25 research outputs found
New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties
Novel Benzofuran and Benzothiophene Biphenyls as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties
Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.
Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles. In support of this endeavor, we characterized the tumor microenvironment of four commonly used models and demonstrate they encompass a range of immunogenicities, from highly immune infiltrated RENCA tumors to poorly infiltrated B16F10 tumors. Tumor cell lines for each model exhibit different intrinsic factors in vitro that likely influence immune infiltration upon subcutaneous implantation. Similarly, solid tumors in vivo for each model are unique, each enriched in distinct features ranging from pathogen response elements to antigen presentation machinery. As RENCA tumors progress in size, all major T cell populations diminish while myeloid-derived suppressor cells become more enriched, possibly driving immune suppression and tumor progression. In CT26 tumors, CD8 T cells paradoxically increase in density yet are restrained as tumor volume increases. Finally, immunotherapy treatment across these different tumor-immune landscapes segregate into responders and non-responders based on features partially dependent on pre-existing immune infiltrates. Overall, these studies provide an important resource to enhance our translation of syngeneic models to human tumors. Future mechanistic studies paired with this resource will help identify responsive patient populations and improve strategies where immunotherapies are predicted to be ineffective
Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses In Vivo
International audienceB-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to rechallenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8 镁 T cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance antitumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell-directed checkpoint modulators
Supplementary Figure 4 from Activating Inducible T cell Co-stimulator (ICOS) yields anti-tumor activity alone and in combination with anti-PD-1 checkpoint blockade
Uncropped gel images</p
Supplementary Figure 2 from Activating Inducible T cell Co-stimulator (ICOS) yields anti-tumor activity alone and in combination with anti-PD-1 checkpoint blockade
Flow cytometry gating strategy for ICOS on individual T cell populations.</p
Supplementary Figure 7 from Activating Inducible T cell Co-stimulator (ICOS) yields anti-tumor activity alone and in combination with anti-PD-1 checkpoint blockade
Healthy human donor CD4+ T cells were pre-activated with antiCD3/CD28 for 48 hours and then re-stimulated with plate-bound anti-CD3 in the presence of increasing concentrations of soluble or plate-bound feladilimab or isotype control for 72 hours. IFNg levels were then assessed from cell-free supernatants using Meso Scale Discovery (MSD)-based detection.</p
Supplementary Table 6 from Activating Inducible T cell Co-stimulator (ICOS) yields anti-tumor activity alone and in combination with anti-PD-1 checkpoint blockade
Example TIL marker expression phenotypes from clinical patient
case studies of feladilimab monotherapy and in combination with pembrolizumab.</p
Supplementary Figure 12 from Activating Inducible T cell Co-stimulator (ICOS) yields anti-tumor activity alone and in combination with anti-PD-1 checkpoint blockade
Clinical case studies of feladilimab monotherapy and in
combination with pembrolizumab.</p
Supplementary Figure 6 from Activating Inducible T cell Co-stimulator (ICOS) yields anti-tumor activity alone and in combination with anti-PD-1 checkpoint blockade
Feladilimab-mediated ICOS co-stimulation results in differential
phenotypic changes and cytokine production in CD4+ non-Treg and Treg populations.</p