Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative disorder that predominantly affects infants and young children. Hematopoietic stem cell transplantation (HSCT) is standard of care, but post-HSCT relapse is common, highlighting the need for innovative therapies. While adoptive immunotherapy with chimeric antigen receptor (CAR) T cells has improved outcomes for patients with advanced lymphoid malignancies, it has not been comprehensively evaluated in JMML. In the present study, we use bulk and single-cell RNA sequencing, mass spectrometry, and flow cytometry to identify overexpression of CLL-1 (encoded by CLEC12A) on the cell surface of cells from patients with JMML. We develop immunotherapy with CLL-1 CAR T cells (CLL1CART) for preclinical testing and report in vitro and in vivo anti-leukemia activity. Notably, CLL1CART reduce the number of leukemic stem cells and serial transplantability in vivo. These preclinical data support the development and clinical investigation of CLL-1-targeting immunotherapy in children with relapsed/refractory JMML.
Authors
- Mignon L. Loh (ORCID: https://orcid.org/0000-0003-4099-4700)
- William C. Temple
- Alex G. Lee (ORCID: https://orcid.org/0000-0003-0107-5920)
- Stefanie Bachl (ORCID: https://orcid.org/0009-0002-2732-2125)
- Bonell Patiño-Escobar (ORCID: https://orcid.org/0000-0003-2622-4822)
- Benjamin S. Braun (ORCID: https://orcid.org/0000-0002-7363-9185)
- Elliot Stieglitz (ORCID: https://orcid.org/0000-0001-7032-4623)
- Soheil Meshinchi (ORCID: https://orcid.org/0000-0002-6276-4423)
- Shubhmita Bhatnagar (ORCID: https://orcid.org/0000-0002-2721-9307)
- José M. Rivera (ORCID: https://orcid.org/0000-0002-9126-4559)
- Adila Izgutdina (ORCID: https://orcid.org/0000-0002-3296-3261)
- Arun P. Wiita (ORCID: https://orcid.org/0000-0002-7465-6964)
- Chujing Zhang
- Sarah K. Tasian (ORCID: https://orcid.org/0000-0003-1327-1662)
- Carolina E. Morales (ORCID: https://orcid.org/0000-0001-7657-0817)
- Emilio Ramos
- Sibapriya Chaudhuri
- Abhilash Barpanda (ORCID: https://orcid.org/0000-0001-8158-4949)
- Sherin Xirenayi
- Hanna Shin (ORCID: https://orcid.org/0009-0000-5834-2845)
- Julia Meyer (ORCID: https://orcid.org/0000-0001-5945-9885)
- Juwita Werner (ORCID: https://orcid.org/0009-0007-9635-2519)
- Kamal Mandal
- Sydney Abelson (ORCID: https://orcid.org/0009-0003-0883-4165)
- Khadija Yousuf
- Jackson K Dardis
Institutions
- Gladstone Institutes (US)
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Children's Hospital of Philadelphia (US)
- University of California, San Francisco (US)
- Department of Biotechnology (IN)
- Medizinische Hochschule Hannover (DE)
- Fred Hutch Cancer Center (US)
- Seattle Children's Hospital (US)
- Parker Institute for Cancer Immunotherapy (US)
- Chan Zuckerberg Initiative (United States) (US)
- UCSF Benioff Children's Hospital (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1038/s41467-025-59040-6
- Citations
- 2
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Else Kröner-Fresenius-Stiftung
- Deutsche Krebshilfe
- National Institutes of Health
- National Cancer Institute