Long-Term Follow-Up of Gemogenovatucel-T (Vigil) Survival and Molecular Signals of Immune Response in Recurrent Ovarian Cancer

Rocconi, Rodney P.; Stanbery, Laura; Silva, Luciana Madeira da; Barrington, Robert A.; Aaron, Phylicia; Manning, Luisa; Horvath, Staci; Wallraven, Gladice; Bognar, Ernest; Walter, Adam; Nemunaitis, John

doi:10.3390/vaccines9080894

Cited by 11 publications

(12 citation statements)

References 52 publications

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“…Functional immune activation of Vigil in correlation with clinical benefit has been demonstrated via ELISPOT assay [ 18 , 19 ]. Moreover, Vigil appears to increase CD3+/CD8+ T cell circulation in advanced solid tumor patients and expands MHC-II expression activity, as determined by NanoString analysis, in correlation with clinical benefit [ 20 , 21 ]. Safety and evidence of efficacy of Vigil has been evaluated in several tumor types in addition to ovarian cancer [ 18 , 19 , 22 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

Network based analysis identifies TP53m-BRCA1/2wt-homologous recombination proficient (HRP) population with enhanced susceptibility to Vigil immunotherapy

et al. 2021

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Thus far immunotherapy has had limited impact on ovarian cancer. Vigil (a novel DNA-based multifunctional immune-therapeutic) has shown clinical benefit to prolong relapse-free survival (RFS) and overall survival (OS) in the BRCA wild type and HRP populations. We further analyzed molecular signals related to sensitivity of Vigil treatment. Tissue from patients enrolled in the randomized double-blind trial of Vigil vs. placebo as maintenance in frontline management of advanced resectable ovarian cancer underwent DNA polymorphism analysis. Data was generated from a 981 gene panel to determine the tumor mutation burden and classify variants using Ingenuity Variant Analysis software (Qiagen) or NIH ClinVar. Only variants classified as pathogenic or likely pathogenic were included. STRING application (version 1.5.1) was used to create a protein-protein interaction network. Topological distance and probability of co-mutation were used to calculated the C-score and cumulative C-score (cumC-score). Kaplan–Meier analysis was used to determine the relationship between gene pairs with a high cumC-score and clinical parameters. Improved relapse free survival in Vigil treated patients was found for the TP53m-BRCAwt-HRP group compared to placebo (21.1 months versus 5.6 months p = 0.0013). Analysis of tumor mutation burden did not reveal statistical benefit in patients receiving Vigil versus placebo. Results suggest a subset of ovarian cancer patients with enhanced susceptibility to Vigil immunotherapy. The hypothesis-generating data presented invites a validation study of Vigil in target identified populations, and supports clinical consideration of STRING-generated network application to biomarker characterization with other cancer patients targeted with Vigil.

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Section: Introductionmentioning

confidence: 99%

Network based analysis identifies TP53m-BRCA1/2wt-homologous recombination proficient (HRP) population with enhanced susceptibility to Vigil immunotherapy

et al. 2021

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“…Previous analyses of Vigil relationship to BRCA1/2 -wt, HRP and TP53 mutation ( p53 -mu) subpopulations revealed correlation to clinical benefit 5 – 7 , 19 , 20 . These subpopulations were explored via KM analysis to assess the effect of combination biomarkers BRCA1/2 -wt, HRP, p53 -mu and genes identified as significant following multivariate analysis in this study on Vigil and placebo treatment effects as measured by OS and RFS.…”

Section: Methodsmentioning

confidence: 97%

“…Nevertheless, we have studied patient subpopulations most sensitive to Vigil therapy based on molecular profile using NanoString assessment, and demonstrated that TIS high score (tumor inflammation score) and MHC-II expression correlated with ELISPOT reactivity and clinically to OS and RFS 19 . Likewise, using NanoString technology to assess OS and RFS in patients enrolled in the VITAL study 20 , we showed marked benefit in patients with BRCA1/2 -wt and HRP profiles and improved outcomes in patients whose tumors had mutant TP53 ( p = 0.0013).…”

Section: Introductionmentioning

confidence: 99%

ENTPD1/CD39 as a predictive marker of treatment response to gemogenovatucel-T as maintenance therapy in newly diagnosed ovarian cancer

