Melanoma Vaccines Show Promise
While checkpoint immunotherapies, such as ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) have been hailed as a breakthrough in the way melanoma is treated, about half of patients do not respond. Researchers are pursuing multiple strategies to understand why this happens and to develop novel strategies to jumpstart an immune response. One approach showing promise in early clinical trials, comes in the form of a new personalized vaccine being developed by Ugur Sahin of Johannes Gutenberg-Universität Mainz and BioNTech.
Sahin creates personalized vaccines for each patient after analyzing tumor samples to determine which protein fragments – what researchers call neoantigens – are most likely to spur an immune response. Each vaccine includes up to 20 of these neoantigen targets and takes about six weeks to develop. The vaccine is then given to the patient by injecting it directly into a lymph node or by infusing it intravenously.
Sahin is currently testing “two flavors” in the clinic. The first, called IVAC-MUTANOME, is injected directly into a patient’s lymph node where it is more likely to meet dendritic cells that can present the antigens to tumor-killing T cells, who will then home in and destroy any tumor cells harboring these proteins. So far, 13 patients with advanced melanoma have been treated with the experimental IVAC-MUTANOME vaccine. Each patient receives at least eight vaccinations over regular intervals. One concern with personalized vaccines such as these is that a patient’s T cells may not react to any of the neoantigens included in the vaccine, but fortunately this was not the case. Sahin and his colleagues found that 60% of the neoantigens included in the vaccine prompted a T cell response in patients. “We saw a strong immune response against tumor antigens in all patients,” Sahin stressed. The vaccine significantly reduced the cumulative rate of metastatic relapse, resulting in sustained progression-free survival. In one patient, who had a metastatic lymph node removed after being vaccinated four times, the vaccine prompted T cells to react to all 10 tumor antigens within it. IVAC-MUTANOME is currently being tested in combination with Keytruda versus Keytruda alone in a Phase II clinical trial in patients with advanced melanoma (NCT03815058). Learn more about this and other clinical trials here.
The second flavor of Sahin’s vaccines, called Lipo-MERIT, encases the tumor antigens in a sphere of fat particles and then widely distributes them throughout the body using an intravenous infusion. In this case, the vaccine is not personalized to individual patients, rather it is composed of four antigens commonly expressed at high levels on melanoma tumors. The Lipo-MERIT vaccine is currently being tested in patients with advanced melanoma (NCT02410733). This clinical trial will enroll 115 Stage III and IV melanoma patients, including those that did not respond to checkpoint inhibitor therapies. These patients will receive eight doses delivered intravenously at regular intervals. So far, while premature, the results are promising. PET scans of patients done three hours after being given the 6thvaccine reveal a buildup of T cells in the spleen, which is a staging ground for activated T cells. Additional investigations uncovered that, “the T cells are recognizing tumor cells and doing their job killing them,” Sahin said. Out of 22 patients with metastatic tumors who had progressed on checkpoint inhibitors, four patients had a partial response, eight had stable disease, and ten had progressive disease, he reported. Preliminary data in 70 patients found it caused minor flu-like symptoms that were short-lived.
While these early studies suggest that vaccine approaches such as these may one day complement currently approved checkpoint inhibitors, more work is needed to validate the efficacy and safety of this approach.
Targeted and immune-based therapies have transformed the way we treat melanoma for many patients facing advanced melanoma. However, still too many patients aren’t benefiting from these new approaches. Several MRA-funded investigators are hard at work developing, testing, and refining the use of therapeutic vaccines to help even more people with melanoma.
- Patrick A Ott M.D. – Dana Farber Cancer Institute
- Nicolas Chevrier Ph.D. – University of Chicago
- Nina Bhardwaj M.D., Ph.D. – Icahn School of Medicine at Mount Sinai
Learn more about these and other MRA Grant Awards at CureMelanoma.org/Grants.