Cellular immunotherapy targeting CLL-1 for juvenile myelomonocytic leukemia

Juwita Werner, Alex G. Lee, Chujing Zhang, Sydney Abelson, Sherin Xirenayi, Jose Rivera, Khadija Yousuf, Hanna Shin, Bonell Patiño-Escobar, Stefanie Bachl, Kamal Mandal, Abhilash Barpanda, Emilio Ramos, Adila Izgutdina, Sibapriya Chaudhuri, William C. Temple, Shubhmita Bhatnagar, Jackson K. Dardis, Julia Meyer, Carolina Morales, Soheil Meshinchi, Mignon L. Loh, Benjamin Braun, Sarah K. Tasian, Arun P. Wiita and Elliot Stieglitz ()
Additional contact information
Juwita Werner: University of California
Alex G. Lee: University of California
Chujing Zhang: University of California
Sydney Abelson: University of California
Sherin Xirenayi: University of California
Jose Rivera: University of California
Khadija Yousuf: University of California
Hanna Shin: University of California
Bonell Patiño-Escobar: University of California
Stefanie Bachl: University of California
Kamal Mandal: University of California
Abhilash Barpanda: University of California
Emilio Ramos: University of California
Adila Izgutdina: University of California
Sibapriya Chaudhuri: University of California
William C. Temple: University of California
Shubhmita Bhatnagar: Children’s Hospital of Philadelphia
Jackson K. Dardis: Children’s Hospital of Philadelphia
Julia Meyer: University of California
Carolina Morales: University of California
Soheil Meshinchi: Fred Hutchinson Cancer Center
Mignon L. Loh: University of Washington
Benjamin Braun: University of California
Sarah K. Tasian: Children’s Hospital of Philadelphia
Arun P. Wiita: University of California
Elliot Stieglitz: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59040-6

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