Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Hodgkin lymphoma, Biological therapies, Antibody Therapy, Translational Research, Lymphomas, non-Hodgkin lymphoma, B Cell lymphoma, Checkpoint Inhibitor, drug development, Diseases, indolent lymphoma, aggressive lymphoma, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy
Results: IMT-009 is a highly selective antibody to CD161 that strongly blocks its interaction with CLEC2D. In presence of CLEC2D-expressing target cells, NK cell degranulation, cytokine production and cellular cytotoxicity towards lymphoma tumor targets is highly suppressed which is overcome by treatment with IMT-009. Similarly, IMT-009 reversed CLEC2D-mediated inhibition and restored T cell activity (TCR signaling, cytokine production) in a Jurkat cell reporter system, and enhanced polyfunctionality of primary antigen-specific human T cells shown by secretion of TNF-α, IL-2, and IFN-γ, and direct T cell mediated cytotoxicity. IMT-009 also released CD161-mediated suppression of antigen recall response by PBMC derived effector memory CD161+ CD4+ T cells, resulting in an increased frequency of CD161+ IFN-γ+ cells and an increase in their proliferation. These data together show that IMT-009 is highly effective in overcoming CLEC2D mediated suppression of both T and NK cell functions.
To prioritize indications that will likely benefit from IMT-009, we performed IHC for CLEC2D in a diverse set of tumor indications and found that B cell lymphomas of various subtypes have high CLEC2D protein expression by H score. Also, DLBCL was found to have the second highest median RNA expression of CLEC2D in TCGA. Furthermore, analysis of publicly available single-cell RNA-sequencing (scRNA-seq) data from B cell lymphoma including CNS lymphoma revealed CLEC2D to be highly expressed within the B lineage cells including the abundant malignant cell population (Fig2). KLRB1 (gene encoding for CD161) was also found to be expressed on a subset of tumor infiltrating CD4 and CD8 T cells in these datasets (Fig2). To confirm this, we tested CD161 expression in B cell lymphomas by immunofluorescence. Results showed CD161+ cells infiltrated in Hodgkin Lymphoma, and post-R-CHOP treated DLBCL, highlighting the potential sensitivity of these malignancies to IMT-009 treatment. Together, these results indicate that B cell lymphomas may exhibit an immunosuppressive environment mediated by the CLEC2D/CD161 axis. To test the anti-tumor benefit of IMT-009 in a human B cell lymphoma model, we treated CD34+ humanized mice implanted with Raji, a Burkitt lymphoma cell line with IMT-009. The group of mice treated with IMT-009 had a mean tumor growth inhibition of 35% and the anti-tumor response correlated with increased frequency of CD161+ T and NK cells. We further show that IMT-009 can synergize with Rituximab in NK cell mediated killing of B cell lymphoma cell lines in vitro.
Conclusion: B cell malignancies tend to respond poorly to anti-PD-1 therapy4,5. This lack of efficacy could be driven by a highly immunosuppressive environment mediated by the CLEC2D/CD161 axis. Our results support evaluation of IMT-009 as a novel cancer immunotherapy to disrupt CLEC2D/CD161 signaling, with strong therapeutic potential in lymphomas.
Disclosures: Bernstein: Immunitas Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Scanlon: Immunitas Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Fusco: Immunitas Therapeutics: Ended employment in the past 24 months. Irvine: Immunitas Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Brown: Immunitas Therapeutics: Ended employment in the past 24 months. Colbert: Immunitas Therapeutics: Ended employment in the past 24 months. Huggins: Immunitas Therapeutics: Current Employment. Ross: Immunitas Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Tang: Immunitas Therapeutics: Current Employment. Malu: Immunitas Therapeutics: Current Employment, Current holder of stock options in a privately-held company.
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