In Situ Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model

Abstract

How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated nonablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade. We therefore assessed the impact of nonablative 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 effect, and radical surgery (R0 resection) was used to analyze the long-term effect of this radiation protocol before surgery. Nonablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8 T cells, limiting the negative effect 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 with a short course of nonablative 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. A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Nonablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting. .

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

“…The outcomes after induction chemotherapy followed by EPP and adjuvant hemithoracic radiation have been disappointing, with median survivals ranging between 16 and 20 months in trials that included more than 40 patients . However, patients who completed adjuvant hemithoracic radiation had a median survival of 29 to 39 months and achieved excellent local control . These results and studies in animal models and in vitro experiments suggest that, in contrast to current belief, mesotheliomas are sensitive to radiation .…”

“…Research in mice demonstrated that nonablative, hypofractionated radiation induces a specific activation of the immune system against mesothelioma with the development of an in situ vaccination, which is maintained through memory T cells directed against the tumor . Evidence from these mouse experiments and from palliative radiation in patients with mesothelioma suggest that a dose of radiation lower than 25 Gy in 5 fractions to the whole hemithorax may still be effective and limit the risks of pneumonitis in the underlying lung .…”

“…However, the optimal combination therapy remains debated. The outcomes after induction chemotherapy followed by EPP and adjuvant hemithoracic radiation have been disappointing, with median survivals ranging between 16 and 20 months in trials that included more than 40 patients . However, patients who completed adjuvant hemithoracic radiation had a median survival of 29 to 39 months and achieved excellent local control .…”

“…However, patients who completed adjuvant hemithoracic radiation had a median survival of 29 to 39 months and achieved excellent local control . These results and studies in animal models and in vitro experiments suggest that, in contrast to current belief, mesotheliomas are sensitive to radiation . Cho et al developed a protocol that starts with hemithoracic radiation to deliver an optimal dose of radiation to the tumor before surgical resection …”

Radio-immunotherapy and chemo-immunotherapy as a novel treatment paradigm in malignant pleural mesothelioma

“…We then assessed the impact of local radiation on the immune system in combination with radical surgery in our mouse mesothelioma model to reproduce the SMART protocol (28). Blunt surgery and radical surgery were performed to analyze the short and long term impact of radiation and surgery.…”