Therapeutic Synergies in the Fight Against Cancer
Surgery, radiation, and chemotherapy are the mainstays of oncology, composing most of the firstline standard of care for virtually all cancers. As newer strategies are introduced into the therapeutic arsenal, particularly for earlier stages of disease, they are almost always tested in addition to, rather than instead of, the standard of care. Not only are these newer strategies proving effective in combination with the older methods, but surprisingly strong synergies are emerging among them. Several CCR investigators are finding ways to exploit these synergies for the benefit of patients.
Vaccine Trials and Tribulations
"Cancer vaccines have had a hard time over the last several years," remarked James Hodge, Ph.D., Senior Scientist in the Laboratory of Tumor Immunology and Biology. Hodge described a series of failed Phase 3 clinical trials for cancer vaccines as monotherapies against late-stage disease that forced companies like Cell Genesys and Therion Biologics out of business. One reason these trials failed, Hodge believes, is that cancer vaccines are probably least effective as a last resort against late-stage disease. Studies have shown that the immune response is blunted in patients that have recently undergone chemotherapy or have had several courses of chemotherapy prior to receiving a vaccine.
As the safety of cancer vaccines has been established over time, however, clinical researchers have been able to administer vaccines to patients closer to the time of diagnosis. In such patients, where a clear standard of care exists, the natural strategy is to test a new therapy in combination with existing care. But first, the safety of any novel combination must be established in preclinical models.
James Hodge, Ph.D. (Photo: R. Baer)
"Combining radiation and vaccine therapy in our preclinical models was a real eye-opener," said Hodge. He and his colleagues designed an experiment in which the vaccine was essentially set up to fail on its own—they injected tumor cells into a mouse engineered to express the human tumor antigens targeted by the vaccine and then withheld the treatment until eight days later. As expected, neither vaccine alone nor radiation therapy alone was sufficient to reduce the large tumor burden achieved in the meantime. However, in those mice given a combination of radiation and vaccine, 60 percent were cured outright. "That’s something we hardly ever see in preclinical models," said Hodge. "And it was all we needed to move forward into the clinic."
Radiation and Immunotherapy—The Theory
Radiation works by producing cellular damage that evokes programmed cell death. "The oxidizing radicals damage cancer cells, but also the normal tissues as well," explained Aradhana Kaushal, M.D., Staff Clinician in the Radiation Oncology Branch. "The idea is that the normal cells can repair themselves, but of course they are affected by radiation too, which is why we see side effects." Radiation oncologists work on trying to limit the effects of radiation to cancer cells, whether by physically constricting the beam of radiation to focus on a tumor mass or by co-administering compounds that will either enhance the vulnerability of tumors or reduce the vulnerability of healthy cells (see "Radiating Change," CCR connections 3(1)).
Cancer vaccines work by training the immune system to recognize and destroy cancer cells. Cancer cells have distinct molecular markers—antigens—that, when processed by specialized antigen-presenting cells (APCs), help the immune system to recognize and target the cells bearing them for destruction by cytotoxic T cells. APCs are drawn to diseased or damaged cells because the cells give off stress signals that let the system know that they need to be cleared away. It makes sense, therefore, that levels of radiation that may not be sufficient to kill cancer cells outright might be sufficient to boost signs of stress and disease that the immune system can recognize.
Chemotherapy and immunotherapy can also have synergistic effects.
James Gulley, M.D., Ph.D., Head of the Clinical Trials Group in the Laboratory of Tumor Immunology and Biology, is enthusiastic about a trial he is currently running to combine vaccine therapy with a form of radiation therapy in patients with metastatic prostate cancer who have run out of proven therapeutic options. The radiation, in this case, is coming not from an external beam but from a compound, samarium-153, that contains a short-lived isotope.
Samarium-153 is not very effective in killing tumor cells. Instead, it is given to patients to ease the pain of metastatic bone cancer. The drug accumulates in areas of the bone that contain cancer and provides pain relief. Hodge has done the preclinical studies, demonstrating that the radiation delivered by samarium-153 has a similar immune-boosting effect as beam radiation in a cell culture model. Gulley is taking the work into the clinic, comparing tumor progression in patients who receive samarium-153 with or without their prostate cancer vaccine. "I am really quite intrigued by the results so far," Gulley said, cautioning however that the data are not yet mature for his randomized Phase 2 trial.
Timing Is Everything
Chemotherapy is a blunt instrument, killing any cell that is dividing rapidly, including cells of the immune system. And unlike radiation, it is seldom focused on a particular tumor or organ and thus usually also disrupts the immune system. But Gulley and Hodge are finding that, if delivered correctly, chemotherapy and immunotherapy can also have synergistic effects.
A strong hint on the importance of timing in vaccine trials came from the results of a human trial in which patients with prostate cancer that did not respond to hormone therapy were initially given either of two treatments—an experimental prostate cancer vaccine or an FDA-approved androgen receptor antagonist, nilutamide. Untreated, these patients would likely develop metastases within a year. Neither treatment improved the odds much: patients who were randomized to receive the vaccine alone progressed similarly to those who received the nilutamide. "However, the interesting thing was that after six months, patients who had rising PSA [prostate-specific antigen] levels but no metastases visible on scans could add in the other treatment," explained Gulley. Surprisingly, the patients that started out on vaccine first and then added nilutamide after six months had much slower disease progression and actually lived longer.