Zachary Morris has certainly done some memorable things. As a Rhodes Scholar, he once attended an evening reception at Buckingham Palace, played a game of pick-up football with former President Bill Clinton, and traveled to South Africa to take a Robben Island Prison tour, led by the late Nelson Mandela. But something the young radiation oncologist did during his medical residency could prove even more momentous. He received a special opportunity from the American Board of Radiology to join others in studying how to pair radiation therapy with the emerging cancer treatment strategy of immunotherapy.
Morris’s studies in animals showed that the two treatments have a unique synergy, generating a sustained tumor-specific immune response that’s more potent than either therapy alone. But getting this combination therapy just right to optimize its cancer-fighting abilities remains complicated. Morris, now a researcher and clinician at the University of Wisconsin School of Medicine and Public Health, Madison, has received a 2017 NIH Director’s Early Independence Award to look deeper into this promising approach. He and his collaborators will use what they learn to better inform their future early stage clinical trials of radio-immunotherapy starting with melanoma, head and neck cancers, and neuroblastoma.
Most people think of radiation therapy in its more traditional, high-dose form that irradiates tumor cells, causing breaks in their DNA and killing them. What Morris and others have learned over the past several years is that the surviving tumor cells don’t escape unscathed. Fragments of damaged DNA wind up in their cytoplasm and can “trick” them into behaving as if they have been infected with a DNA virus. These cells then activate an internal response that leads to them to display proteins at the cell surface that can alert immune cells to target or even kill the damaged cancer cell.
Once initiated, the attack can expose mutated proteins from the tumor cells (but not in normal tissues) for other parts of the immune system to see them. This primes the immune system to recognize the tumor cells elsewhere in the body, much in the same way that a vaccine delivered in the arm generates enduring immunity throughout the body against an infectious invader.
After this radiation-induced vaccination, Morris begins the immunotherapy to bolster the deadly attack against the tumor. He infuses directly into the radiated tumor the FDA-approved antibody dinutuximab and an immune-stimulatory protein called IL2.
With his early Independence Award, Morris will further explore in animal studies the best timing and dose of radiation to generate this vaccination effect. He also hopes to learn how best to sequence the radiation and immunotherapy to maximize the immune response to the tumor.
Morris will also dive deeper into a potential problem in the vaccination process that he and his colleagues have encountered in animal studies. Tumors make chemicals that attract regulatory immune T cells, or Tregs. Their job is to suppress an immune response, which in this case is beneficial to the tumor but bad for the patient.
Even during low-dose radiation, Tregs are depleted in treated tumors due to their extreme sensitivity to the therapy. But Morris and colleagues have discovered something unusual. If all tumors in an animal are not treated with some radiation, their Tregs will hone in on the site where he delivers his radiation-induced vaccination and prevent or slow the immune response. Morris will test whether the best solution is to expose all tumors to just a tad of radiation. That way the Tregs residing in these tumors won’t meddle in the immune response under way against the primary tumor as it is being converted into a personalized cancer vaccine.
Delivering just a tiny dose of radiation to all tumor sites is difficult to do with conventional radiation without also wiping out the good immune cells. To get around this problem, Morris and colleagues are using molecularly targeted radiation therapy. They attach a radioactive material to a substance that is taken up selectively by the tumor. Such agents are currently available to treat people with certain lymphomas (cancers that start in immune cells called lymphocytes), thyroid cancers, and neuroblastoma.
Morris hopes that he and his collaborators can help the field move this strategy forward as part of a treatment for other solid tumors. Morris and his colleagues certainly aren’t alone. Radio-immunotherapy is a very active and promising area of research that should have an interesting story to tell in the months and years ahead.
Radiation Therapy for Cancer (National Cancer Institute/NIH)
Zachary Morris (University of Wisconsin School of Medicine and Public Health, Madison)
Morris Project Information (NIH RePORTER)
NIH Director’s Early Independence Award (Common Fund)
NIH Support: Common Fund