n a new approach, the cancer vaccines were developed by first sequencing the genomes of patients’ tumors and samples of the patients’ healthy tissues to identify mutated proteins called neoantigens unique to the tumor cells. Then, using computer algorithms and laboratory tests, the researchers were able to predict and test which of those neoantigens would be most likely to provoke a potent immune response and would be useful to include in a vaccine.
The vaccines were given to melanoma patients who had surgery to remove their tumors but whose cancer cells had spread to the lymph nodes, an indicator the deadly skin cancer is likely to recur. These clinical findings set the stage for a phase I vaccine trial, approved by the Food and Drug Administration as part of an investigational new drug application. The trial will enroll six patients.
Data on the immune response seen in the first three patients is reported in the paper. If additional testing in more patients indicates the vaccines are effective, they may one day be given to patients after surgery to stimulate the immune system to attack lingering cancer cells and prevent a recurrence.
It’s too early to say whether the vaccines will be effective in the long term, the researchers cautioned. The study was designed to evaluate safety and immune response; however, none of the patients has experienced adverse side effects.
Earlier attempts at vaccines have focused on targeting normal proteins commonly expressed at high levels in particular cancers. Those same proteins also are found in healthy cells, making it difficult to stimulate a potent immune response.
The new approach investigated by the Washington University team merges cancer genomics with cancer immunotherapy.
«This is about as personalized as vaccines can get," said
Melanomas are notorious for having high numbers of genetic mutations caused by exposure to ultraviolet light. Biopsy samples of melanomas typically carry 500 or more mutated genes. Using prediction algorithms, the researchers narrowed their search for vaccine candidates by identifying neoantigens that not only were expressed in a patient’s tumor but also were likely to be seen by that patient’s immune system as «
Biochemical validation of neoantigen peptide expression on the cancer cells’ surfaces was performed in collaboration with William Hildebrand’s group at the University of Oklahoma Health Sciences Center and provided critical assurance that the vaccine would elicit the most effective T cells to combat the melanoma.
«You can think of a neoantigen as a flag on each cancer cell," said first author Beatriz Carreno, PhD, associate professor of medicine. «Each patient’s melanoma can have hundreds of different flags. As part of validating candidate vaccine neoantigens, we were able to identify the flags on the patients’ cancer cells. Then we created customized vaccines to a select group of flags on each patient’s tumor.»
Carreno and her colleagues selected a set of seven unique neoantigens for each vaccine and used specialized immune cells called dendritic cells, derived from the patients, to carry those neoantigens to the immune system. Dendritic cells play an important role in waking up the immune system, reminding T cells to attack the cancer.
After the vaccine infusions, the patients’ blood was drawn every week for about four months. By analyzing the blood samples, the researchers could see that each patient mounted an immune response to specific neoantigens in their vaccines. The vaccines also stimulated diverse clones of
«Our team has developed a new strategy for personalized cancer immunotherapy," Linette said. «Many researchers have hypothesized that it would be possible to use neoantigens to broadly activate the human immune system, but we didn’t know that for sure until now. We still have much more work to do, but this is an important first step and opens the door to personalized
The research was supported by the
Carreno BM, Magrini V,
Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of
Siteman Cancer Center, the only National Cancer