ZIA BC 010944 (ZIA) | |||
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Title | Strategies for Cancer Immunotherapy Development: Preclinical Studies | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Schlom, Jeffrey | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,047,782 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (10.0%) |
Breast (10.0%) Colon/Rectum (10.0%) Lung (10.0%) Ovarian Cancer (10.0%) Prostate (8.0%) |
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Research Type | |||
Vaccines Systemic Therapies - Discovery and Development |
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Abstract | |||
Recent accomplishments include the following: [] ANALYSES OF FUNCTIONS OF AN ANTI-PD-L1/TGFbetaR2 BISPECIFIC FUSION PROTEIN (M7824). M7824 (MSB0011359C) is a novel first-in-class bifunctional fusion protein consisting of a fully human IgG1 anti-PD-L1 monoclonal antibody (with structural similarities to avelumab) linked to the extracellular domain of two TGFbeta receptor 2 (TGFbetaR2) molecules serving as a TGFbeta Trap. Avelumab has demonstrated clinical activity in a range of human cancers and has been approved by the FDA for the therapy of Merkel cell and bladder carcinomas. Preclinical studies have shown this anti-PD-L1 is capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC). In the studies reported here, it is shown that M7824 is also capable of mediating ADCC of a wide range of human carcinoma cells in vitro, employing natural killer (NK) cells as effectors, albeit not as potent as anti-PD-L1 employing some tumor cells as targets. The addition of the IL-15 superagonist fusion protein complex ALT-803 enhanced the ADCC capacity of both anti-PD-L1 and M7824, and to levels that both agents now demonstrated similar levels of ADCC of tumor cells. TGFbeta is a known immunosuppressive entity. Studies reported here show TGFbeta1 induced reduction of several NK activation markers as well as reduction of endogenous NK lytic activity and NK-mediated ADCC of tumor cells. These phenomena could be reduced or mitigated, however, by M7824, but not by anti-PD-L1. M7824, but not anti-PD-L1, was also shown to reduce the immunosuppressive activity of regulatory T cells on human CD4+ T-cell proliferation. These studies thus demonstrate the dual functionalities of M7824 and provide the rationale for its further clinical development. [] M7824, A NOVEL BIFUNCTIONAL ANTI-PD-L1/TGFBETA TRAP FUSION PROTEIN, PROMOTES ANTI-TUMOR EFFICACY AS MONOTHERAPY AND IN COMBINATION WITH VACCINE. Tumors evade host immune surveillance through multiple mechanisms, including the generation of a tumor microenvironment that suppresses immune effector function. Secretion of TGFbeta and upregulation of immune checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to immune evasion and tumor progression. We examined the efficacy of a first-in-class bifunctional checkpoint inhibitor, the fusion protein M7824, comprising the extracellular domain of human TGFbetaRII (TGFbeta Trap) linked to the C-terminus of human anti-PD-L1 heavy chain (aPD-L1). We demonstrate that M7824 reduces plasma TGFb1, binds to PD-L1 in the tumor, and decreases TGFbeta-induced signaling in the tumor microenvironment in mice. In murine breast and colon carcinoma models, M7824 decreased tumor burden and increased overall survival as compared to targeting TGFbeta alone. M7824 treatment promoted CD8+ T cell and NK cell activation, and both of these immune populations were required for optimal M7824-mediated tumor control. M7824 was superior to TGFbeta- or aPD-L1-targeted therapies when in combination with a therapeutic cancer vaccine. These findings demonstrate the value of using M7824 to simultaneously target TGFbeta and PD-L1/PD-1 immunosuppressive pathways to promote anti-tumor responses and efficacy. The studies also support the potential clinical use of M7824 as a monotherapy or in combination with other immunotherapies, such as therapeutic cancer vaccines, including for patients who have progressed on aPD-L1/aPD-1 checkpoint blockade therapies. [] ADCC EMPLOYING AN NK CELL LINE (haNK) EXPRESSING THE HIGH AFFINITY CD16 ALLELE WITH AVELUMAB, AN ANTI-PD-L1 ANTIBODY. NK-92 cells, and their derivative, designated aNK, were obtained from a patient with non-Hodgkin lymphoma. Prior clinical studies employing adoptively transferred irradiated aNK cells have provided evidence of clinical benefit and an acceptable safety profile. aNK cells have now been engineered to express IL-2 and the high affinity (ha) CD16 allele (designated haNK). Avelumab is a human IgG1 anti- |