6 questions in cancer immunotherapy

1. Are the responses that have been observed in some blood cancer patients who receive T-cell therapies durable, and can they be repeated in more patients?

Some of the greatest excitement in the immunotherapy field is coming from ongoing trials of patients’ own immune cells that are engineered with a cancer-targeting receptor to kill their cancer cells.

In one such trial, led by researchers at Fred Hutch, patients’ T cells are programmed with synthetic receptors called CARs to kill blood cancers bearing a marker called CD19. Trial researchers have preliminarily reported high rates of complete remissions in patients with certain late-stage, CD19-positive blood cancers who had very few conventional treatment options available to them before they received the CAR T cells.

“The results are simply astounding,” said study investigator Dr. Stanley Riddell in a video interview earlier this year.

But it’s important to remember that these CAR T-cell trials are still ongoing, Riddell and other Fred Hutch experts said. One issue that still must be resolved is whether the patients with the most dramatic responses — the far-flung tumors that disappear within weeks after a single infusion of T cells — are still cancer-free months and years later.

“Obviously time will tell,” Riddell said. He noted that while some patients have been in remission for well over a year, some of the patients on the trial have relapsed. The investigators now are studying their responses to figure out exactly why, information that they can then use to improve the CAR T-cell strategy.

Riddell said that ultimately, the goal — which is still years out — is to launch trials of the experimental cells in patients with earlier-stage disease after the strategy has been thoroughly tested in late-stage patients with few other options. These patients’ cancers will have had less time to accumulate mutations that may enable them to escape the engineered T cells, he said.

“I think that we’re on the right track with CD19,” he said. “I don’t think we’re there yet, but it’s promising.”

The Hutch’s Dr. Aude Chapuis works on another T-cell therapy strategy, which involves inserting naturally occurring anti-cancer receptors into a patients’ T cells. Results from the group’s latest trial of these cells in patients with a particular type of advanced leukemia have not been published yet, but Chapuis says preliminary results give her hope.

“We’re certainly not there yet, but there’s a huge potential” for both kinds of T-cell immunotherapies, Chapuis said. “Now we really have to find ways to broaden it to other patients.”

Chapuis listed several strategies, still being worked out in the lab, that may eventually translate into an improved clinical therapy, including engineering multiple types of immune cells (instead of one type of cell) to engage against cancer and treating patients with drugs designed to keep the engineered T cells active.

It’s also important to keep searching for new, possibly better, T-cell targets on cancer cells, several experts said.

For example, lymphoma immunotherapy specialist Dr. Oliver Press is collaborating with the Hutch’s Dr. Brian Till to develop CAR T cells that kill lymphoma cells bearing a marker called CD20; they hope to open a trial testing that therapy later this year. The field is also moving toward T-cell therapies that simultaneously target more than one cancer marker at a time, Press and other Fred Hutch experts said, which would make it more difficult for any cancer cells to escape T-cell attacks.

2. Can T-cell therapies be used against common solid tumors?

The dramatic successes seen so far in T-cell therapy trials have been in certain blood cancer patients. But the cancers that kill the most people in the U.S. are solid tumors, according to the American Cancer Society: lung, breast, colorectal, pancreatic and prostate cancers.

And solid tumors pose particular challenges for immunotherapies that aren’t factors in liquid tumors, where the cancer cells are in the bloodstream and more accessible to immune cells, several Hutch researchers said.

“There are a lot of factors within the tumor microenvironment that can shut down T cells, and these factors may not be the same for every solid tumor,” said Dr. Ingunn Stromnes, an immunology research associate at Fred Hutch who is developing a T-cell therapy for pancreatic cancer. In the microscopic milieu of a pancreatic tumor, for example, Stromnes cited interference by other types of immune cells and immunosuppressive signals sent by cancer cells as factors that can block or dampen anti-cancer immune responses.

One way to overcome this challenge is to engineer T cells to interpret “shut down” signals as “stay awake” signals, Stromnes said. She and collaborators are currently developing molecules to engineer into T cells that would do this, and she expects that within the year, preclinical testing will reveal a way to enhance the anti-cancer response.

Finding the right targets for T-cell therapies is another big challenge. For example, last fall, Stromnes and her collaborators at Fred Hutch published results of a mouse study showing that T cells programmed to kill pancreatic cancer cells bearing a marker called mesothelin boosted survival by more than 75 percent — a respectable number considering this cancer kills most of its human victims within five years of diagnosis.

“We’re going to get T cells into the clinic as soon as possible” by later this year, if all goes well, Stromnes said, “because we think we have something that’s going to work.”

New technologies now enable researchers to quickly and affordably sequence the genomes of individual tumors — something that wasn’t possible a decade ago. With efficient genomic sequencing, multiple groups across the Hutch and around the world are seeking T-cell targets in many tumor types.

3. Can we get targeted, immune-boosting drugs to work for more patients?

Another emerging form of immunotherapy includes drugs known as immune checkpoint inhibitors, which block signals that tamp down T cells’ cancer-killing activity. In some patients, these drugs have proved extremely effective. The most famous example may be former President Jimmy Carter, whose treatment with a checkpoint inhibitor known as pembrolizumab (Keytruda) swiftly killed off melanoma that had spread to his brain and liver.

However, these drugs only work in some patients. How can they be made to work for more people?

The problem is that most cancers don’t trigger much of an immune response to begin with, said Dr. Mary “Nora” Disis, a solid tumor immunotherapist at the University of Washington and Fred Hutch. And recent evidence shows that patients with existing anti-cancer immune responses have the best responses to treatment with these drugs. The solution in this case, Disis said, will be to find ways to stimulate an immune response within a tumor that can then be boosted with a checkpoint inhibitor.

Some existing drugs could play this role, she said, such as certain chemotherapies that have immune-stimulating effects.

“We now need to go back and look at many things that have been shown to boost immunity and focus on how we can really integrate immune therapy now into standard of care,” Disis said.

Dr. Lee Cranmer, head of the Hutch’s Bob and Eileen Gilman Family Sarcoma Research Program, pointed out that the opposite question is also relevant.

“There’s some people who don’t derive significant benefit or only minimal benefit, and we don’t want to be giving patients things with potential toxicities without being able to focus them better,” said Cranmer, who has been active in clinical trials of checkpoint inhibitors. “So one of our objectives [in the field] is taking something we already have and saying, ‘OK, how can we focus [this treatment on those most likely to benefit],’ rather than saying ‘OK, let’s just throw this at you and see if it does something.’”

4. Can immunotherapy prevent cancer?

“For me," Disis said, "the biggest big hairy question is, ‘How can we use the immune system to even prevent the development of cancer?’ And I think we can."

But it’s a long-term goal, she added.

Her group is one of a handful around the country developing preventive cancer vaccines. She and collaborators are currently testing a vaccine to prevent breast cancer in early phase clinical trials for women who are at risk of breast cancer relapse. The experimental vaccine is the first preventive vaccine to train the immune system against multiple cancer markers at once. In three to five years, Disis hopes, the vaccine will move into clinical use with women at high risk of developing breast cancer in the future.

She said that to really make significant progress, the field needs a coordinated effort to characterize the genomic signatures and immune environments associated with precancerous growths — such as polyps in the colon that are at risk of becoming cancerous. This effort would reveal targets for vaccines and strategies for using immune-boosting drugs to stop this process before cancer forms.