Results of an early clinical trial for an investigational ovarian cancer vaccine illustrate both the promise and the limitations of immunotherapy approaches to treating cancer.
The study, led by Kunle Odunsi of the Roswell Park Cancer Institute in Buffalo, N.Y., and reported in the Proceedings of the National Academy of Sciences, shows encouraging preliminary clinical effects against a particularly deadly type of ovarian cancer. Yet the technical details of the findings seem to support the view of some experts that immunotherapy alone may not be enough to eradicate the toughest cancers.
In this case, the test vaccine did what researchers had hoped it would in this Phase 1 trial, which was designed to assess safety (its effectiveness will be further evaluated in the next step in the trial process). The vaccine induced a significant immune system response, essentially training specialized immune cells (T cells) to recognize tumor cells and mount an attack. It also lengthened the time it took for the disease to progress to a median of 19 months in the group of 18 women with advanced epithelial ovarian cancer, a group whose life expectancy is usually measured in weeks, not months.
Importantly, the investigators found evidence of antibodies to the vaccine construct in some – but not all – women up to 12 months after their last vaccine injection. That suggests that in some women there was a lasting “memory” in the immune system for the malignant cells.
This finding parallels other evidence that “you can generate an immune response that, in theory, can be very long-lived,” says James Gulley, a senior clinician in the National Cancer Institute's (NCI) Laboratory of Tumor Immunology and Biology, who was not involved in the study. “This means that you can potentially improve subsequent therapies for the patient, because the immune response could continue to be boosted by cancer cells that are killed by, say, chemotherapy or radiation and are therefore feeding information back into the immune system. So the impact could continue to snowball, and you may eventually induce a significant improvement in survival even when you don’t have a large shrinkage of disease up front.”
Not all the women in the Odunsi study showed such a lasting effect, suggesting that there was “immune escape,” the authors wrote. In other words, the immune system was no longer able to recognize the tumor cell "signature," so malignant cells could escape detection and continue dividing. This suggests patients might need booster shots of the vaccine, or that some patients would need another anti-cancer approach.
Gulley, who is the principal investigator for six ongoing clinical trials of cancer vaccines initiated by the NCI, is one of many cancer experts promoting a new approach to cancer therapy: combining different treatment modalities to attack tumors from multiple angles. He and two colleagues in the NCI’s immunotherapy group wrote a review in the July issue of Clinical Cancer Research describing the need for "paradigm shifts” in cancer care to exploit vaccine therapy, including using it to prime the immune system to respond better to other anti-cancer treatments.
“Both combination and sequence are important,” says Gulley. “Some anti-cancer drugs may not work well at exactly the same time as vaccines, or if given in a certain sequence with vaccines. But perhaps they could work better if the vaccine is given first, followed by another drug or combined with either chemotherapy or radiation. We’ve looked at all of those approaches and have found some very nice data to suggest that certain combinations can be potentially beneficial.”
Gulley is particularly enthused about the potential for combining cancer vaccines with an investigational drug that shuts off one avenue the immune system uses to quell an immune response when it is no longer needed. The drug blocks the expression of a particular marker on the surface of T cells, an antigen known as CTLA4 (for common T cell leukocyte antigen 4). In a normal immune response, CTLA4 is expressed on T cells after these specialized attack cells are activated to destroy an offending pathogen, essentially sending a message to the cell that its job is done and it can back off now.
“Anti-CTLA4 drugs help take the brakes off the immune system, and allow a much broader and fuller immune response,” Gulley explains.
Gulley’s group is one of several studying combination therapies using anti-CTLA4 and a vaccine in early-phase clinical trials. At the NCI, 18 patients have been enrolled in a prostate cancer trial; preliminary data shows evidence of clinical benefit, according to Gulley. Two other groups studying prostate cancer, one in the Netherlands and one at the University of California, San Francisco, are also seeing early indications of a beneficial effect, he says.
“This is an area that is helping us unlock the vaccine’s potential for getting a robust immune response,” Gulley says. Using combination therapies like these together with other more traditional modalities, such as chemotherapy, radiation, or anti-cancer drugs, could further boost response, he says.
“I think the days of medical empiricism are over,” he says. “We’ve learned that we can no longer just take this kind of ‘one size fits all’ approach. We really need to figure out how the drugs work, in what patient populations they work best, and then design regimens for those specific populations.”