Proteogenomic Analysis of Responders Versus Nonresponders in a Phase 1 Trial of Th17-Inducing Dendritic Cell Vaccination for Advanced-Stage Ovarian Cancer
Abstract
Background and Rationale: Ovarian high-grade serous cancer (HGSC), the most common malignancy of the female reproductive system, has caused the most deaths of all gynecological cancers and is often only diagnosed when the cancer is at its worst. Standard treatment for ovarian cancer usually includes surgery to remove the tumor combined with chemotherapy and, after these treatments, most medical tests, physical exams, and scans show that all signs of the cancer are gone. However, after 12-18 months, in most patients, the same cancer returns (recurrence), and at this point, it is usually resistant to chemotherapy treatments and is generally considered incurable. There is a clear need to develop new strategies that complement surgery and chemotherapy and reduce the risk that ovarian cancer comes back. Our research focuses on the use of powerful immune-stimulating cells called dendritic cells (DC) to activate immune responses against ovarian tumor cells. DC vaccines prepared from blood drawn from the patient have strong potential as a treatment to prevent ovarian tumors from recurring after surgery and chemotherapy. We have found that DC can be stimulated to cause a specific immune response, known as a Th17 T cell response, against ovarian cancer. This is an exciting prospect because previous studies have shown that ovarian cancer patients with a Th17 immune response enjoy prolonged survival. In partnership with the Mayo Clinic, we recently completed a phase I clinical trial of Th17-inducing DC vaccination for advanced (stage IIIC–IV) ovarian cancer patients following initial surgery and chemotherapy. DC vaccination induced durable immune responses and, of 18 evaluable patients, 39% remained cancer-free for at least 49.2 months after starting the trial, and overall survival was 55%. With the caveat that this trial included a small number of patients, the effectiveness of this vaccine is markedly better than other recently reported novel therapies, such as maintenance PARP inhibitor treatment in patients without BRCA mutation or deficiencies in homologous recombination. Study Design: The clinical results revealed a clear distinction between patients where the cancer returned quickly (within 12-18 months) and where the cancer did not return as quickly (4-5 years). In this study, we propose that investigation of tumor and blood tissue will reveal biomarkers that indicate which patients are likely to respond and which patients are unlikely to respond to this DC vaccine. The goals are (1) to identify markers associated with clinical response and (2) to identify markers associated with immune response. To achieve this, we will conduct a holistic and comprehensive proteogenomic analysis of primary tumor tissue and serial blood/plasma samples drawn pre-vaccination and at week 19 and week 107 post-vaccination. The analytical tools will include RNAseq (which measures total gene expression), quantitative phosphoproteomics (which measures the activity of key signaling pathways involved with tumor progression), whole exome sequencing (which sequences all of the protein-coding regions of genes in tumor cells), and plasma proteomics (which measures blood proteins that may be associated with tumor progression or immune responses). Clinical Impact: This proposal has exceptional clinical impact at multiple levels. First, the identification of biomarkers associated with response to Th17-inducing DC vaccination may help to identify which ovarian cancer patients are most likely to benefit from DC vaccination in future clinical trials. This would also help patients who are less likely to respond to DC vaccination to pursue other treatments that may be more beneficial. Second, knowledge of biomarkers associated with immune response parameters (which may in turn correlate with clinical response) may allow identification of molecular biomarkers or pathways that can be targeted by drug treatments to enhance clinical responses to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110460
Entities
People
- Martin Cannon
Organizations
- United States Army
- University of Arkansas for Medical Sciences