Glioblastoma is termed an immunologically ‘cold’ tumor – a disadvantage for treatment with immunotherapy – because the brain tumor contains very few immune cells that are required to generate an immune response against the tumor.
In a report published in Nature, however, scientists at Dana-Farber Cancer Institute say they have shown that a personalized ‘neoantigen’ vaccine can spur a response against glioblastoma, with immune T-cells generated by the vaccine migrating into the brain tumor, creating a ‘hotter,’ inflamed environment around the cancer cells. The neoantigen vaccine approach has been pioneered in the laboratory of Catherine Wu, MD, at Dana-Farber.
“This is the first time it has been shown that a vaccine can generate immune cells against the tumor that can traffic from the bloodstream into a glioblastoma tumor,” said David Reardon, MD, senior author of the study. Reardon is clinical director of the Center for Neuro-Oncology at Dana-Farber.
A hallmark of cancer is the presence of DNA mutations that alter the growth properties of cancer cells. The personalized vaccine used in the Nature study takes advantage of the fact that some of these mutations cause cancer cells to display peptide molecules called neoantigens on their surface. Because these neoantigens aren’t present on the surface of normal cells, they are ideal targets for recognition and attack by the immune system. Cancers whose cells contain a higher number of neoantigens tend to be more responsive to immunotherapy. Glioblastoma is a ‘cold’ tumor because it has a relatively low burden of mutations and, correspondingly, fewer neoantigens.
This phase 1/1b trial was designed to assess feasibility and safety of the vaccine approach. The vaccine was extremely safe with no significant side effects. To create the vaccine for an individual patient, tumor tissue removed during initial surgery underwent DNA analysis and comparison with normal DNA from the patient to identify neoantigens expressed by the tumor cells. Small proteins (peptides) from the neoantigens were synthesized in a laboratory and formed the basis of the vaccine. When given to the patient, the neoantigens in the vaccine ‘train’ the immune system to detect and attack the glioblastoma tumor cells.
Co-authors from the Department of Neurosurgery at Brigham and Women’s Hospital extracted tumor tissue from which the personalized vaccines were developed.
“This personalized approach to creating a vaccine that can reinvigorate a patient’s immune system represents the culmination of a collaboration between experts in neurosurgery and neuro-oncology,” said co-author Antonio Chiocca, MD, chair of the Department of Neurosurgery at Brigham and Women’s. “We’re thrilled to have played a role in this innovative work.”
Ten patients were enrolled in the reported vaccine study. One patient was withdrawn because of too few neoantigens present in their tumor and another had disease that progressed rapidly before the vaccine was formulated. The vaccines created for the remaining eight patients contained between seven and 20 neoantigen peptides. Although all eight patients vaccinated on the study died from progressive tumor, their survival was longer than typically observed for GBM patients.
Of the eight patients who received the vaccine, a robust T-cell response was observed against multiple vaccinated neoantigens in the two patients who did not receive dexamethasone when the vaccine was administered. Dexamethasone is a strong anti-inflammatory steroid medication that is routinely given to brain cancer patients due to brain swelling caused by the tumor. The other patients, who all received dexamethasone during their vaccination, did not respond.
“Based on the two patients that did exhibit a response the results showed that a personalized neoantigen vaccine can activate immune cells in the bloodstream and, moreover, these cells can migrate to the site of the tumor,” said the lead author, Derin Keskin, PhD. This was shown by using a novel approach to molecularly track T-cells with specific reactivity against the immunizing neoantigens – an approach designed by the team at the Dana-Farber Translational Immunogenomics Laboratory, co-led by Keskin, Ken Livak, PhD, and Sachet Shukla, PhD. Reardon said, “These results provide proof of principle that the personalized vaccine is one strategy for converting an immunologically cold tumor into an inflamed tumor.”
“Having demonstrated that the vaccine can stimulate an immune response in glioblastoma,” said Reardon, “the next step is to add an immunotherapy drug called a checkpoint inhibitor, aimed at freeing the immune response from molecular ‘brakes’ so that the T-cells can react more strongly against the tumor.” The neoantigen vaccine coupled with the checkpoint inhibitor are expected to be synergistic, leading to a stronger anti-tumor immune response. Furthermore, glioblastoma patients will receive Avastin instead of steroids to treat brain swelling.
Additional authors of the report are affiliated with Dana-Farber, Massachusetts General Hospital, Brigham and Women’s Hospital, the Broad Institute of MIT and Harvard, Neon Therapeutics, Harvard Medical School, and other organizations.
Support for the research was provided by the Ben and Catherine Ivy Family Foundation, the Blavatnik Family Foundation, the ABC2 Foundation, the Broad Institute SPARC program; National Institutes of Health grants NCI-1RO1CA155010-02, NHLBI-5R01HL103532-03; the Francis and Adele Kittredge Family Immuno-Oncology and Melanoma Research Fund; the Faircloth Family Research Fund; NIH/NCI R21 CA216772-01A1; NCI-SPORE-2P50CA101942-11A1;NHLBI-T32HL007627; the Zuckerman STEM Leadership Program; the Benoziyo Endowment Fund for the Advancement of Science; P50 CA165962 (SPORE) and P01 CA163205; the DFCI Center for Cancer Immunotherapy Research fellowship; and the Howard Hughes Medical Institute Medical Research Fellows Program.