The Feasibility of Combining Brain Radiation and Fingolimod in Healthy Rodents and in Humans With Newly Diagnosed Glioblastoma

Abstract PURPOSE: Severe and long-lasting lymphopenia occurs in 40% of patients with malignant gliomas and is associated with inferior survival. Inadvertent irradiation of circulating lymphocytes is a major contributor to this lymphopenia. Fingolimod causes striking but reversible lymphopenia by sequestering circulating lymphocytes in lymphoid tissues. Fingolimod could potentially reduce iatrogenic immunosuppression by decreasing the number of lymphocytes in circulation during radiation. However, combining radiation with fingolimod should result in severe lymphopenia. These pilot studies were conducted to determine the safety of this approach in mice and humans. METHODS: Ten BALB/c mice received focal brain irradiation (4Gy x 10 fractions). Half of the mice received intraperitoneal fingolimod (3mg/kg) before and during the two weeks of radiation. Five patients with newly diagnosed glioblastoma were given fingolimod one week prior to and during the six weeks of concurrent radiation and temozolomide. RESULTS: Mice treated with fingolimod and radiation had more severe lymphopenia than those treated with radiation alone. However, lymphocyte counts and weight loss recovered similarly in both treatment cohorts and no added toxicities were noted. Humans receiving fingolimod developed severe lymphopenia which deepened when radiation and temozolomide were initiated. This was well tolerated and no grade III-IV opportunistic infections were noted. CONCLUSIONS: These pilot studies demonstrate the feasibility and safety of combining fingolimod with radiation in mice and humans. This novel approach to reducing the number of circulating lymphocytes exposed to radiation deserves further study given the importance of the host immune system on cancer survival and response to immunologic interventions.