-0002-9091-488X)
- Sarah Yoo (ORCID: https://orcid.org/0009-0000-8418-0843)
- Besnik Qeriqi (ORCID: https://orcid.org/0000-0001-8327-1081)
- Daoqi You (ORCID: https://orcid.org/0000-0003-4363-5893)
- Renata Mammone (ORCID: https://orcid.org/0000-0003-1814-2392)
- Winson Cai (ORCID: https://orcid.org/0000-0001-7121-0986)
- Satoshi Kaito (ORCID: https://orcid.org/0000-0001-7966-291X)
- Sydney Souness (ORCID: https://orcid.org/0009-0002-4738-3910)
- Jasmine S. Um (ORCID: https://orcid.org/0009-0004-5907-6453)
- Martin Akerman (ORCID: https://orcid.org/0000-0003-4457-1166)
- Alexander M. Lewis (ORCID: https://orcid.org/0000-0001-8003-9535)
- Cynthia Castro (ORCID: https://orcid.org/0009-0002-7626-8903)
- Maria Adriana Cuibus
- Charlotte Wishnack
- Jaime Alvarez-Perez
- Omar Abdel-Wahab
- Qing Chang
- Quinlan Sievers
- Kevin Chen
- Filemon S Dela Cruz
- Jennifer Lewis
- Erin Burns
- Takeshi Fujino
- Serena C Mathew
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Envisa (France) (FR)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-04-30
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-0920
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00