Increasing radiation dose improves immunotherapy outcome and prolongation of tumor dormancy in a subgroup of mice treated for advanced intracerebral melanoma.

Previously, we developed a clinically relevant therapy model for advanced intracerebral B16 melanomas in syngeneic mice combining radiation and immunotherapies. Here, 7 days after B16-F10-luc2 melanoma cells were implanted intracerebrally (D7), syngeneic mice with bioluminescent tumors that had formed (1E10(5) to 7E10(6) photons per minute (>1E10(6), large; <1E10(6), small) were segregated into large-/small-balanced subgroups. Then, mice received either radiation therapy alone (RT) or radiation therapy plus immunotherapy (RT plus IT) (single injection of mAbPC61 to deplete regulatory T cells followed by multiple injections of irradiated granulocyte macrophage colony stimulating factor transfected B16-F10 cells) (RT plus IT). Radiation dose was varied (15, 18.75 or 22.5 Gy, given on D8), while immunotherapy was provided similarly to all mice. The data support the hypothesis that increasing radiation dose improves the outcome of immunotherapy in a subgroup of mice. The tumors that were greatly delayed in beginning their progressive growth were bioluminescent in vivo-some for many months, indicating prolonged tumor "dormancy," in some cases presaging long-term cures. Mice bearing such tumors had far more likely received radiation plus immunotherapy, rather than RT alone. Radiotherapy is a very important adjunct to immunotherapy; the greater the tumor debulking by RT, the greater should be the benefit to tumor immunotherapy.