Pramod Srivastava, MD, PhD
A new method to identify protein mutations in cancer cells may help researchers create a personalized vaccine to treat patients with recurrent ovarian cancer, according to a study that was published online in the Journal of Experimental Medicine
“We tried to develop a method for determining which sequences in a tumor can be seen by the immune system,” Pramod Srivastava, MD, PhD, director of the Carole and Ray Neag Comprehensive Cancer Center at UConn Health and one of the principal investigators on the study, said in a phone interview with OncLive
. “We’re trying to see which of these differences, if any, are such that they can be used to stimulate immune response of the patient.”
In the study, researchers from the University of Connecticut used NetMHC, a tool that predicts binding of peptides to a number of different HLA alleles using artificial neural networks, to determine how strongly the immune system recognizes a change in the cancer. In the past, researcher thought that if the immune system sees a changed protein very strongly, it would make a good vaccine. However, Srivastava says the study found this to be untrue in the models tested in the study.
To explore this further, a new tool was developed to identify the small proportion of neoepitopes that protect the host through an antitumor T cell response. This tool, called DAI (Differential Agretopicity Index), measures the numerical difference in NetMHC scores between the mutated and unmutated alleles and the conformational stability of the MHC I–peptide interaction.
“There are so many differences that it’s hard to figure out what is actually immunogenic,” Srivastava said. “What we have done here is we’ve developed a method to narrow down the choices…using this method, we can create a vaccine that can be used to eliminate the recurrence of tumor.”
Srivastava says based on the success of this study, the researchers are planning a phase I study to test the method in the form of a personalized vaccine for ovarian cancer patients whose cancer has recurred. The study is expected to enroll 15-20 patients who have been diagnosed with ovarian cancer and undergone surgery and chemotherapy. Patients will receive an injection of their own personalized vaccine once a month.
Blood and tumor samples will be collected for DNA sequencing using DAI, which will identify no more than 10 differences as potential targets. In order to make the vaccine, peptides will be artificially created that contain these characteristics.
The trial is expected to begin in December 2014 and finish in March of next year. Once approved by the FDA, the clinical trial will be led by Angela S. Kueck, MD, a gynecological oncologist at UConn Health.
“We will see if the vaccine is safe, if it is feasible and if it generates immune response,” Srivastava said.
Patients with ovarian cancer usually respond well to surgery and chemotherapy; however, the cancer usually recurs in about 2 years. “Of these, most women die about 2-3 years after recurrence so there is a very huge unmet medical need,” Srivastava said.
Evidence has suggested that ovarian cancer is more susceptible to attack by the immune system, Srivastava suggested. It has been shown that if the patient’s immune system has been active in the cancer, the patient will do better.
In a report presented at the 2013 AACR Annual Meeting, a novel two-step immunotherapy consisting of adoptive T-cell therapy and a dendritic cell vaccine demonstrated promising activity in a phase I clinical trial for women with advanced ovarian cancer. Out of 31 patients treated with the vaccine, 19 (61%) showed a clinical benefit from the combination immunotherapy.