Approximately one-half of patients with newly diagnosed cancer and many patients with persistent or recurrent tumors receive radiotherapy (RT), with the explicit goal of eliminating tumors through direct killing. The current RT dose and schedule regimens have been empirically developed. Although early clinical studies revealed that RT could provoke important responses not only at the site of treatment but also on remote, nonirradiated tumor deposits-the so-called "abscopal effect"- the underlying mechanisms were poorly understood and were not therapeutically exploited. Recent work has elucidated the immune mechanisms underlying these effects and has paved the way for developing combinations of RT with immune therapy. In the wake of recent therapeutic breakthroughs in the field of immunotherapy, rational combinations of immunotherapy with RT could profoundly change the standard of care for many tumor types in the next decade. Thus, a deep understanding of the immunologic effects of RT is urgently needed to design the next generation of therapeutic combinations. Here, the authors review the immune mechanisms of tumor radiation and summarize the preclinical and clinical evidence on immunotherapy-RT combinations. Furthermore, a framework is provided for the practicing clinician and the clinician investigator to guide the development of novel combinations to more rapidly advance this important field. CA Cancer J Clin 2017;67:65-85. © 2016 American Cancer Society.

Background: Preclinical data have shown that proton pump inhibitors (PPI) can modulate the microbiome, and singlearm studies suggested that antibiotics (ATB) may decrease the efficacy of immune checkpoint inhibitors (ICI), but randomized controlled trial data are lacking. This pooled analysis evaluated the effect of ATB and PPI on outcome in patients randomized between ICI and chemotherapy. Patients and methods: This retrospective analysis used pooled data from the phase II POPLAR (NCT01903993) and phase III OAK (NCT02008227) trials, which included 1512 patients with previously treated non-small-cell lung cancer (NSCLC) randomly assigned to receive atezolizumab (n ¼ 757) or docetaxel (n ¼ 755). The main objective of this analysis was to assess the impact of ATB and PPI use on overall survival (OS) and progression-free survival (PFS). Results: A total of 169 (22.3%) patients in the atezolizumab group and 202 (26.8%) in the docetaxel group received ATB, and 234 (30.9%) and 260 (34.4%), respectively, received PPI. Multivariate analysis in all patients revealed that ATB were associated with shorter OS [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.04e1.39], as was PPI (HR 1.26, 95% CI 1.10e1.44). Within the atezolizumab population, OS was significantly shorter in patients who received ATB (8.5 versus 14.1 months, HR 1.32, 95% CI 1.06e1.63, P ¼ 0.01) or PPI (9.6 versus 14.5 months, HR 1.45, 95% CI 1.20e1.75, P ¼ 0.0001). PPI use was associated with shorter PFS in the atezolizumab population (1.9 versus 2.8 months, HR 1.30, 95% CI 1.10À1.53, P ¼ 0.001). There was no association between ATB and PPI use and PFS or OS within the docetaxel population. Conclusion:In this unplanned analysis from two randomized trials, data suggest that ATB or PPI use in patients with metastatic NSCLC is associated with poor outcome and may influence the efficacy of ICI.

GC has received grants, research support or is coinvestigator in clinical trials by Bristol-Myers-Squibb, Celgene, Boehringer Ingelheim, Roche, Tigen Pharma, Iovance and Kite. GC has received honoraria for consultations or presentations by Roche, Genentech, BMS, AstraZeneca, Sanofi-Aventis, Nextcure and GeneosTx. GC has patents in the domain of antibodies and vaccines targeting the tumor vasculature as well as technologies related to T-cell expansion and engineering for T-cell therapy. GC receives royalties from the University of Pennsylvania. FH reports grants from Prostate Cancer Foundation, Bristol-Myers-Squibb, Accuray Inc, Bioprotect, and non-financial support from Roche ImFlame cooperative group, European Organization for Research and Treatment of Cancer (EORTC) chairman Gynecology Cancer Group. FH has received honoraria for consultations from

Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk cT1b-c to cT2a (with no involvement of pelvic lymph nodes and no clinical evidence of metastatic spread) prostatic carcinoma, treated by radiation.