Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• CD117 is a receptor on hematopoietic stem cells and acute myeloid leukemia (AML) cells.
• CD117-targeting chimeric antigen receptor T cells (CART117) are explored for AML treatment and stem cell transplant conditioning.
• Preclinical models are essential for evaluating CART117 safety and efficacy.

Purpose of the Study:

• To develop and evaluate human and mouse CART117 in preclinical models.
• To assess the safety and feasibility of targeting CD117 for AML therapy.
• To investigate factors influencing CART117 efficacy and toxicity.

Main Methods:

• Development of human and murine CART117 constructs.
• Testing in humanized and immunocompetent mouse models of AML.
• Evaluation of anti-tumor activity, systemic toxicity, and hematopoietic effects.
• Assessment of varying lymphodepletion strategies (chemotherapy, radiation) and regulatory T cell depletion.

Main Results:

• Human CART117 demonstrated potent anti-AML activity but caused significant hematopoietic toxicity in humanized mice.
• Murine CART117 (mCART117) induced systemic and hematopoietic toxicity without significant anti-leukemic benefit in immunocompetent mice.
• mCART117 selectively eliminated splenic CD117+ cells but not bone marrow cells; lymphodepleting chemotherapy amplified toxicity.
• Radiation-based lymphodepletion reduced systemic toxicity but not anti-leukemic efficacy.
• Severe pancytopenia and mortality occurred in immunodeficient mice without lymphodepletion, mimicked by regulatory T cell depletion in immunocompetent mice.
• Increased CD117 expression on AML improved mCART117 efficacy and toxicity profile.

Conclusions:

• CART117 targeting of CD117 presents a potential therapeutic strategy for AML.
• Significant systemic and hematopoietic toxicities are associated with CART117 therapy, particularly in preclinical models.
• Factors such as CD117 expression levels, lymphodepletion methods, and host immune status critically influence CART117 efficacy and safety.
• Further research is needed to optimize CART117 therapy for AML, balancing anti-leukemic activity with manageable toxicity.