Neon’s Early Vaccine Study Is a Peek at Immunotherapy’s Third Wave

Xconomy Boston — 

In this new age of cancer immunotherapy, two versions have been approved. The first are checkpoint inhibitors, which have begun to change the way skin, lung, and other cancers are treated. The second are CAR-T cell therapies, which have shown promise in blood cancers. A third type of cancer immunotherapy is just now reaching clinical studies, and some early returns are in.

Neon Therapeutics (NASDAQ: NTGN) today is disclosing results from an early study of a personalized vaccine that, for manufacturing, first requires extracting a sample of a patient’s own tumor. The process currently takes a few months and adds an extra degree of difficulty to a field that is already testing the cutting edge of biology.

The results “look promising” but come with plenty of caveats, according to the study’s lead investigator. “I wouldn’t say I’m convinced that this has activity. We don’t know,” said Patrick Ott, the clinical director of Dana Farber Cancer Institute’s Center for Immuno-Oncology in Boston. (Neon spun out of research at Dana Farber. Ott did some consulting for Neon, but says he has no current ties to the company.)

The Phase 1 trial of Neon’s NEO-PV-01 recruited 82 patients with various solid tumors. They first received the Bristol-Myers Squibb (NYSE: BMY) immunotherapy nivolumab (Opdivo), then 12 weeks later received the Neon vaccine. The top-line results of the study showed about 40 percent of the participants—those with advanced melanoma, a type of skin cancer—did quite well based on how long their tumors were kept from growing. Others, with bladder and lung cancers, also did well.

But there are several reasons to temper enthusiasm. Among them: The staggered dosing of Opdivo and NEO-PV-01 makes it difficult to tell if good results are from the vaccine or a delayed effect of Opdivo, said Ott.

Another reason is that the regimen hasn’t been studied head-to-head against a checkpoint inhibitor—a test that would provide more definitive answers.

It’s also unclear if the combination will help patients live longer, the gold standard for a cancer medicine. And other immunotherapy combinations have showed early promise only to flounder later.

Neon CEO Hugh O’Dowd, a former Novartis (NYSE: NVS) oncology executive, called it “the first demonstration of clinical activity” for this kind of cancer treatment, which is called a neoantigen vaccine.

Neon has competitors in the neoantigen vaccine field, among them Gritstone Oncology (NASDAQ: GRTS), and Genocea Biosciences (NASDAQ: GNCA). Messenger RNA drug developers Moderna (NASDAQ: MRNA) and BioNTech are in the mix with different methods, as are Advaxis (NASDAQ: ADXS), Agenus (NASDAQ: AGEN), and others. (This article by consulting firm Back Bay Life Science Advisors takes a deeper look at the field.)

Neoantigen vaccines contain a cocktail of engineered neoantigens—proteins that form on the surface of tumor cells as they mutate. These neoantigens can drive tumor growth, but they also serve as genetic fingerprints that the immune system can recognize if it’s tuned properly.

Some research in recent years has linked the presence of neoantigens to better responses to immunotherapy. This paper published in the New England Journal of Medicine in 2014, for instance, showed that a melanoma patient’s response to checkpoint inhibitors depended on the presence, and abundance, of neoantigens.

Very Complicated

Logistical challenges await Neon and other neoantigen vaccine developers as they advance. NEO-PV-01 involves a complex process: sample a patient’s tumor, use DNA sequencing technology to identify the neoantigens, and use those insights to develop a vaccine personalized to each patient. Another complex cancer treatment, known as CAR-T, has struggled commercially and takes two to three weeks to produce. O’Dowd says it currently takes 8 weeks for Neon to get one of its vaccines to a patient. CAR-T developers have been trying to shave days off their production time. Every minute counts with patients whose advanced cancers are moving fast.

Asked about Neon’s eight-week turnaround, O’Dowd said the company plans to make “marked reductions” this year alone. “These are cancer patients, we want to drive the therapy as fast as feasible and we’re motivated to do so,” he says.

Both Neon and Gritstone raised more than $100 million in private funding before going public in 2018. With today’s news, Neon is the first to report significant efficacy data; Gritstone and Genocea should follow by the end of 2020. Others have tests underway as well.

The key statistic for Neon officials is progression-free survival (PFS), or how long tumors were held in check for patients who received Opdivo and NEO-PV-01. After a median 13.4 months of follow-up, more than half of a group of 34 patients with advanced melanoma were still progression-free; that is, their disease hadn’t spread.

For participants with lung and bladder cancer, their tumors were held in check for a median of 5.6 months before they began to grow again. (The median follow-up for the lung patients was 12 months, and 14.7 months for the bladder patients.)

Neon says that in all cases, these numbers are superior to historical PFS benchmarks for checkpoint inhibitors alone. Neon cites several studies of checkpoint inhibitors used alone to treat skin, lung, and bladder cancer. In those studies, the checkpoint monotherapy kept tumors from spreading for a median of 3 to 7 months in melanoma patients; in lung and bladder cancers, anywhere from 2 to 4 months.

Neon’s president of R&D Richard Gaynor said Neon tried to match its trial against studies of patients with similar baseline characteristics. That’s “imperfect,” he acknowledged, but “we think we can get a good measure of similar patient groups.”

“Seeing a consistency in all three [groups] is what’s garnering our enthusiasm,” O’Dowd said. There were no serious safety issues tied to the vaccine.

Comparing the numbers to older studies wasn’t all beneficial to Neon. Its combination didn’t produce significantly higher response rates. That is, roughly the same percentage of patients, 47 and 44 percent, showed some kind of benefit, even if temporary, in the Bristol Checkmate-067 study that Neon cites.

For Neon Phase 1 participants with bladder cancer and non-small cell lung cancer, there was similar parity with previous studies. Gaynor said response rates are judged by radiologic images, which don’t capture “the full picture of what the vaccine is doing.”

“The data are in-between a slam dunk and something where you’d say, ‘This looks just like’” monotherapy with a checkpoint inhibitor, Ott said. “There may be something there.”

Neon will try to show just that. It will move NEO-PV-01 into randomized trials and try for clearer answers. The first will be a Phase 2 study of NEO-PV-01 in a subset of newly diagnosed advanced melanoma patients, O’Dowd said. (Other early stage, open label studies are underway, as well, including a test combining the NEO-PV-01 with chemotherapy and Keytruda, the current standard of care for many lung cancer patients.)

“We think there is a signal here that is encouraging enough to explore in Phase 2,” Gaynor said.

Here’s more on the emerging field of neoantigen vaccines, and the challenges that lay ahead.