Repair Assisted Damage Detection (RADD) as a predictive biomarker for immunotherapy response in ovarian cancer.

Objective: Genomic instability has been proposed as a predictive biomarker for immunotherapy in ovarian cancer. We tested a method for measuring DNA damage, a direct measure of genomic instability, in ovarian tumors and its ability to predict immunotherapy response to Vigil (gemogenovatucel-T).

Methods: Eighty-two formalin-fixed paraffin-embedded tumors from the VITAL trial (NCT02346747) underwent DNA damage assessment using Repair Assisted Damage Detection (RADD).

Gemogenovatucel-T (Vigil): bi-shRNA plasmid-based targeted immunotherapy.

We describe in this review the historical evidence leading up to the concept and design of Vigil and subsequent clinical applications including safety and efficacy in a randomized, controlled Phase IIB trial. Vigil (gemogenovatucel-T) is a unique triple function targeted immunotherapy that demonstrates preclinical and clinical systemic anticancer activity. Construction of Vigil involves harvest of autologous malignant tissue for neoantigen targeting (ideally containing clonal neoantigens) followed by a two-day process involving transfection with a plasmid to provide a permissive 'training environment' for the patient's immune system.

3D engineered scaffold for large-scale Vigil immunotherapy production.

Previously, we reported successful cellular expansion of a murine colorectal carcinoma cell line (CT-26) using a three-dimensional (3D) engineered extracellular matrix (EECM) fibrillar scaffold structure. CCL-247 were grown over a limited time period of 8 days on 3D EECM or tissue culture polystyrene (TCPS). Cells were then assayed for growth, electroporation efficiency and Vigil manufacturing release criteria.

Regulatory role of CD39 and CD73 in tumor immunity.

CD39 is the rate-limiting enzyme for the molecular signal cascade leading to the generation of ADP and adenosine monophosphate (AMP). In conjunction with CD73, CD39 converts adenosine triphosphate (ATP) to ADP and AMP, which leads to the accumulation of immunosuppressive adenosine in the tumor microenvironment. This review focuses on the role of CD39 and CD73 in immune response and malignant progression, including the expression of CD39 within the tumor microenvironment and its relationship to immune effector cells, and its role in antigen presentation.

Targeted Combination of Poly(ADP-ribose) Polymerase Inhibitors and Immune Checkpoint Inhibitors Lacking Evidence of Benefit: Focus in Ovarian Cancer.

The emergence of targeted therapeutics in ovarian cancer, particularly poly (ADP-ribose) polymerase inhibitors (PARPi's), has created additional opportunities for patients seeking frontline and recurrent disease management options. In particular, PARPi's have shown clinical benefits in BRCA mutant and/or homologous recombination deficient (HRD) ovarian cancer. Until recently, response was thought to be limited in wild-type, homologous recombination proficient (HRP) cancers.

Clonal Neoantigen: Emerging "Mechanism-based" Biomarker of Immunotherapy Response.

Clonal mutations represent the initiating molecular defects related to cellular transition of a normal phenotype to a malignant phenotype. Molecular genomic assessment utilizing next generation and whole exome sequencing is now being increasingly applied to biomarker determination to refine the use of targeted immune therapies. Case examples followed by retrospective study assessment have convincingly demonstrated clonal neoantigens provide a relevant predictor of response to checkpoint inhibition.

Advances in Targeted Therapy for the Treatment of Cervical Cancer.

Cervical cancer is an international public health crisis, affecting several hundred thousand women annually. While not universally protective due to other risk factors, many such cases are preventable with vaccination against high-risk serotypes of the human papilloma virus (HPV 6, 11, 16, 18, 31, 33, 45, 53, 58). Advanced-stage and recurrent cervical cancers are typically lethal and have been the focus in recent years of the integration of immune checkpoint inhibitors (CPIs) to improve survival.

Pilot Study of Recurrent Ewing's Sarcoma Management with Vigil/Temozolomide/Irinotecan and Assessment of Circulating Tumor (ct) DNA.

Purpose: Treatment options for recurrent or refractory Ewing's sarcoma (ES) are limited. Vigil is a novel autologous tumor cell therapy expressing bi-shRNA furin/GMCSF plasmid, which previously demonstrated monotherapy activity in advanced ES. Herein we report safety and evidence of benefit to Vigil for ES as potential treatment.

NF-κB Signaling in Tumor Pathways Focusing on Breast and Ovarian Cancer.

Immune disorders and cancer share a common pathway involving NF-κb signaling. Through involvement with GM-CSF, NF-κB can contribute to proliferation and activation of T- and B- cells as well as immune cell migration to sites of inflammation. In breast cancer, this signaling pathway has been linked to resistance with endocrine and chemotherapies.

Folate Receptor as a Biomarker and Therapeutic Target in Solid Tumors.

