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CAR T-cells targeting CD117 effectively eliminate mast cells in preclinical models of advanced systemic mastocytosis
Anne Kaiser1,2,3, Veronika Lysenko1, Renier Myburgh1
1Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
Abstract:
Systemic mastocytosis (SM) is characterized by uncontrolled expansion of neoplastic mast cells (MCs) and their accumulation in various tissues and organs, ranging from indolent variants to more advanced forms (advSM). Although several MC- and SM-expressed cell surface antigens have been identified, no immune therapy has been developed for advSM so far. The receptor tyrosine kinase KIT (CD117) is highly expressed on MCs, exceeding the levels of expression on hematopoietic stem and progenitor cells (HSPC). Therefore, targeting CD117 in advSM could be of therapeutic value. In this study, we assessed the therapeutic potential of anti-CD117 chimeric antigen receptor (CAR) T-cells to target neoplastic MCs in SM. In vitro, anti-CD117-CAR T-cells efficiently lysed several SM-related human MC cell lines, MCs differentiated from SM patient-derived induced pluripotent stem (iPS) cells, and neoplastic bone marrow cells obtained from SM patients. Furthermore, in immunocompromised mice engrafted with an advSM-like MC cell line, repetitive applications of anti-CD117-CAR T-cells were able to inhibit MC expansion. These data may pave the way for the development of anti-CD117-CAR T-cell therapies in advSM.
Insights
Chimeric antigen receptor (CAR) T-cells targeting CD117 show promise for treating advanced systemic mastocytosis (advSM). These engineered T-cells effectively eliminated cancer cells in lab tests and reduced tumor growth in mice, offering a potential new therapy for advSM.
Area of Science:
- Immunology
- Oncology
- Hematology
Background:
- Systemic mastocytosis (SM) involves abnormal mast cell (MC) growth and accumulation.
- Advanced SM (advSM) lacks effective immune therapies despite identified MC-specific antigens.
- The CD117 receptor tyrosine kinase is highly expressed on neoplastic MCs in SM.
Purpose of the Study:
- To evaluate the therapeutic potential of anti-CD117 chimeric antigen receptor (CAR) T-cells against neoplastic MCs in SM.
- To determine if CAR T-cells can target and eliminate cancer cells in SM.
Main Methods:
- Developed and tested anti-CD117 CAR T-cells.
- Assessed CAR T-cell efficacy in vitro against SM cell lines, patient-derived MCs, and bone marrow cells.
- Evaluated CAR T-cell therapy in an immunocompromised mouse model of advSM.
Main Results:
- Anti-CD117 CAR T-cells demonstrated potent lysis of various SM-related neoplastic MCs in vitro.
- CAR T-cells inhibited MC expansion in a mouse model of advSM after repetitive administration.
- Neoplastic bone marrow cells from SM patients were targeted by the CAR T-cells.
Conclusions:
- Anti-CD117 CAR T-cells are a promising strategy for targeting neoplastic MCs in SM.
- These findings support the development of anti-CD117 CAR T-cell therapy for advSM.
- Targeting CD117 offers a potential therapeutic avenue for patients with advanced systemic mastocytosis.
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