By: Sharon Begley
The largest study to date of a “cancer vaccine” plus one of the immunotherapy drugs that has revolutionized cancer treatment found that they kept patients’ tumors in check longer, on average, than drugs alone, but that the benefit was still only a few months for two forms of cancer, study sponsor Neon Therapeutics reported on Monday.
It was a hint that an experimental therapy often described as the next great hope for immune-based approaches to fighting cancer will not be a silver bullet.
In the study, the 21 patients with metastatic bladder cancer, and the 27 with metastatic non-small-cell lung cancer, had a median progression-free survival (PFS) of 5.6 months, meaning half saw their tumors grow or spread before that time.
The 34 metastatic melanoma patients did dramatically better: After 13.4 months, the PFS had not yet been reached. That is, fewer than half the patients had experienced cancer growth or further metastasis by that point.
By comparison, in clinical trials of the immunotherapy drugs called checkpoint inhibitors, median progression-free survival has been about two to four months in non-small cell lung, and two to three months in bladder cancer. In metastatic melanoma it has been three to seven months, said Kristen Mueller of the Melanoma Research Alliance, “so this is above the range. Still, I’d want to know how durable the benefit is,” meaning whether some patients are truly cured, as seems to happen with checkpoint drugs.
The Phase 1b study is the first to show improved outcomes in cancer patients receiving a neoantigen vaccine, which boosts production of immune cells that specifically target rogue molecules on the surface of tumor cells. But the trial comes with several caveats.
It did not measure overall survival, or how long patients lived, which is considered a more rigorous way to assess cancer therapies (though the Food and Drug Administration has approved cancer drugs based on progression-free survival).
Also, it did not have a comparison arm; all of the patients received the same treatment: seven doses of Neon’s vaccine, spread over 12 weeks, plus the checkpoint drug nivolumab (sold by Bristol-Myers Squibb as Opdivo). As a result, the researchers could not compare the results to other patients in the same trial who received, say, only nivolumab. The latter comparison is considered the gold standard.
“I don’t know that this is breakthrough data,” said Jill O’Donnell-Tormey, CEO of the Cancer Research Institute, which has supported immunotherapy research for decades. But “it looks like the median PFS in all [three] cancers are better than the PFS” of patients who receive only nivolumab or another checkpoint inhibitor. “Still, these are comparisons to historical data and would need to be confirmed in a randomized Phase 2 study.”
The percentage of patients who showed any response to the neoantigen vaccine plus nivolumab, called the objective response rate and measured by tumors shrinking or metastases vanishing, was also much higher in melanoma, at 47%, compared to 24% for bladder cancer and 22% for lung cancer. With checkpoint drugs, the objective response rate has been 27% to 44% in melanoma and 18% to 26% in lung cancer, suggesting that vaccine plus checkpoint drug is better than drug alone. (There are no comparable comparison data for bladder cancer.)
Neon, based in Cambridge, Mass., called the data encouraging enough to move into a larger, Phase 2 trial with its NEO-PV-01 vaccine. None of the vaccinated patients suffered a serious adverse event, though some experienced pain or inflammation at the injection site, fatigue, or flu-like illness.
The results underlined a key aspect of immunotherapies: Although they have cured some patients with cancer that previously was invariably fatal, the majority of patients — O’Donnell-Tormey puts it at 60% — do not respond. In the year since Neon went public, its stock has been hammered, falling from $13 a share to just over $4 at Friday’s market close.
The rationale for neoantigen vaccines involves the clear shortcomings of checkpoint inhibitors like nivolumab, pembrolizumab (Merck’s Keytruda), and ipilimumab (Bristol’s Yervoy). Each blocks the molecular force field that tumor cells create to fend off immune cells that try to attack them. With the force field removed, T cells and others supposedly have a clear shot at the tumors.
“But checkpoint drugs rely on the T cells that are there,” said Dr. Patrick Ott of Dana-Farber Cancer Institute in Boston, a lead researcher in the Neon trial. In some patients, the natural T cell army is sufficient to eliminate tumors, as Keytruda did when former President Jimmy Carter received it in 2015 for melanoma that had spread to his brain. But in other patients, who for whatever reason do not produce enough T cells or whose T cells eventually lose their oomph (a phenomenon called exhaustion), the checkpoint drugs either do not work in the first place or eventually stop working.
So while the checkpoint drugs rely on an all-volunteer T-cell army, neoantigen vaccines act like a draft board calling up as many recruits as possible.
To produce its vaccine, Neon first determines the genome sequences of tumor cells, identifying all of the mutant molecules they produce and dangle from their surface. These dangling molecules are antigens, and because they are the products of new, cancer-related mutations they’re called neoantigens. Injecting patients with millions of copies of the neoantigens should, in theory, trigger the immune system to produce T cells that attack the neoantigens and therefore the tumor.
Since vaccines can’t be packed with an infinite number of neoantigens, Neon has to make choices. One of the melanoma patients in its study had 50 neoantigens; another had more than 8,000. “You have to pick a needle in a haystack,” Neon CEO Hugh O’Dowd told STAT ahead of the announcement — or, more precisely, 30 needles, the number of neoantigens in its vaccine. “Not all neoantigens are created equal.”
To choose those most likely to draft effective T cells, Neon has developed an algorithm that scores them, said Dr. Richard Gaynor, president of R&D: “If you have 50 mutations you have a tough time getting 30 really good neoantigens. If you have 8,000 it’s a piece of cake” because the algorithm has so many to choose from.
Ott called the Neon results “promising,” suggesting that neoantigen vaccines have the potential to make checkpoint drugs work for more patients than the minority who currently benefit. As for why the vaccine-Opdivo combination did not produce longer progression-free survival in patients with bladder or lung cancer, he said, “There can be a myriad of things that can compromise the immune response to cancer,” including T cells not being able to penetrate deep into tumors and other immune cells calling off the T cells’ attack.
“To expect a neoantigen vaccine to make every patient a responder is probably not realistic,” Ott said. “But the fact that you don’t get a 100% response rate doesn’t mean that the vaccine approach won’t provide a benefit” to some patients.
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.