Custom cancer vaccines safely fight and kill tumors in early human trials

Melanoma cells

With swift shots to the arm, doctors safely and effectively prime our immune systems to fight off deadly infectious diseases. Now, with tightly crossed fingers, they plan to do the same for cancers.

In two early clinical trials involving 19 patients with skin cancer, personalized vaccines appeared safe and effective at spurring immune responses to attack and destroy tumors. The vaccines worked by coaching killer immune cells—T cells—to destroy tumors by seeking out uniquely mutated proteins on each patient’s one-of-a-kind cancer cells, while leaving healthy cells unharmed.

The results of the two trials, both published this week in Nature, follow years of basic research and animal studies on this strategy. Researchers are optimistic, but there are big hurdles ahead of these small trials, including bigger trials with more patients and controls. If those go well, researchers will likely have to figure out how to streamline creating vaccines for individual patients, which is currently tedious and expensive.

“The two studies confirm the potential of this type of approach,” Cornelis Melief, a cancer immunologist at Leiden University Medical Centre in the Netherlands, wrote in an accompanying commentary. “Controlled, randomized phase II clinical trials with more participants are now needed to establish the efficacy of these vaccines in patients with any type of cancer.”

The immune force

Researchers have worked for decades to get our immune systems to fight off pernicious cancers. Immune cells are naturally equipped to do it; they just need a little nudge. For instance, some current cancer immunotherapies work by simply disabling proteins that cancer cells use to hide from immune responses. The binding of these proteins, such as PD-1 and PD-L1, signals T cells to stand down, like using a Jedi mind-trick—these are not the cancer cells you’re looking for. By interfering with these proteins, the immunotherapies allow T cells to stay on task and attack cancer on their own.

But that doesn’t always work; sometimes T cells still aren’t motivated to attack, even if they haven’t been bamboozled. Another strategy is for doctors to collect T cells from a patient, genetically engineer the cells in lab to ensure they identify and fight cancers, then put them back in the patient. This method has proven highly effective at wiping out cancers in human trials—with the scary caveat that it occasionally kills patients by triggering an extreme, full-body immune response.
While researchers and biotech start-ups are feverishly working to make that strategy less deadly, the vaccine method could provide a safer middle ground.

Both the new trials used the same basic protocol: researchers sequenced genes in the healthy cells and tumor cells of patients with melanoma, a type of skin cancer. Then they identified unique mutations that have amassed in the patients’ cancer cells but are absent in their healthy cells. After picking through to find mutant proteins most likely to trigger an immune response—called “neoantigens”—the researchers created mutation-based vaccines. When bits of these mutated proteins are presented to T cells by other immune cells, the T cells become trained to seek out the mutant proteins and destroy the cancer cells carrying them.

A cancer-killing shot

In the first trial, led by Dr. Catherine Wu of the Dana-Farber Cancer Institute in Boston, researchers synthesized cocktails of long peptides that represented up to 20 neoantigens specific to each patients’ tumors. Six patients got five vaccinations in a month, then boosters at 12 and 20 weeks. Four started the trial with melanoma that had already spread to their lymph nodes (stage IIIB/C). After two years, all four showed no signs of cancer recurrence. The remaining two started with melanoma that had spread to their lungs (stage IVM1b). Both had recurrence within the first year, but with follow-up treatment of an anti-PD-1 immunotherapy, they both became cancer free.

In the second trial, led by Dr. Ugur Sahin of Biopharmaceutical New Technologies (BioNTech) Corporation in Mainz, Germany, researchers vaccinated 13 patients with stage III or IV melanoma. For their vaccines, the researchers used RNA fragments representing up to 10 neoantigens. In this case, immune cells can take up the RNA and create peptide fragments to present to T cells. Of the 13 patients, eight were cancer free for the follow-up period of 12 to 23 months. The other five all had relapses, but one became cancer free after an ant-PD-1 immunotherapy.

In both studies, researchers confirmed that patients had cancer-killing T cells activated by the vaccines. And these seemed to cause no serious side effects, only mild issues including flu-like symptoms, injection site reactions, rashes, and fatigue.

“Although the numbers of people who were treated in these studies were small, both studies indicated potential benefits,” Dr. Melief concluded.

But neither contained a control group, so it’s not certain that the cancer remissions were entirely due to the vaccination. Researchers are moving on to bigger, controlled trials to prove safety and efficacy. Along the way, they’ll also likely work on making personalized vaccine development faster and affordable.

Nature, 2017. DOI: 10.1038/nature22991  (About DOIs).

Nature, 2017. DOI: 10.1038/nature23003  (About DOIs).

Source: https://arstechnica.com/science/2017/07/custom-cancer-vaccines-safely-fight-and-kill-tumors-in-early-human-trials/

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BETH MOLE
Beth is Ars Technica’s health reporter. She’s interested in biomedical research, infectious disease, health policy and law, and has a Ph.D. in microbiology.

EMAIL beth.mole@arstechnica.com // TWITTER @BethMarieMole

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