Previous Radiotherapy Increases the Efficacy of IL-2 in Malignant Pleural Effusion: Potential Evidence of a Radio-Memory Effect?

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 PD1/PDL1 inhibitors. Here we explored whether this effect also occurs with other forms of immune therapy, specifically interleukin-2 (IL-2). We retrospectively assessed outcomes in patients with malignant pleural effusion (MPE) who had previously received radiotherapy for non-small-cell lung cancer (NSCLC) within 18 months before the intrapleural infusion of IL-2 or cisplatin. Radiotherapy sites included lungs, thoracic lymph nodes, and intracranial. All patients received intrapleural infusion of IL-2 or cisplatin, and most had had several cycles of standard chemotherapy for NSCLC. We identified 3,747 patients with MPE (median age 64 years [range 29-88)) treated at one of several institutions from August 2009 through February 2015; 642 patients had been treated with IL-2 and 1102 with cisplatin and had survived for at least 6 months afterward. Among those who received IL-2, 288 had no radiotherapy, 324 had extracranial (i.e., thoracic) radiotherapy, and 36 had intracranial radiotherapy. The median follow-up time for surviving patients was 38 months. Patients who had received extracranial radiotherapy followed by IL-2 had significantly longer PFS than patients who had not received extracranial radiotherapy (i.e., either no radiotherapy or intracranial radiotherapy). Patients who had received intracranial or extracranial radiotherapy followed by IL-2 had significantly longer OS than did other patients. No survival advantage was noted for prior radiotherapy among patients who received intrapleural cisplatin. We speculate that previous radiotherapy could enhance the efficacy of subsequent intrapleural infusion of IL-2, a "radio-memory" effect that could be beneficial in future studies.