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A comprehensive preclinical study supporting clinical trial of oncolytic chimeric poxvirus CF33-hNIS-anti-PD-L1 to treat breast cancer.

ABSTRACT: CF33-hNIS-anti-PD-L1 is an oncolytic chimeric poxvirus encoding two transgenes: human sodium iodide symporter and a single-chain variable fragment against PD-L1. Comprehensive preclinical pharmacology studies encompassing primary and secondary pharmacodynamics and biodistribution and safety studies were performed to support the clinical development of CF33-hNIS-anti-PD-L1. Most of the studies were performed in triple-negative breast cancer (TNBC) models, as the phase I trial is planned for patients with TNBC. Biological functions of virus-encoded transgenes were confirmed, and the virus demonstrated anti-tumor efficacy against TNBC models in mice. In a good laboratory practice (GLP) toxicology study, the virus did not produce any observable adverse effects in mice, suggesting that the doses proposed for the clinical trial should be well tolerated in patients. Furthermore, no neurotoxic effects in mice were seen following intracranial injection of the virus. Also, the risk for horizontal transmission of CF33-hNIS-anti-PD-L1 was assessed in mice, and our results suggest that the virus is unlikely to transmit from infected patients to healthy individuals. Finally, the in-use stability and compatibility of CF33-hNIS-anti-PD-L1 tested under different conditions mimicking the clinical scenarios confirmed the suitability of the virus in clinical settings. The results of these preclinical studies support the use of CF33-hNIS-anti-PD-L1 in a first-in-human trial in patients with TNBC.

SUBMITTER: Chaurasiya S

PROVIDER: S-EPMC8718831 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Oncolytic poxvirus CF33-hNIS-?F14.5 favorably modulates tumor immune microenvironment and works synergistically with anti-PD-L1 antibody in a triple-negative breast cancer model.

Project description:Triple-negative breast cancer is the most aggressive subtype of breast cancer and is difficult to treat. Breast cancer is considered to be poorly immunogenic and hence is less responsive to immunotherapies. We tested whether the oncolytic poxvirus CF33-hNIS-?F14.5 could modulate tumor immune microenvironment and make the tumors responsive to the immune checkpoint inhibitor anti-PD-L1. We found that virus infection causes the upregulation of PD-L1 levels on triple-negative breast cancer cells in vitro as well as in vivo in mice. In a mouse model of orthotopic triple-negative breast cancer, the virus was found to increase tumor infiltration by CD8+ T cells. Likewise, in mice treated with CF33-hNIS-?F14.5 high levels of proinflammatory cytokines IFN? and IL-6 were found in the tumors but not in the serum. The levels of immune modulation were even higher in mice that were treated with a combination of the virus and anti-PD-L1 antibody. While CF33-hNIS-?F14.5 and anti-PD-L1 antibody failed to exert significant anti-tumor effect as a single agent, a combination of the two agents resulted in significant anti-tumor effect with 50% mice experiencing complete tumor regression when both agents were injected intra-tumorally. Furthermore, the 'cured' mice did not develop tumor after re-challenge with the same cancer cells suggesting that they developed immunity against those cancer cells. Taken together, our study shows that CF33-hNIS-?F14.5 favorably modulates tumor immune microenvironment in triple-negative breast cancer model making them responsive to the immune checkpoint inhibitor anti-PD-L1, and hence warrants further studies to determine the clinical applicability of this combination therapy.

| S-EPMC7051185 | biostudies-literature

CF33-hNIS-antiPDL1 virus primes pancreatic ductal adenocarcinoma for enhanced anti-PD-L1 therapy.

Project description:Immunotherapeutic strategies that combine oncolytic virus (OV) and immune checkpoint inhibitors have the potential to overcome treatment resistance in pancreatic ductal adenocarcinoma (PDAC), one of the least immunogenic solid tumors. Oncolytic viral chimera, CF33-hNIS-antiPDL1 genetically modified to express anti-human PD-L1 antibody and CF33-hNIS-Δ without the anti-PD-L1 gene, were used to investigate the immunogenic effects of OVs and virus-delivered anti-PD-L1 in PDAC in vitro. Western blot, flow cytometry, and immunofluorescence microscopy were used to evaluate the effects of CF33-hNIS-Δ and IFNγ on PD-L1 upregulation in AsPC-1 and BxPC-3 cells, and CF33-hNIS-antiPDL1 production of anti-PD-L1 and surface PD-L1 blockade of AsPC-1 and BxPC-3 with or without cocultured activated T cells. The cytosolic and cell surface levels of PD-L1 in PDAC cell lines varied; only BxPC-3 showed high cell surface expression. Treatment of these cells with CF33-hNIS-Δ and IFNγ significantly upregulated PD-L1 expression and translocation of PD-L1 from the cytosol onto the cell surface. Following coculture of activated T cells and BxPC-3 with CF33-hNIS-antiPDL1, the cell surface PD-L1 blockade on BxPC-3 cells by virus-delivered anti-PD-L1 antibody increased granzyme B release and prevented virus-induced decrease of perforin release from activated CD8+ T cells. Our results suggest that CF33-IOVs can prime immune checkpoint inhibition of PDAC and enhance antitumor immune killing.