Folate is a B vitamin necessary for basic biological functions, including rapid cell turnover occurring in cancer cell proliferation. Though the role of folate as a causative versus protective agent in carcinogenesis is debated, several studies have indicated that the folate receptor (FR), notably subtype folate receptor alpha (FRα), could be a viable biomarker for diagnosis, progression, and prognosis. Several cancers, including gastrointestinal, gynecological, breast, lung, and squamous cell head and neck cancers overexpress FR and are currently under investigation to correlate receptor status to disease state.

Systemic benefit of radiation therapy abscopal effect.

Evidence of a systemic response related to localized radiation therapy (RT) in cancer management is rare. However, enhancing the immune response immunotherapy followed by localized RT has shown evidence of tumor shrinkage to non-irradiated metastatic disease thereby inducing an "abscopal effect." Combined induction of the cGAS-STING pathway and activation of IFN-gamma signaling cascade related to RT within an activated immune environment promotes neoantigen presentation and expansion of cytotoxic effector cells enabling enhancement of systemic immune response.

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

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.

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

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.

Small-cell breast carcinoma with response to atezolizumab: a case report.

Small-cell carcinoma of the breast is a rare disease with little research outlining molecular targets or optimal therapeutic management. We summarize a young female patient with poorly differentiated high-grade carcinoma with neuroendocrine features/small-cell carcinoma. A 31-year-old female presented with a large left breast mass.

Subclonal landscape of cancer drives resistance to immune therapy.

Tumor mutation burden (TMB) is often used as a biomarker for immunogenicity and prerequisite for immune checkpoint inhibitor (ICI) therapy. However, it is becoming increasingly evident that not all tumors with high TMB respond to ICIs as expected. It has been shown that the ability of T-cells to infiltrate the tumor microenvironment and elicit a specific immune response is dependent not only on the TMB, but also on intra-tumor heterogeneity and the fraction of low-frequency subclonal mutations that make up the tumor.

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

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.

Homologous recombination proficiency in ovarian and breast cancer patients.

Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2 results in homologous recombination deficiency (HRD) and can be a target for therapeutic strategies including poly (ADP-ribose) polymerase inhibitors (PARPi). However, response is limited in patients who are not HRD, highlighting the need for reliable and robust HRD testing.

Gemogenovatucel-T (Vigil) maintenance immunotherapy: 3-year survival benefit in homologous recombination proficient (HRP) ovarian cancer.

Objective: Previously, Vigil demonstrated clinical benefit to prolong relapse free and overall survival in the BRCA wild-type (BRCA-wt), homologous recombination proficient (HRP) patient population. Here we provide long term follow up of 3 years in the HRP patient population enrolled in the Phase 2b VITAL study.

Methods: HRP patients treated with Vigil (n = 25) or placebo (n = 20) who were enrolled in the Phase 2b, double-blind, placebo-controlled (VITAL study, NCT02346747) were followed for safety, OS and RFS.

Case Report: Marked Survival Advantage of Two Colorectal Cancer Patients with Liver Metastases Treated with Vigil and FOLFOX-6.

Colorectal cancer is the third most diagnosed cancer in the United States. Five-year survival rates remain low and many patients will develop liver metastasis. Vigil is an immunotherapy manufactured from autologous tumor cells and transfected ex vivo with a plasmid that encodes the GM-CSF gene and bifunctional shRNA construct to knockdown furin.

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

Aim: To determine the relationship between gene expression profile (GEP) and overall survival (OS) by NanoString following treatment with Vigil.

Patients And Methods: Recurrent ovarian cancer patients ( = 21) enrolled in prior clinical trials.

Results: GEP stratified by TIS vs.

coli in cancer and therapeutic implications.

Inactivating mutations of the () gene and consequential upregulation of the Wnt signaling pathway are critical initiators in the development of colorectal cancer (CRC), the third most common cancer in the United States for both men and women. Emerging evidence suggests mutations are also found in gastric, breast and other cancers. The gene, located on chromosome 5q, is responsible for negatively regulating the b-catenin/Wnt pathway by creating a destruction complex with Axin/Axin2, GSK-3b, and CK1.

Ovarian Cancer Immunotherapy and Personalized Medicine.

Ovarian cancer response to immunotherapy is limited; however, the evaluation of sensitive/resistant target treatment subpopulations based on stratification by tumor biomarkers may improve the predictiveness of response to immunotherapy. These markers include tumor mutation burden, PD-L1, tumor-infiltrating lymphocytes, homologous recombination deficiency, and neoantigen intratumoral heterogeneity. Future directions in the treatment of ovarian cancer include the utilization of these biomarkers to select ideal candidates.

Corrigendum to "Long-term follow-up of Phase 2A trial results involving advanced ovarian cancer patients treated with Vigil® in frontline maintenance" [Gynecol. Oncol. Rep. 34 (2020) 100648].

[This corrects the article DOI: 10.1016/j.gore.