Researchers have now come up with a whole vaccine approach that merges cancer genomics with cancer immunotherapy.
Researchers have now come up with a whole vaccine approach that merges cancer genomics with cancer immunotherapy. Investigators at Washington University School of Medicine in St. Louis have developed and tested personalized melanoma vaccines that can direct a powerful immune response against unique mutations in patients' tumors.
Early data from a clinical trial published April 2, 2015 in Science Express, showed the tailor-made vaccines given to three patients with advanced melanoma appeared to increase the number and diversity of T-cells responding to the tumors. This new type of vaccine is developed by first sequencing the genomes of patients' tumors and samples of the patients' healthy tissues to identify mutated proteins (neoantigens) unique to the tumor cells. The researchers were able to predict and test which of those neoantigens would be most likely to provoke a potent immune response by using computer algorithms and laboratory tests.
In this proof-of-principal study, the vaccines were given to melanoma patients who already had surgery to remove their tumors, but whose cancer cells had spread to the lymph nodes. Senior author Gerald Linette, MD, PhD, who is a Washington University medical oncologist, said the custom-designed vaccines can elicit a very strong and broad immune response. He said there is still much more work to do, but this is an important first step that opens the door to a new type of personalized immune-based cancer treatments.
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. Study investigator Elaine Mardis, PhD, who is co-director of the McDonnell Genome Institute at Washington University, said this approach is about as personalized as vaccines can get because it involves a unique set of mutated proteins in a patient's tumor that would be most likely to be recognized by the immune system as foreign.
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. The researchers used prediction algorithms to narrow 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 foreign.
In this study, the researchers selected a set of seven unique neoantigens for each vaccine, and used dendritic cells derived from the patients to carry the neoantigens to the immune system. After the vaccine infusions, the patients' blood was drawn every week for about 4 months so the researchers could see that each patient mounted an immune response to specific neoantigens in their vaccines.
The vaccines also stimulated diverse clones of T-cells against neoantigens, suggesting this approach also could be used to activate a range of T-cells and target them to mutations in other cancers with high mutation rates, such as lung cancer, bladder cancer, and certain colorectal cancers.