Researchers at the Johns Hopkins Kimmel Cancer Center have demonstrated a significantly prolonged survival of mice with glioblastoma, the most common form of human brain cancer and one associated with poor survival. Survival of the mice was more than double with the novel triple therapy combination therapy compared to mice treated only with two of the three therapies.
Michael Lim, MD, director of brain tumor immunotherapy and associate professor of neurological surgery at Johns Hopkins University in Baltimore and colleagues, treated the mice with a triple combination-radiation therapy plus two immunotherapy antibodies, an anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody and an anti-4-1BB (CD137) antibody. The study is published in a recent PLOS One article.
Mice with implanted mouse-origin glioblastoma cells lived an average of 24 days when they received the two antibodies alone compared to 67 days when treated with the two antibodies plus radiation therapy. Half of the mice that received the triple combination lived 100 days or more. These mice were also protected against developing more tumors when exposed to new glioma cells.
The triple therapy resulted in a large number of tumor-infiltrating T-cells and a glioma-specific immune memory response.
An anti-CTLA4 antibody, ipilimumab (Yervoy) is already approved by the Food and Drug Administration for treatment of metastatic melanoma and is currently being tested for other solid tumors. The antibody serves to lift a break on the immune system, allowing a robust immunotherapy response to cancer in some patients. 4-1BB is a cell surface protein expressed on T-cells that have been activated and has been shown to contribute to the cytotoxic function of T-cells in the context of cancer. A previous mouse study had suggested that the combination of the anti-CTLA4 and anti-4-1BB antibodies boosted immunity against cancer while also reducing inflammation and autoimmune effects which may be beneficial for future clinical treatment of human patients.
Patients treated with ipilimumab can have very severe immune-related adverse events including colitis. To overcome these adverse events, an approach has been to combine an anti-CTLA4 blockade with activation of 4-1BB as the combination of the two therapies appear to increase cancer immunity while reducing inflammation and autoimmune responses, even though both antibodies individually can cause inflammation to select organs, according to the previous preclinical studies.
While CTLA-4 inhibition allows lymphocytes to proliferate, anti-4-1BB stimulates lymphocytes, “in essence, taking your foot off the brake while pushing down on the accelerator at the same time,” said Lim.
Adding radiotherapy to immunotherapy has been shown to enhance the immune response, at least partly, by releasing cancer-specific antigens from dead tumor cells that can be recognized by activated lymphocytes.
A benefit of this triple therapy combination is the ability of the immune system to build up a memory response to the glioma cells which may deter recurrence.
The issue of whether immune checkpoint inhibitor antibodies such as anti-4-1BB and anti-CTLA4 can penetrate the blood brain barrier is not that important, Lim told OncoTherapy Network. “These antibodies attach to the immune cells in the periphery and the immune cells then traffic to the tumor in the central nervous system in their activated state.”
“I think our findings are exciting in that we have a therapy that circumvents the blood-brain barrier and introduces a new paradigm for radiation in that radiation is used to kindle the immune response rather than its traditional application of trying to be a definitive therapy,” said Lim.
The researchers are currently developing human clinical trials to test combination therapies against brain tumors. According to Lim, there is already an ongoing CTLA-4 antibody plus radiosurgery trial in glioblastoma patients at Johns Hopkins Kimmel Cancer Center.