Wednesday, October 19, 2016
Scientists have been trying to create an effective therapeutic cancer vaccine for decades, with little success. Here we explore the hurdles and promise.
In June 2016, drug maker Galena Biopharma announced it was shuttering a phase III trial of its NeuVax cancer vaccine for women with early-stage breast cancer. Data from the trial indicated that women receiving the vaccine fared no better than those in the control group.
This disappointing result had an all-too-familiar ring: Many other cancer vaccines have likewise failed in late-stage clinical trials. In the past three years alone, vaccines targeting pancreatic cancer, brain cancer, lung cancer, and melanoma have all gone belly up.
At a time when immunotherapy as a field is flourishing, cancer vaccines seem to be struggling to stay afloat.
“There has been, unfortunately, a string of failures in the cancer vaccine field,” says Dmitriy Zamarin, a cancer immunologist at Memorial Sloan Kettering who researches vaccines.
And that has given vaccines a bad name. “People look down on cancer vaccines because of the low efficacy or lack of efficacy that has been seen so far,” he says.
Finding the Right Target
The idea behind a therapeutic cancer vaccine is simple: Give the immune system a whiff of cancer’s scent and then release the hounds. The scent in this case is a distinguishing molecular marker called an antigen, which an immune cell can recognize as dangerous, combined with a general instigator of immune activity called an adjuvant. The hope is that immune cells, educated by the vaccine, will then find and kill cancer in the body.
(Preventive cancer vaccines work in a different way — they prevent infections with viruses like HPV and hepatitis B that can lead to cancer.)
The biggest challenge in therapeutic cancer vaccine development, Dr. Zamarin says, is finding the right target. Most vaccines tested to date have targeted antigens that are not truly tumor specific.
HER2/neu, for instance — the antigen in Galena’s NeuVax vaccine — is enriched on breast cancer cells but is also found on many normal cells. “It’s basically such an important signaling molecule that the immune system constantly sees it,” Dr. Zamarin says. “It’s very hard to develop an effective immune response to such a broadly expressed self-antigen.”
A better choice, he says, is to target antigens that are more specifically associated with cancer. “The more unique the target is to the tumor, the better the target for the vaccine,” he notes.
For many years, truly cancer-specific antigens were hard to come by. The biotechnology to find them just didn’t exist. But in recent years, with advances in genetic sequencing methods, it’s been possible to find these molecular needles in the cancer haystack.
Because they are prone to making genetic mistakes, cancer cells accumulate DNA mutations at a high rate. Some of these mutations create unique versions of proteins that look different from the normal versions. Scientists call these novel creations neo-antigens. Because they are specific to cancer cells, and absent from normal cells, neo-antigens make an attractive target for vaccines. Several clinical trials of neo-antigen vaccines are currently under way; one will open at MSK within the next two months.Back to top
Even with the best antigen, however, a cancer vaccine by itself may not be able to curb the growth of a tumor. That’s because, as researchers are learning, the environment surrounding a tumor often suppresses immune responses. As tumors grow, they produce molecules that actively prevent immune cells from doing their job. So even if a vaccine is able to switch on immune cells, they may not be able to enter the tumor area. Or, if they do enter, they may be immediately shut down.
That’s why, increasingly, scientists think that combination therapies — with vaccines as one component — may be the best approach. They are especially interested in the combination of vaccines and checkpoint inhibitors, drugs that “release the brakes” on the immune system and allow it to mount a stronger attack against cancer.
At MSK, researchers are conducting a clinical trial of one such combination involving a checkpoint inhibitor and a cancer vaccine targeting an antigen called WT1, which is found on several different types of cancer, including ovarian cancer. The WT1 vaccine was developed at MSK by physician-scientist David Scheinberg, Director of the Center for Experimental Therapeutics. The combo is being given to patients with WT1-positive ovarian cancer who have had a complete response to chemotherapy.
The hope is that by stimulating an immune response to WT1 in a context in which there is minimal disease, it may be possible to delay the time to recurrence — or, better yet, prevent it completely. “Because we know that basically 90 percent of these patients will recur,” Dr. Zamarin says.Back to top
Vaccine Success Stories
By the time a person has a tumor, the immune system has clearly failed to stop cancer’s growth — despite the presence of cancer antigens in the body. So what makes scientists think that giving these same antigens back to the patient is going to do any good?
According to Dr. Zamarin, one answer may be that the initial immune response was just too weak. “Those T cells may be there, but there might not be enough of them,” he says. “If you generate more of them, you might be able to overwhelm the inhibition of these tumor-specific immune cells.”
And there are vaccine success stories, he says. One comes from a vaccine designed to treat the precancerous lesions that can sometimes lead to cervical cancer called cervical intraepithelial neoplasia (CIN). CIN is caused by infection with HPV, the human papillomavirus.
Patients who received a therapeutic DNA-based vaccine made up of antigens from the HPV virus saw their lesions regress. “About half of the patients completely cleared the tumor just as a result of the vaccination,” Dr. Zamarin says. “This is roughly double what you see without the vaccine. So it tells you that in the right kind of setting, generating an immune response that otherwise may have been ineffective can successfully control or even eradicate these sorts of lesions.”Back to top
Not Your Parents’ Vaccine
While most cancer vaccines developed thus far involve injecting the body with specific antigens, scientists now realize there are many ways to vaccinate. Even chemotherapy and radiation can be considered vaccines since they kill cancer cells and expose the immune system to antigens.
Dr. Zamarin is most excited about vaccines that involve what are called oncolytic viruses — viruses that preferentially infect cancer cells and cause them to burst, or lyse. These agents are appealing because they are very good at attracting immune attention, functioning in some ways like antigen and adjuvant in one.
“These viruses don’t just kill cancer cells — they also generate this marked inflammatory response,” he says.
By releasing a slew of cancer antigens in the context of an immune system primed for response, there is a good chance that at least one of them will trigger an immune attack.
While most of the research done so far has been in mice, the vaccine is moving toward clinical trials in humans. “We’re hoping that it’s going to make it to clinic within the next year and a half,” Dr. Zamarin says.
Another oncolytic virus–based vaccine, called T-VEC, is already FDA approved for the treatment of melanoma.Back to top