A new kind of personalized vaccine—one made by exposing a patient’s own immune cells to the contents of a patient’s own tumor cells—has been shown to improve immune responses and increase survival rates in patients with ovarian cancer. The vaccine, which was evaluated in a pilot clinical trial conducted at the University of Pennsylvania School of Medicine, was administered alone or in combination with other immunomodulatory drugs. Because the vaccine performed so well, amplifying T-cell responses against both common antigens and patient-specific neoantigens expressed on tumors, the scientists who ran the trial concluded that the vaccine warrants further clinical testing.
The new findings appeared April 11 in the journal Science Translational Medicine, in an article entitled “Personalized Cancer Vaccine Effectively Mobilizes Antitumor T Cell Immunity in Ovarian Cancer.” According to this article, about half of the vaccinated patients showed signs of antitumor T-cell responses, and those “responders” tended to live much longer without tumor progression than those who didn't respond. One patient, after two years of vaccinations, was disease-free for another five years without further treatment.
The article also indicated that vaccination “amplified T cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes, as well as novel T cell clones of markedly higher avidity against previously recognized neoepitopes.”
“This is the first time ever that a personalized vaccine made from the contents of whole cancer cells has been shown to produce immune responses against neoantigens,” said Lana E. Kandalaft, Ph.D., the article’s corresponding author and an adjunct researcher at the Lausanne Branch of the Ludwig Institute for Cancer Research. “We've also shown that these immune responses are not just any responses, but the type that kills tumor cells, and that they correlate with better progression-free survival and better overall survival of patients.”
The study conducted by Dr. Kandalaft and colleagues addressed a longstanding conundrum of ovarian cancer treatment. Ovarian tumor cells are known to express neoantigens, which are randomly mutated proteins expressed by cancer cells that can be detected as signs of disease by the immune system. Yet the malignancy has so far proved largely resistant to immunotherapies, including traditional cancer vaccines, that stimulate an attack by killer T cells.
Ovarian cancer’s ability to resist immunotherapy is at least partly due to a factor secreted by tumors, vascular endothelial growth factor A (VEGF-A), keeps killer T cells from infiltrating the tumor. Ovarian tumors also harbor T regulatory cells (Tregs), whose job it is to suppress killer T cells.
Many researchers are trying to computationally predict the neoantigens expressed by a patient's tumors and synthesize the bits—or neoepitopes—recognized by T cells to make personalized vaccines. But, while promising, such approaches are labor intensive and time-consuming, and thus, relatively expensive.
Dr. Kandalaft and colleagues wondered if, alternatively, the contents of cancer cells taken from tumor samples—or “whole tumor lysates”—might suffice to make vaccines that train the body to detect the neoepitopes expressed on tumors.
“This would be the cost-effective way of producing an individualized cancer vaccine,” asserts Dr. Kandalaft.
Dr. Kandalaft and colleagues devised a novel method for making a vaccine of this sort while she was still at the Perelman School of Medicine at the University of Pennsylvania. In this method, the lysate from cancer cells is gently treated with acid to turn its antigens into more potent stimulators of immune responses. The researchers applied the method to tumors taken from each patient in the study.
Next, the rearchers collected certain immune cells from each patient and coaxed them to turn into dendritic cells, which gobble up suspicious biological detritus and “present” antigens to T cells to help stimulate an immune response.
For the clinical trial, the researchers pulsed the dendritic cells from each patient with her tumor lysate to generate living and personalized dendritic cell vaccines. These vaccines were then injected into the lymph nodes of each corresponding patient. “The lymph nodes,” explained Dr. Kandalaft, “are the headquarters where dendritic cells meet T cells.”
One cohort of patients received just the personalized vaccine. A second received vaccine along with bevacizumab, a standard therapy that blocks blood vessel formation in tumors by targeting VEGF-A—the same factor that bars killer T cells from entering tumors. The third cohort got, in addition to bevacizumab, low doses of cyclophosphamide. This chemotherapy, another standard of care for recurrent ovarian cancer, also happens to suppress Tregs—which are recruited into tumors to shut down killer T cells.
“The regimen used for the third cohort really made a difference—first in eliciting an immune response in patients who received it, and then in the progression-free survival and the overall survival of those patients a year and even two years after receiving the therapy,” noted Dr. Kandalaft.
Although the study met all of its endpoints, it was not a randomized, placebo-controlled trial. The researchers did, however, compare their results with historical patient data of ovarian cancer recurrence and the outcomes recorded in their practice. “At one year, 100% of the patients in cohort 3 were alive, as compared to 60% when patients receive just bevacizumab and cyclophosphamide but no vaccine,” said Dr. Kandalaft.
Their therapeutic strategy, Dr. Kandalaft maintained, would also be eminently suited to swift implementation if it passes muster in larger, randomized, and placebo-controlled trials.
“We aren't giving patients any completely new drugs in combination with this personalized vaccine,” she pointed out. “Bevacizumab and cyclophosphamide are routinely used to treat recurrent ovarian cancer. All we did was add the vaccine. This means that we should be able to easily integrate this personalized immunotherapy into the current standard of care for recurrent ovarian cancer.”