Rocconi

Stanbery²,

Tang³

et al. 2022

Commun Med

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Background Broadened use of predictive molecular and phenotypic profiling amongst oncologists has facilitated optimal integration of targeted- and immuno-therapeutics into clinical care. However, the use of predictive immunomarkers in ovarian cancer (OC) has not consistently translated into clinical benefit. Vigil (gemogenovatucel-T) is a novel plasmid engineered autologous tumor cell immunotherapy designed to knock down the tumor suppressor cytokines, TGFβ1 and TGFβ2, augment local immune function via increased GMCSF expression and enhance presentation of clonal neoantigen epitopes. Methods: All patients enrolled in the VITAL trial (NCT02346747) of maintenance Vigil vs. placebo as front-line therapy with homologous recombination proficient (HRP) stage IIIB-IV newly diagnosed ovarian cancer underwent NanoString gene expression analysis. Tissue was obtained from surgically resected ovarian tumor tissue following surgical debulking. A statistical algorithm was used to analyze the NanoString gene expression data. Results Using the NanoString Statistical Algorithm (NSA), we identify high expression of ENTPD1/CD39 (which functions as the rate-limiting step in the production of the immune suppressor adenosine from ATP to ADP) as a presumptive predictor of response to Vigil versus placebo regardless of HRP status on the basis of relapse free survival (median not achieved vs 8.1 months, p = 0.00007) and overall survival (median not achieved vs 41.4 months, p = 0.013) extension. Conclusion NSA should be considered for application to investigational targeted therapies in order to identify populations most likely to benefit from treatment, in preparation for efficacy conclusive trials.

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“… 54 Vigil has demonstrated induction of circulating mononuclear cell increase and gIFN production to autologous tumor via ELISPOT study. 55 - 57 Moreover, increase in circulating CD8+ cells has been observed following Vigil therapy. 57 …”

Section: Discussionmentioning

confidence: 99%

Pilot Study of Combination Gemogenovatucel-T (Vigil) and Durvalumab in Women With Relapsed BRCA-wt Triple-Negative Breast or Ovarian Cancer

Barve

Aaron

Manning

et al. 2022

Clin Med Insights Oncol

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Background: Gemogenovatucel-T (Vigil) is a triple-function autologous tumor cell immunotherapy which expresses granulocyte-macrophage colony-stimulating factor and decreases expression of furin and downstream TGF-β1 and TGF-β2. Vigil has suggested survival benefit in frontline maintenance ovarian cancer patients who are BRCA-wt. In addition, Vigil demonstrates relapse-free and overall survival advantage in homologous recombination-proficient patients with OC. Further evidence of clinical benefit and safety has been demonstrated in combination with atezolizumab. Methods: In this pilot study (NCT02725489), the concurrent combination of the programmed death-ligand 1 (PD-L1) inhibitor durvalumab and Vigil was explored in advanced BRCA-wt relapsed triple-negative breast cancer (TNBC) patients and stage III-IV recurrent/refractory OC patients. Patients received the combination regimen of Vigil (1 × 10e6-10e7 cells/dose intradermally, up to 12 doses) and durvalumab (1500 mg/dose intravenous infusion, up to 12 months) once every 4 weeks. The primary objective was to evaluate safety of this combination. The study included 13 BRCA-wt patients (TNBC, n = 8; OC, n = 5). Results: The most common treatment-emergent adverse events (⩾20%) in all patients included injection-site reaction (92.3%), myalgia (38.5%), bruise at injection site (23.1%), and pruritus (23.1%). Three grade 3 treatment-related adverse events were observed and related to durvalumab. There were no grade 4/5 treatment-related adverse events. Median progression-free survival was 7.1 months and the median overall survival was not reached. Prolonged progression-free survival was improved in patients with PD-L1+ tumors (n = 8, hazard ratio = 0.304, 95% confidence interval, 0.0593-1.56, 1-sided P = .04715) compared with those with PD-L1− tumors. Conclusions: Vigil plus durvalumab was well tolerated and showed promising clinical activity in advanced BRCA-wt TNBC and stage III-IV recurrent/refractory OC patients.

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Long-Term Follow-Up of Gemogenovatucel-T (Vigil) Survival and Molecular Signals of Immune Response in Recurrent Ovarian Cancer

Cited by 11 publications

References 52 publications

Network based analysis identifies TP53m-BRCA1/2wt-homologous recombination proficient (HRP) population with enhanced susceptibility to Vigil immunotherapy

Network based analysis identifies TP53m-BRCA1/2wt-homologous recombination proficient (HRP) population with enhanced susceptibility to Vigil immunotherapy

ENTPD1/CD39 as a predictive marker of treatment response to gemogenovatucel-T as maintenance therapy in newly diagnosed ovarian cancer

Pilot Study of Combination Gemogenovatucel-T (Vigil) and Durvalumab in Women With Relapsed BRCA-wt Triple-Negative Breast or Ovarian Cancer

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