Phase 1 Safety and Feasibility Study of a Personal Neoantigen-Targeting Vaccine in Combination with Immune Checkpoint Blockade in Ovarian Cancer
Abstract
Immune checkpoints are molecules that stimulate or suppress the immune system. These molecules are frequently "hijacked" by cancer cells to protect themselves from the immune system. Inhibition of these immune checkpoints or checkpoint blockade (CPB) is a form of cancer immunotherapy, which acts by shutting down these checkpoints to stimulate the immune system against the cancer cells. Since its inception, CPB has revolutionized the treatment of multiple cancers such as skin, lung, kidney, and bladder cancers, and, in many cases, has outperformed previous standard-of-care (SOC) therapies including chemotherapy and radiation therapy. The excitement around CPB stems from evidence of complete remissions or prolonged responses in patients with advanced, widely metastatic cancers that have been refractory to chemotherapy and targeted therapies, and had no remaining treatment options. However, the success of CPB in other tumors has not thus far translated in epithelial ovarian cancer (EOC), where clinical trials of CPB showed only modest effectiveness, with relatively infrequent durable responses. These results point to the urgent unmet need of novel strategies to extend the benefit of CPB therapy in EOC, which is a high priority for ovarian cancer immunotherapy. In order to overcome this problem, we have focused on molecules that are present on cancer cells and can be recognized by the immune system, so-called "neoantigens". Neoantigens are expressed only on cancer cells, but not on normal cells, and can therefore stimulate the immune system very effectively. In our institution, we have developed and implemented very sophisticated algorithms to identify these neoantigens in cancers from different patients (including patients with ovarian cancer), and have developed a pipeline for making a vaccine that targets these neoantigens, called "Neovax". These vaccines are personalized, i.e., they are customized for each patient, based on the specific neoantigens that are present on the cancer of each patient, and have been created for patients with various cancers, including ovarian cancer. Dr Wu, a co-investigator in this application, recently completed a clinical trial of Neovax in patients with melanoma (a form of skin cancer), and found that Neovax is highly effective at stimulating patients immune system against the cancer cells and inducing shrinkage of tumors. Importantly, when Neovax was followed by CPB therapy, two patients achieved a complete response (i.e., disappearance of all their tumors in their CT scans) after only a few doses of CPB therapy that was administered after completion of vaccination with Neovax. Based on these promising results, we propose a novel immunotherapy strategy for ovarian cancer that combines Neovax with CPB (in this case, a drug called nivolumab). In this application, we propose to conduct a clinical trial of Neovax with nivolumab in EOC to assess whether this approach is feasible and safe for EOC patients and whether there is any preliminary evidence of clinical activity. We are also proposing a series of correlative studies on samples of patients who will participate in this study to answer key biologic questions such as whether this approach stimulates the immune system against ovarian cancer cells, how does the tumor and the microenvironment change after vaccination and CPB therapy, who responds to this therapy, and how does resistance develop. We expect this proposal to have a near-term clinical impact and that, based on the results of the proposed clinical trial, combined Neovax and nivolumab will promptly enter Phase II/III clinical evaluation with the ultimate goal of being incorporated in the clinical management of patients with EOC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810132
Entities
People
- Panagiotis A Konstantinopoulos
Organizations
- Dana–Farber Cancer Institute
- United States Army