An Update on Cancer Vaccines - New Paradigms
Many deadly infectious diseases that were capable of killing millions are now tamed because of vaccines, which stimulate the immune system to recognize and attack pathogens before they can cause disease. Soon it may be the same for cancer.
The first major step toward this goal came recently when the FDA approved and Merck began marketing Gardasil for the prevention of human papillomavirus (HPV) infection, a major cause of cervical cancer. HPV vaccines represent one type of cancer vaccine, which may prevent cancer before it occurs, while therapeutic cancer vaccines may help turn a patient’s immune system against already-existing cancer cells.
"There is an enormous amount of progress being made in the field of cancer vaccines," says Dr. Jeffrey Schlom, chief of NCI's Laboratory of Tumor Immunology and Biology, in the Center for Cancer Research (CCR).
However, he points out, therapeutic cancer vaccines - those that attack solid tumors, rather than preventing conditions that cause cancer - will most likely be used to treat early-stage disease or metastatic disease where the overall tumor burden is low.
"There are limits to what vaccines can do," Dr. Schlom says. This is because with a large tumor mass, the lymphocytes activated by the vaccine must pit themselves against a large number of cancer cells, where the odds are unfavorable. "A good analogy is hand-to-hand combat," he explains. Research in the last few years has indicated that vaccines may be most effective following surgery to remove the bulk of the cancer and when used in conjunction with other standard treatments.
The strategy may be particularly effective if a vaccine is administered simultaneously with chemotherapy or radiation, which seems to make tumors more vulnerable to detection and attack, as well as with vaccine boosters and cytokines to augment the immune response. Dr. Schlom described this phenomenon in a review article in the July 1 issue of Clinical Cancer Research, where he contrasted the dynamic immune processes triggered by vaccines with passive therapies such as drugs or radiation.
Randomized phase II trials testing these vaccine strategies have shown an increase in median survival of 4 to 8 months over controls, with overall survival as long as 3 to 5 years at the time the data were published. Survival could be much longer, as many of these trials continue.
Dr. James Gulley of NCI's CCR is leading five phase I and II clinical vaccine trials at the NIH Clinical Research Center to test immunostimulant additives, antibodies, and viral vectors that produce tumor-associated antigens, as well as the effect of vaccines injected into tumors.
"With vaccines alone we have seen clinical responses in patients with prostate, ovarian, and breast cancer. The addition of an anti-CTLA-4 antibody to a vaccine appears to further improve the clinical benefit in a proportion of patients with metastatic prostate cancer," he notes.
Dr. Philip Arlen of CCR collaborates with Dr. Gulley and is leading two phase II trials at the Clinical Research Center to test the combination of hormones or low-dose, single-agent chemotherapy (which is less toxic than standard multidrug regimens) with vaccines in patients with prostate or breast carcinomas. Preliminary results of these studies show that the vaccine treatments are well tolerated, and some patients have received treatment for more than a year without disease progression.
"We have preliminary evidence that therapeutic cancer vaccines can provide patient benefit," Dr. Arlen says. "Here at NCI, we're able to go further with small, cutting-edge studies that address how we should utilize them - in what populations, for example, and with what combination of treatments." He is currently planning clinical trials to test hormone therapy and allogeneic stem cell transplantation as part of the vaccine treatment strategy.
More than a dozen vaccines are in or nearing phase III trials to refine their use, including dosing, booster schedules, and the site of vaccine administration. But for now, the FDA has not approved any therapeutic cancer vaccines.
"I'd like to think that cancer vaccines will be approved by the FDA within the next 5 years," says Dr. Schlom, "perhaps one or two within the next couple of years. But we can't say for sure because we need a paradigm shift, first, in the way that vaccine trials are designed and how they are evaluated."
Dr. Schlom points out the case of Provenge, a vaccine for advanced prostate cancer that was reviewed by the FDA this past spring, showing an increase in patient survival but not a reduction in tumor progression, which was the study's primary endpoint. "Most likely, this was because the vaccine was able to keep the disease in check, but not able to reduce the overall tumor load," he says.
Ethically, patients must be offered treatments with demonstrated benefit before they are offered experimental ones. So a patient who enters a therapeutic vaccine trial has likely already gone through surgery, disease metastasis, and then one or more rounds of adjuvant treatment, including chemotherapy, radiation, or hormone treatments. "By this time, many patients have large tumor masses again, which is not the ideal setting for a vaccine trial," says Dr. Schlom."We're just getting to the point where we're able to think about doing these studies in combination with or versus standard-of-care therapy," says Dr. Schlom, noting that NCI and FDA held a conference at NIH last February to discuss how vaccines and other immunotherapies can best be brought through development to licensure. "But for advanced disease," he says, "other immunotherapies will likely be more useful."
For more information about cancer vaccines, view the NCI fact sheet online.
- Brittany Moya del Pino