Targeting therapies to some combination of neoantigens, distinctive markers on the surface of cancerous cells that the immune system learns to recognize, and which vary from patient to patient, represents an advance in the specificity of targeted cancer immunotherapy. It should, in principle, better rouse the immune system to attack cancerous cells, while producing fewer side-effects. Researchers here report on an early human trial of this sort of approach; the initial results look promising, certainly from the perspective of an absence of serious side-effects, though a more robust demonstration of the ability to reduce tumor burden is still needed.
A personal cancer treatment vaccine that targets distinctive “neoantigens” on tumor cells has been shown to stimulate a potent, safe, and highly specific immune anti-tumor response in melanoma patients. Antigens are molecules that are displayed on the surface of cells and stimulate the immune system. Neoantigens are molecules on cell’s surfaces that are produced by DNA mutations that are present in cancer cells but not in normal cells, making neoantigens ideal targets for immune therapy against cancer. The vaccines used in the phase I trial contained up to 20 neoantigens, derived from an individual patient’s tumor. The vaccines were administered to patients to train their immune system to recognize these neoantigens, with the goal of stimulating the immune system to destroy the cancer cells that display them.
While other immunotherapies, such as checkpoint inhibitor drugs, also trigger immune responses against cancer neoantigens, they are not designed to be specific. They can also induce responses against normal tissue antigens, leading the immune system to attack normal tissues and cause toxicity in a subset of patients. The researchers found that the personal vaccine induced a focused T cell response against several tumor neoantigens, beyond what is normally seen in response to existing immunotherapies.
The vaccine was administered to six patients with melanoma whose tumors had been removed by surgery and who were considered at high risk for recurrence. The vaccinations were started at a median of 18 weeks after surgery. At a median of 25 months after vaccination, four of the six patients showed no evidence of cancer recurrence. In the other two patients, whose cancer had spread to their lungs, the disease recurred after vaccination. At that point, they began treatment with the drug pembrolizumab, which inhibits the PD-1 immune checkpoint. Both patients had complete resolution of their tumors and remain free of disease according to imaging scans.
The study results suggest, that a personalized neoantigen vaccine can potentially overcome two major hurdles in cancer therapy. One is the heterogeneity of tumors – the fact that they are made up of cells with a variety of different traits, which often allows cancers to evade drugs targeted to malignant cells having a single genetic abnormality. The vaccine, because it contains many different neoantigens from the tumor, targets multiple genetic types of tumor cells. A second hurdle in cancer is to generate an immune response sharply focused on cancer cells while avoiding normal cells and tissues. This aim was achieved by the vaccine, which appeared to have few “off-target” effects, causing only flu-like symptoms, fatigue, rashes, and irritation at the site of the vaccine injection, according to the report.