In an era of cancer immunotherapy, vaccines are getting fresh consideration as a therapeutic approach.

Frustrated for years by lackluster results, cancer vaccine research is now advancing more briskly, revitalized by the success of a handful of new medicines that unleash the immune system on tumors.

Estimates vary, but one count puts the number of cancer vaccine candidates in clinical testing across the industry at over 300. Several leading biotechs in the space, including Cambridge-based Moderna Therapeutics and BioNTech in Germany, have raised hundreds of millions of dollars on the promise of their pipelines.

At the same time, recent improvements in gene sequencing and machine learning have made the tailoring of vaccines to an individual patient’s cancer technically feasible.

“This ability to access [sequencing] technology opens up a field of vaccine research and development that hasn’t been available to us in the past,” said Sean Marett, chief operating officer at BioNTech, in an interview.

The hope is that these advances could enable researchers to sidestep some of the hurdles that have hindered prior efforts. Yet, researchers caution, translating technological gains into therapies remains a work in progress.

Solving immunosuppression

When viruses infect the human body, the immune system mobilizes defenses to seek out and destroy the foreign invader.

Why don’t cancers provoke the same response? Spurred to unchecked growth by the steady accumulation of mutations, cancerous cells are also an invader. Yet tumors often remain hidden from the watchful eyes of cellular defenders like T cells.

Researchers have long been intrigued by the idea of a cancer vaccine, drawn in by hints of an immune role in cases of “spontaneous” remissions to cancer. But most efforts have come up short.

A few, such as Dendreon’s prostate cancer vaccine Provenge (sipuleucel-T), have made it through to patients, yet remain isolated examples.

In the past seven years, however, a new class of immunotherapies known as checkpoint inhibitors has dramatically recast the cancer field. These drugs, and the research that led to them, have elevated cancer immunology — once overlooked — to a preeminent position in oncology.

In this light, cancer vaccines no longer look as far-fetched.

“The checkpoint inhibitors have not only revived our interest in immunotherapy — and vaccines as a component of that — but has really changed the way we think about our natural immunological response to cancer,” said Michael Sabel, a professor of surgical oncology at the University of Michigan, in an interview.

Checkpoint inhibitors are frequently described as removing the brakes on the body’s immune response to cancer. Essentially, the drugs block a suppressive mechanism co-opted by tumors to evade destruction.

Solving immunosuppression — at least in part — could be the key that opens the door for vaccines to play a greater role.

“With the discovery of how important immunosuppression was, it became clear that a vaccine, on its own without something that also deals with the suppression, was never going to work,” explained Jill O’Donnell-Tormey, head of the Cancer Research Institute, a New York-based nonprofit.

The “missing piece”

Just as the immuno-oncology field has moved toward combination treatment, drugmakers are also pairing cancer vaccines with checkpoint inhibitors — essentially teaching the immune system what to look for while also removing the blindfold.

Tom Hudson, head of oncology discovery and early development at AbbVie and a clinical immunologist, calls checkpoints inhibitors the “missing piece” that could catalyze vaccine research further.

AbbVie, while not yet a player in immuno-oncology, inked a deal last fall with Turnstone Biologics to license three viral immunotherapies that it hopes can also function as an immune-activating vaccine. The first, in two Phase 1/2 studies, will be paired with an approved PD-1 checkpoint inhibitor.

Vaccines could also offer a way to improve the number of patients who benefit from immunotherapy, or to help turn so-called “cold” tumors more immunoreactive.

“There are many types of tumors where there are just not enough T cells that infiltrate the tumor microenvironment,” explains Nisarg Shah, a postdoctoral fellow in the Wyss Institute at Harvard University.

“In that case, cancer vaccines could play an important role in training the immune cell to recognize this particular mass of tumor cells as something that needs to be destroyed.”

Shah pointed to checkpoint inhibitors as a possible complement, suggesting there could be synergy between the two approaches.

Bigger immuno-oncology players are getting involved, too.

Merck & Co. has partnered with Moderna, and last year the two began an early-stage trial of a personalized cancer vaccine, testing the mRNA-based therapy together with Merck’s flagship checkpoint inhibitor Keytruda (pembrolizumab).

In May, Merck invested $125 million in the well-funded biotech to expand the collaboration to cover work on another vaccine targeting mutations of an oncogene known as KRAS.