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Published on: November 12, 2019
AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells
R Leo Sakemura1,2, Mehrdad Hefazi1,2, Michelle J Cox1
1T Cell Engineering, Mayo Clinic, Rochester, Minnesota.
Abstract:
The receptor tyrosine kinase AXL is a member of the TYRO3, AXL, and proto-oncogene tyrosine-protein kinase MER family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)-cell therapy. To test this, we determined the impact of AXL inhibition on CD19-targeted CAR T (CART19)-cell functions. Our results demonstrate that T cells and CAR T cells express high levels of AXL. Specifically, higher levels of AXL on activated Th2 CAR T cells and M2-polarized macrophages were observed. AXL inhibition with small molecules or via genetic disruption in T cells demonstrated selective inhibition of Th2 CAR T cells, reduction of Th2 cytokines, reversal of CAR T-cell inhibition, and promotion of CAR T-cell effector functions. AXL inhibition is a novel strategy to enhance CAR T-cell functions through two independent, but complementary, mechanisms: targeting Th2 cells and reversing myeloid-induced CAR T-cell inhibition through selective targeting of M2-polarized macrophages.
Insights
AXL inhibition can enhance chimeric antigen receptor T (CAR T)-cell therapy efficacy. Blocking AXL targets immunosuppressive cells and improves CAR T-cell functions, overcoming resistance to cancer immunotherapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The receptor tyrosine kinase AXL is implicated in cancer progression and immunotherapy resistance.
- AXL expression in immunosuppressive cells reduces the effectiveness of immunotherapies like CAR T-cell therapy.
Purpose of the Study:
- To investigate the potential of AXL inhibition as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)-cell therapy.
- To determine the impact of AXL inhibition on CD19-targeted CAR T (CAR T19)-cell functions.
Main Methods:
- Assessed AXL expression in T cells and CAR T cells.
- Utilized small molecule inhibitors and genetic disruption to inhibit AXL in T cells.
- Evaluated the effects of AXL inhibition on CAR T-cell effector functions and cytokine production.
Main Results:
- T cells and CAR T cells, particularly activated Th2 CAR T cells and M2-polarized macrophages, express high levels of AXL.
- AXL inhibition selectively impacted Th2 CAR T cells, reduced Th2 cytokines, and reversed CAR T-cell inhibition.
- AXL inhibition promoted CAR T-cell effector functions.
Conclusions:
- AXL inhibition is a promising strategy to enhance CAR T-cell therapy efficacy.
- AXL inhibition works through dual mechanisms: targeting Th2 cells and reversing myeloid-induced inhibition of CAR T cells.
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