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M. Patel
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-008 - Phase 1/2 Study of Mocetinostat and Durvalumab (MEDI4736) in Patients with Advanced Solid Tumors and Non Small Cell Lung Cancer (NSCLC) (ID 5521)
14:30 - 14:30 | Author(s): M. Patel
- Abstract
Background:
Immune checkpoint inhibitors produce durable clinical responses in a subset of patients, however strategies are needed to improve clinical efficacy of these agents and overcome innate or acquired resistance to therapy. Growing evidence suggests that tumors evade immune detection through modulation of intrinsic immunogenicity and inhibition of both innate and adaptive anti-tumor immune responses. Mocetinostat, a class I histone deacetylase inhibitor, has multiple potential immunomodulatory features including: 1) induction of tumor associated antigens and major histocompatibility complex Class I and Class II expression on tumor cells, 2) induction of immunogenic cell death via activation and cross-presentation of tumor antigens by antigen presenting cells, 3) enhanced function of T effector cells, and 4) decreased function of immunosuppressive cell subsets including regulatory T cells and myeloid derived suppressor cells. Given these pleiotropic immune activating effects, combination therapy of mocetinostat and PD-L1 blocking mAb, durvalumab, is a rational approach to restoring or enhancing the clinical activity of immune checkpoint blockade in patients with NSCLC.
Methods:
This open-label Phase 1/2 study is evaluating the tolerability and clinical activity of mocetinostat in combination with durvalumab. Secondary objectives include pharmacokinetics, incidence of anti-drug antibodies, and changes in tumor PD-L1 expression. Exploratory objectives evaluate changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations and cytokines. Phase 1 explores increasing doses of mocetinostat administered orally (50, 70, 90 mg three times weekly [TIW]) in combination with durvalumab in patients with advanced solid tumors. The regimen begins with a 7-Day Lead-in Period of mocetinostat single agent TIW followed by the combination regimen with durvalumab (1500 mg intravenously every 28 days). Phase 2 evaluates the clinical activity of mocetinostat and durvalumab, as assessed by Objective Response Rate (ORR) by RECIST 1.1., in patients with NSCLC who have previously received at least one platinum containing doublet chemotherapy regimen for advanced disease. Four population cohorts are included: 1) immunotherapy naïve, no/low PD-L1 expression, 2) immunotherapy naïve, high PD-L1 expression, 3) prior clinical benefit with PD-L1 or PD-1 inhibitor treatment followed by progression, 4) prior treatment with PD-L1 or PD-1 inhibitor with progression within 16 weeks of initiation of treatment. Tumor PD-L1 expression will be determined by the SP263 assay. The sample sizes for the populations are based on two-stage Simon Optimal Designs. Status: Enrollment into the study opened in June 2016. Clinical Trial Information: NCT02805660
Results:
Section not applicable
Conclusion:
Section not applicable
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-057 - Viroimmunotherapy with Vesicular Stomatitis Virus Expressing Interferon-β (Vsv-IFNβ) in a Murine Model of NSCLC (ID 6217)
14:30 - 14:30 | Author(s): M. Patel
- Abstract
Background:
VSV-IFNβ is a live, replicating oncolytic virus with activity against NSCLC. We have previously shown that VSV-IFNβ leads to an inflamed tumor microenvironment and enhances anti-tumor immunity in a syngeneic mouse model. Furthermore, we have observed increased PDL-1 expression on tumor cells after intratumoral injection with VSV-IFNβ. Here, we have further explored the mechanisms by which VSV-IFNβ exerts its immunologic effects and combined therapy with anti-PD1 and anti-PDL1 antibodies.
Methods:
VSV-human and murine IFNβ (hIFNβ and mIFNβ, respectively) and VSV-IFNβ-NIS are manufactured by the Imanis Life (Rochester, MN) and titered on Vero cells by limiting dilution method. H460, H2009, H838, H2030, and A549 human NSCLC cells were grown in RPMI with 10% serum. LM2 cells (murine lung adenocarcinoma cells) were grown in DMEM with 10% serum. For cytotoxicity assays, NSCLC cells are treated with VSV-IFNβ at varying MOI. CCK8 assay was used to estimate cell viability 72 hours later. For in vivo experiments, A/J mice are injected with 2x10[6] LM2 cells in the flank. After tumors form, unilateral intratumoral injections are given at varying doses on days 1,3, and 5. For combination experiments, VSV-IFNβ is given in combination with intraperitoneal anti-PD1 or PDL1 antibodies or Isotype IgG or with JAK inhibitor, ruxolitinib. Tumor infiltrating leukocytes (TIL) were analyzed by flow cytometry for presence of CD8/CD4 T cells, Tregs, and MDSCs after VSV-IFNβ infection.
Results:
VSV-IFNβ treatment on human NSCLC cells induced PDL-1 expression by Western blot and flow cytometry, but not VSV-GFP which is abrogated by pretreatment with ruxolitinib. Furthermore, viral replication was enhanced by pretreatment with ruxolitinib. In vivo immune effects of combination ruxolitinib and VSV-IFNβ are ongoing. TILs were examined by flow cytometry after intratumoral injection of VSV-mIFNβ or VSV-hIFNβ. There was increased T-cell infiltration, decreased Tregs and increased PDL-1 expression in both groups. Antitumor activity was similar between VSV-mIFNβ and VSV-hIFNβ suggesting that effects observed are mediated by the virus rather than exogenous IFNβ. CD4 T cell depletion had no effect on antitumor responses or on immune infiltration of CD8 T cells in the tumor microenvironment. CD8 T cell depletion experiments and combination treatments of VSV-IFNβ and VSV-IFNβ-NIS with Anti-PD1/PDL1 antibodies are ongoing.
Conclusion:
VSV-IFNβ is a promising oncolytic agent for non-small cell lung cancer and induces an inflamed tumor microenvironment in a process that is independent of exogenous IFNβ and CD4 T cells. Our data support clinical testing of VSV-IFNβ with checkpoint blockade for NSCLC.
