Effect Of Low-Dose Radiotherapy On Abscopal Responses To Hypofractionated Radiotherapy And Anti-PD1 In Mice and NSCLC Patients

Hypofractionated radiotherapy (HFRT) can induce antitumor T cell responses, particularly in combination with immune checkpoint inhibitors (ICI), but abscopal effects are often precluded by insufficient T cell infiltration of distant non-irradiated tumors. Additional non-cytotoxic low-dose radiotherapy (LDRT) of distant tumors may enhance the abscopal response, but clinical evidence and preclinical studies for this scenario are lacking. We investigated whether the triple treatment consisting of HFRT, ICI, and LDRT could achieve better systemic antitumor response in bilateral mouse tumor models and in patients with stage IV non-small cell lung cancer (NSCLC). Our analyses of bilateral mouse tumor models show that HFRT treatment of the primary tumor combined with LDRT treatment of the abscopal tumor and anti-PD1 therapy enhances the abscopal response compared to HFRT/anti-PD1, HFRT/LDRT, or LDRT/anti-PD1 double treatments; complete cures were observed in more than half of the mice treated with triple therapy. The enhanced abscopal effect was associated with an increased infiltration of CD8+ effector T cells and an upregulated expression of T cell-attracting chemokines. Of nine patients with metastatic NSCLC who were treated with this triple therapy, three and two patients showed partial responses and stable disease, respectively. Among nine relatively large (175.7 ± 42.3 cm3) LDRT lesions, six lesions decreased by 28% in size, on average. Our study demonstrates preclinically that LDRT of established metastases significantly enhances the abscopal response to HFRT plus ICI, and provides insights into the mechanisms underlying the enhanced abscopal effect. It also shows that additional LDRT was excellently tolerated by patients with advanced NSCLC and suggests abscopal responses even of large tumors not suitable for high-dose RT.