Interleukin-2 boosts local and abscopal antitumor effect of radiotherapy combined with anti-PD-1: A translational research from clinical radio-memory effect.

e14244 Background: Preclinical and clinical studies have shown that prior receipt of radiotherapy enhances antitumor immune responses, a phenomenon we call the “radio-memory effect.” However, all of the evidence regarding this effect to date comes from work with anti-PD-1 or anti-PD-L1 inhibitors. Here we explore whether this effect also occurs with other forms of immune therapy, specifically interleukin-2 (IL-2). If so, whether this triple combination therapy could produce synergetic anti-tumor effect. Methods: 1. Clinical work: we retrospectively assessed outcomes in patients with malignant peritoneal effusion (MPE) who had previously received radiotherapy for colon or rectum cancer within 18 months before the intrapleural infusion of IL-2 or cisplatin. All patients received intrapleural infusion of IL-2 or cisplatin, and most had had several cycles of standard chemotherapy for colon or rectum cancer. 2. Translational work: MC38 cell line (5×10 6 ) was subcutaneously inoculated into the right lower extremity of C57/BL mice to construct a primary tumor model. Six days later, MC38 cell line (1×10 6 ) was subcutaneously inoculated into the left lower limb to construct a second tumor model. The main research is as follows: To explore the optimal radiation dose and fraction for radiotherapy; Whether the addition of IL-2 will further enhance the efficacy of radiotherapy combined with anti-PD-1; To explore the optimal combination model of radiation, anti-PD-1 and IL-2; Whether the addition of IL-2 will increase the abscopal effect produced by radiotherapy and anti-PD-1. Results: 1. We identified 3,747 patients with MPE (median age 66 years [range 24–81)) treated at one of several institutions from August 2009 through May 2016; 412 patients had been treated with IL-2 and 592 with cisplatin and had survived for at least 3 months afterward. 2. Hypofractionated radiotherapy (12Gy × 2) combined with IL-2 is better; IL-2 will enhance the efficacy of radiotherapy combined with anti-PD-1; IL-2 and anti-PD-1 followed by radiotherapy might maximize the anti-tumor effect; IL-2 might increase the abscopal effect produced by radiotherapy combined with anti-PD-1. Conclusions: We speculate that previous radiotherapy could enhance the efficacy of IL-2 and the anti-tumor effect produced by radiotherapy combined with anti-PD-1 could be enhanced by IL-2. The “radio-memory” effect could be beneficial in future studies.