In situ vaccination after accelerated hypofractionated radiation and surgery in a mesothelioma mouse model

Purpose: How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated non-ablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade.<br /><br />Experimental Design: We therefore assessed the impact of non-ablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short term impact and radical surgery (R0 resection) was used to analyze the long-term impact of this radiation protocol before surgery. <br /><br />Results: Non-ablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8+ T cells limiting the negative impact of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long term antitumor immune protection that was primarily driven by CD4+ T cells. Radical surgery alone or radical surgery with a short course of non-ablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade.     <br /><br />Conclusions: A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Non-ablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting.

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