Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy (PULSAR) in preclinical models enhances single agent immune checkpoint blockade.

Abstract

PURPOSE\nHarnessing the immune-stimulatory effects of radiation by combining it with immunotherapy is a promising new treatment strategy. However, more study characterizing immunotherapy and radiation dose scheduling for the optimal therapeutic effect is essential for designing clinical trials.\n\n\nMETHODS AND MATERIALS\nThe new ablative radiation dosing scheme personalized ultra-fractionated stereotactic adaptive radiotherapy (PULSAR) was tested in combination with α-PD-L1 therapy in immune activated and resistant syngeneic immunocompetent mouse models of cancer. Specifically, tumor growth curves comparing immunotherapy and radiotherapy dose sequencing were evaluated in immunologically cold and hot tumor models. The response relative to cytotoxic killer T cells was evaluated using an α-CD8 depleting antibody, and immunological memory was tested by tumor re-challenge of cured mice.\n\n\nRESULTS\nWe report that both radiation and immunotherapy sequencing as well as radiotherapy fraction spacing affects the combination treatment response. Better tumor control was achieved by giving α-PD-L1 therapy during or after radiation, and spacing fractions 10 days apart (PULSAR) achieved better tumor control than traditional daily fractions. We showed that CD8+ depleting antibody abrogated tumor control in the PULSAR combination treatment and certain treatment schedules induced immunological memory.\n\n\nCONCLUSIONS\nThese results illustrate that radiation therapy dosing and scheduling impacts tumor control in combination with checkpoint blockade therapies. PULSAR styled radiation dosing is more complimentary in combination with single agent immunotherapy than traditional daily fractions in this preclinical model. Pre-clinical investigation could prove helpful in designing clinical trials investigating combination therapy.