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AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells.

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.

SUBMITTER: Sakemura RL

PROVIDER: S-EPMC10530462 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells.

Sakemura R Leo RL Hefazi Mehrdad M Cox Michelle J MJ Siegler Elizabeth L EL Sinha Sutapa S Hansen Michael J MJ Stewart Carli M CM Feigin Jennifer M JM Manriquez Roman Claudia C Schick Kendall J KJ Can Ismail I Tapper Erin E EE Horvei Paulina P Adada Mohamad M MM Bezerra Evandro D ED Kankeu Fonkoua Lionel Aurelien LA Ruff Michael W MW Forsman Cynthia L CL Nevala Wendy K WK Boysen Justin C JC Tschumper Renee C RC Grand Cory L CL Kuchimanchi Kameswara R KR Mouritsen Lars L Foulks Jason M JM Warner Steven L SL Call Timothy G TG Parikh Sameer A SA Ding Wei W Kay Neil E NE Kenderian Saad S SS

Cancer immunology research 20230901 9

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 ...[more]

PMID: 37378662

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Project description:Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cells in vitro and in vivo using various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of tests in vitro to evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cells in vivo. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cells in vitro. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.

Dataset Information

AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells.

Publications

AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells.

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