Feasibility of adding fingolimod to radiation to reduce lymphopenia in rodents and glioma patients

Introduction: 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. Materials and methods: Ten BALB/c mice received focal brain irradiation (4 Gy × 10 fractions). Half of the mice received intraperitoneal fingolimod (3 mg/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 feasibility studies provide reassuring data on the safety of combining fingolimod with radiation in mice and humans. Further prospective clinical trials are needed to determine if this novel approach to reducing the number of circulating lymphocytes exposed to radiation improves post-radiation lymphocyte counts, responses to immunotherapy, and overall cancer survival.