Abscopal effects with hypofractionated schedules extending into the effector phase of the tumor-specific T cell response

Publication date: Available online 3 February 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Xuanwei Zhang, Gabriele Niedermann
PurposeHypofractionated radiotherapy (hRT) combined with immune checkpoint blockade (ICB) can induce T cell-mediated local and abscopal antitumor effects. We previously observed peak levels of tumor-infiltrating lymphocytes (TILs) between day 5 and day 8 after hRT; since TILs are regarded as radiosensitive, hRT schedules extending into this period might be less immunogenic, prompting us to compare clinically relevant, short and extended schedules with equivalent biologically effective doses in combination with anti-PD1 antibody treatment.Materials and MethodsIn mice bearing two B16-CD133 melanoma tumors, the primary was irradiated with 3 × 9.18 Gy in 3 or 5 days, or with 5 × 6.43 Gy in 10 days; anti-PD1 antibody was given weekly. Mice were followed for tumor growth and survival. T cell responses were determined on days 8 and 15 of treatment. The role of regional lymph nodes was studied by administering FTY720, which blocks lymph node egress of activated T cells. Tumor growth measurements following combination treatment based on short or extended hRT and control treatments were also performed in the wild-type B16 melanoma and 4T1 breast carcinoma models.ResultsIn the B16-CD133 model, growth inhibition of irradiated primary and non-irradiated secondary tumors and overall survival were similar with all three hRT/anti-PD1 combinations, superior to hRT or anti-PD1 monotherapy, and depended strongly on CD8+ T cells. TIL infiltration and local and systemic tumor-specific CD8+ T cell responses were also similar, regardless of whether short or extended hRT was used. Administration of FTY720 accelerated growth of both primary and secondary tumors, strongly reduced their TIL infiltration and increased tumor-specific CD8+ T cells in the lymph nodes draining the irradiated tumor. In the 4T1 model, local and abscopal tumor control were also similar regardless of whether short or extended hRT was used, although the synergy between hRT and anti-PD1 was weaker. No synergies were found in the B16 wild-type model lacking an exogenous antigen.ConclusionsOur data suggest that combination therapy with hRT schedules extending into the period during which treatment-induced T cells infiltrate the irradiated tumor can provoke similar local and systemic antitumor effects as therapy based on shorter schedules, if regional lymph nodes supply sufficient tumor-specific T cells. This has implications for planning clinical RT/ICB trials.



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