ZIA BC 010598 (ZIA) | |||
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Title | Human Immune Responses to Tumor Antigens for Cancer Immunotherapy | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Schlom, Jeffrey | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $785,837 | 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 (20.0%) |
Breast (15.0%) Colon/Rectum (20.0%) Hodgkins disease (5.0%) Leukemia (5.0%) Lung (5.0%) Multiple Myeloma (5.0%) Non Hodgkins Lymphoma (5.0%) Ovarian Cancer (5.0%) Prostate (30.0%) |
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Research Type | |||
Vaccines Systemic Therapies - Discovery and Development |
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Abstract | |||
Recent accomplishments include the following: [ ] PHASE 1 TRIAL OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING PD-L1 AND TGF-beta, IN ADVANCED SOLID TUMORS. M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a TGFbeta ""trap."" In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/ pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade greater than or equal to3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFb1, -b2, and -b3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. [ ] PHASE I STUDY OF A POXVIRAL TRICOM-BASED VACCINE DIRECTED AGAINST THE TRANSCRIPTION FACTOR BRACHYURY. The transcription factor brachyury has been shown in preclinical studies to be a driver of the epithelial-to-mesenchymal transition (EMT) and resistance to therapy of human tumor cells. This study describes the characterization of a Modified Vaccinia Ankara (MVA) vector-based vaccine expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM) and a phase I study with this vaccine. Human dendritic cells (DC) were infected with MVA-brachyury-TRICOM to define their ability to activate brachyury-specific T cells. A dose-escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38) to define safety and to identify brachyury-specific T-cell responses. MVA-brachyury-TRICOM-infected human DCs activated CD8+ and CD4+ T cells specific against the self-antigen brachyury in vitro. No dose-limiting toxicities were observed due to vaccine in cancer patients at any of the three dose levels. Brachyury-specific T-cell responses were observed at all dose levels and in most patients. The MVA-brachyury-TRICOM vaccine directed against a transcription factor known to mediate EMT can be administered safely in patients with advanced cancer and can activate brachyury-specific T cells in vitro and in patients. Further studies of this vaccine in combination therapies are warranted and planned. [ ] ANALYSES OF THE PERIPHERAL IMMUNOME FOLLOWING MULTIPLE ADMINISTRATIONS OF AVELUMAB, A HUMAN IgG1 ANTI-PD-L1 MONOCLONAL ANTIBODY. Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAbs) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb, which has been shown |