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Project description: Not available

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PET imaging and treatment of pancreatic cancer peritoneal carcinomatosis after subcutaneous intratumoral administration of a novel oncolytic virus, CF33-hNIS-antiPDL1

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| S-EPMC8784298 | biostudies-literature

An Oncolytic Poxvirus Encoding hNIS, Shows Antitumor Efficacy and Allows Tumor Imaging in a Liver Cancer Model

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Vaccinia Virus Shuffling: deVV5, a Novel Chimeric Poxvirus with Improved Oncolytic Potency.

Project description:Oncolytic virus (OV) therapy has emerged as a promising approach for cancer treatment with the potential to be less toxic and more efficient than classic cancer therapies. Various types of OVs in clinical development, including Vaccinia virus (VACV)-derived OVs, have shown good safety profiles, but limited therapeutic efficacy as monotherapy in some cancer models. Many different methods have been employed to improve the oncolytic potency of OVs. In this study, we used a directed evolution process, pooling different strains of VACV, including Copenhagen, Western Reserve and Wyeth strains and the attenuated modified vaccinia virus Ankara (MVA), to generate a new recombinant poxvirus with increased oncolytic properties. Through selective pressure, a chimeric VACV, deVV5, with increased cancer cell killing capacity and tumor selectivity in vitro was derived. The chimeric viral genome contains sequences of all parental strains. To further improve the tumor selectivity and anti-tumor activity of deVV5, we generated a thymidine kinase (TK)-deleted chimeric virus armed with the suicide gene FCU1. This TK-deleted virus, deVV5-fcu1 replicated efficiently in human tumor cells, and was notably attenuated in normal primary cells. These studies demonstrate the potential of directed evolution as an efficient way to generate recombinant poxviruses with increased oncolytic potency, and with high therapeutic index to improve cancer therapy.

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A Novel Chimeric Poxvirus Encoding hNIS Is Tumor-Tropic, Imageable, and Synergistic with Radioiodine to Sustain Colon Cancer Regression.

Project description:Colon cancer has a high rate of recurrence even with good response to modern therapies. Novel curative adjuncts are needed. Oncolytic viral therapy has shown preclinical promise against colon cancer but lacks robust efficacy in clinical trials and raises regulatory concerns without real-time tracking of viral replication. Novel potent vectors are needed with adjunctive features to enhance clinical efficacy. We have thus used homologous recombination and high-throughput screening to create a novel chimeric poxvirus encoding a human sodium iodide symporter (hNIS) at a redundant tk locus. The resulting virus (CF33-hNIS) consistently expresses hNIS and demonstrates replication efficiency and immunogenic cell death in colon cancer cells in vitro. Tumor-specific CF33-hNIS efficacy against colon cancer results in tumor regression in vivo in colon cancer xenograft models. Early expression of hNIS by infected cells makes viral replication reliably imageable via positron emission tomography (PET) of I-124 uptake. The intensity of I-124 uptake mirrors viral replication and tumor regression. Finally, systemic delivery of radiotherapeutic I-131 isotope following CF33-hNIS infection of colon cancer xenografts enhances and sustains tumor regression compared with virus treatment alone in HCT116 xenografts, demonstrating synergy of oncolytic viral therapy with radioablation in vivo.

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PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy.

Project description:Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively. Systemic therapeutic targeting of programmed cell death receptor 1 (PD-1) or PD-L1 in combination with intratumoral NDV resulted in the rejection of both treated and distant tumors. These findings have implications for the timing of PD-1/PD-L1 blockade in conjunction with OV therapy and highlight the importance of understanding the adaptive mechanisms of immune resistance to specific OVs for the rational design of combinatorial approaches using these agents.

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Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors.

Project description:Chimeric antigen receptor-modified T cells (CAR T cells) produce proinflammatory cytokines that increase expression of T-cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the proinflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body; HDPDL1) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VECPDL1) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HDPDL1 exhibited no antitumor effect and CAd-VECPDL1 alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VECPDL1 with HER2.CAR T cells enhanced antitumor activity compared with treatment with either HER2.CAR T cells alone or HER2.CAR T cells plus Onc.Ad. The benefits of locally produced PD-L1 mini-body by CAd-VECPDL1 could not be replicated by infusion of anti-PD-L1 IgG plus HER2.CAR T cells and coadministration of Onc.Ad in an HER2+ prostate cancer xenograft model. Overall, our data document the superiority of local production of PD-L1 mini-body by CAd-VECPDL1 combined with administration of tumor-directed CAR T cells to control the growth of solid tumors. Cancer Res; 77(8); 2040-51. ©2017 AACR.

| S-EPMC5392365 | biostudies-literature

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