In Melanoma, Personalized Treatment Vaccines Show Promise

NIH National Cancer Institute| Fri Aug 04 16:11:39 EDT 2017
In Melanoma, Personalized Treatment Vaccines Show Promise

Metastatic melanoma cells. Two small clinical trials show that a vaccine may help to prevent surgically removed melanoma tumors from returning.

Results from a new study show that, in patients with melanoma, a personalized treatment vaccine generated a robust immune response against the cancer and may have helped to prevent it from returning.

For the , published July 5 in Nature, researchers from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard created vaccines that target each tumor’s neoantigens—molecules on the surface of tumor cells that result from tumor-specific genetic alterations. These molecules are new to the immune system and may trigger an immune response.

This type of vaccine could “help address two major challenges for effective cancer immunotherapy: targeting highly heterogeneous tumors, and selectively targeting tumor relative to healthy tissues,” the study’s senior author, Catherine Wu, M.D., of Dana-Farber, and her colleagues wrote.

In an accompanying editorial, Cornelis Melief, M.D., Ph.D., of Leiden University Medical Center, the Netherlands, wrote that although this clinical trial and a related trial published in the same issue were small, the studies confirm the potential of neoantigen vaccines to treat cancer and should lead to larger trials in the future.

Unlike preventive vaccines, treatment vaccines are designed to eliminate existing cancers. The only approved by the Food and Drug Administration is sipuleucel-T (Provenge®), for use in some men with metastatic prostate cancer. Like the vaccines in the melanoma study, sipuleucel-T is personalized for each patient and designed to stimulate an immune response, in this case to an antigen found on most prostate cancer cells.

In their study, the research team wanted to test whether they could produce treatment vaccines that were tailored to the specific biology of each patient’s tumor while limiting the immune system attack on normal cells.

Neoantigens have “long [been] envisioned as optimal targets for an antitumor immune response,” the study authors wrote. But creating personalized cancer treatment vaccines that can target neoantigens has been difficult because it is technically challenging to systematically discover and evaluate neoantigens.

Recent technological advances, such as powerful genetic sequencing methods and machine-learning algorithms, are now helping researchers make headway in identifying neoantigens that might be good vaccine targets, the authors wrote.

In the trial, researchers tested personalized vaccines in six patients with melanoma considered to be at high risk of . Four of the patients had stage III melanoma, and two of them had metastatic disease that had spread to their lungs. All of the patients had their tumors surgically removed, and tumor samples were used to produce the vaccines.

To make the vaccines, the researchers sequenced the of healthy cells and tumor cells to identify genetic mutations specific to each patient’s tumor and the neoantigens associated with those mutations. Next, they used a computer algorithm to predict which neoantigens were most likely to bind to receptors on T cells and, thus, potentially stimulate an immune response.

For each patient, they then produced a -based vaccine that targets up to 20 of these neoantigens. The vaccine uses manufactured, or synthesized, peptides—small protein segments of the target neoantigen to which T cells can bind.

The initial vaccinations were given approximately 18 weeks after surgery. Each patient had five priming, or initial, vaccinations and two booster vaccinations. At a median follow-up of 25 months after vaccination, the four patients with stage III cancer had no recurrence of their cancer.

The two patients who started the trial with lung metastases did have a tumor recurrence. However, both patients went on to receive the checkpoint inhibitor pembrolizumab (Keytruda®), which eliminated their tumors. At the time of the report, both remained disease free.

Side effects related to the vaccine treatment included flu-like symptoms, reactions at the injection site, fatigue, and rash.

The fact that two of the patients in the study had a to pembrolizumab after cancer recurrence is encouraging, said James Gulley, M.D., Ph.D., of NCI’s Center for Cancer Research.

For these patients, it would be relatively uncommon to have a complete response after treatment with a checkpoint inhibitor alone, Dr. Gulley added.

“So the fact that the disease went away when these patients started pembrolizumab suggests that there was already an underlying immune response that pembrolizumab could take advantage of,” he said.

Still, Dr. Gulley said, it’s “early days” for these kinds of studies. He also noted that computer algorithms will improve, making it easier to identify the best neoantigens to target, and that the logistically complex work of producing neoantigen vaccines will become simpler over time.

In another phase I trial of a treatment vaccine published in the same issue of Nature, researchers from Johannes Gutenberg University in Germany also reported positive results.

Using a similar approach as the Dana-Farber/Broad team, they identified up to 10 neoantigens in the tumors of each of 13 patients with melanoma who had undergone surgery to have their tumors removed but were at high risk of recurrence. They then used these neoantigens to create an -based vaccine (which uses RNA to produce the target antigens) for each patient.

Eight of the patients had strong immune responses to the vaccine and did not have a recurrence after the initial vaccination, a period of 12 to 23 months. The other five patients experienced relapses of melanoma shortly after enrolling in the trial and had metastases at the start of vaccination. One patient, whose vaccinations were discontinued because of disease progression, had a complete response after receiving pembrolizumab.

Dr. Gulley explained that researchers are trying different techniques to improve the immune response to treatment vaccines.

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