Five-year survival rates for non–small cell lung cancer (NSCLC) range from 14% to 49% for stage I to stage IIIA disease, and are <5% for stage IIIB/IV disease. Improvements have been made in the outcomes of patients with NSCLC due to advancements in radiotherapy (RT) techniques, the use of concurrent chemotherapy with RT, and the emergence of immunotherapy as first- and second-line treatment in the metastatic setting. RT remains the mainstay treatment in patients with inoperable early-stage NSCLC and is given concurrently or sequentially with chemotherapy in patients with locally advanced unresectable disease. There is emerging evidence that RT not only provides local tumor control but also may influence systemic control. Multiple preclinical studies have demonstrated that RT induces immunomodulatory effects in the local tumor microenvironment, supporting a synergistic combination approach with immunotherapy to improve systemic control. Immunotherapy options that could be combined with RT include programmed cell death-1/programmed cell death ligand-1 blockers, as well as investigational agents such as OX-40 agonists, toll-like receptor agonists, indoleamine 2,3-dioxygenase-1 inhibitors, and cytokines. Here, we describe the rationale for the integration of RT and immunotherapy in patients with NSCLC, present safety and efficacy data that support this combination strategy, review planned and ongoing studies, and highlight unanswered questions and future research needs.

Purpose: The clinical effects of sunitinib on human myeloid-derived suppressor cell (MDSC) subsets and correlation of the T-cell–mediated immune responses and clinical outcomes in patients with oligometastases treated by stereotactic body radiotherapy (SBRT) have been evaluated. Experimental Design: The numbers of granulocytic and monocytic MDSC subsets, effector T cells, and regulatory T cells in the peripheral blood were evaluated pre- and post-sunitinib treatment and concurrent with SBRT. Correlations between MDSC, Treg, and T-cell responses and clinical outcomes were analyzed. Results: Patients with oligometastases of various cancer types had elevated granulocytic MDSC and certain subsets of monocytic MDSC population. Sunitinib treatment resulted in a significant reduction in monocytic MDSC, phosphorylated STAT3, and arginase levels in monocytic MDSC (CD33⁺CD14⁺CD16⁺), and an increase in T-cell proliferative activity in cancer patients. Interestingly, the effects of sunitinib on reducing the accumulation and immune-suppressive function of MDSC were significantly correlated with Treg reduction, in responders but not in nonresponding patients. SBRT synergized the therapeutic effects of sunitinib, especially as related to decreased numbers of monocytic MDSC, Treg, and B cells, and augmented Tbet expression in primary CD4 and CD8 T cells. These effects were not observed in patients receiving radiation therapy alone. Most interestingly, the responders, defined by sunitinib-mediated reduction in CD33⁺CD11b⁺ myeloid cell populations, tend to exhibit improved progression-free survival and cause-specific survival. Conclusions: Sunitinib treatment increased the efficacy of SBRT in patients with oligometastases by reversing MDSC and Treg-mediated immune suppression and may enhance cancer immune therapy to prevent tumor recurrence post-SBRT. Clin Cancer Res; 21(18); 4073–85. ©2015 AACR.

Immune checkpoint blockade has recently emerged as an important therapeutic approach to the management of malignancies across multiple disease settings. Concomitantly, there has been an increasing appreciation for the role of radiotherapy in eliciting and promoting tumor-directed immune responses. In this review, we discuss the clinical evidence to date on combinations of radiotherapy with immune checkpoint inhibitors, both from the standpoint of safety and efficacy. We highlight important but yet-unanswered questions for this combination approach, as well as their implications for future prospective studies.

Purpose: The aim of this review is to highlight key evidence supporting the effect of radiation therapy on tumor immunity. Conclusions: Recent findings in both the preclinical and clinical settings have provided convincing evidence of the ability of radiation therapy to influence tumor-directed immune responses, and have offered critical insights into the underlying mechanisms. Not only does radiation therapy convert the tumor microenvironment to promote robust tumor immunity, but it also enhances the generation of neoantigens and neoepitopes. Radiation therapy also shapes the TCR repertoire of CD8⁺ T cells in conjunction with immune checkpoint blockade. In conclusion, a high priority should be placed on developing rational strategies to integrate radiation therapy with immunotherapy in the clinical setting, with an emphasis on careful patient selection and identifying important correlative endpoints.

Background: HIV-infected individuals have a higher incidence of head and neck cancer (HNC). Methods: Case series of 94 HIV-infected HNC patients (HIV-HNC) at 6 tertiary care referral centers in the US between 1991 and 2011. Clinical and risk factor data were abstracted from the medical record. Risk factors for survival were analyzed using Cox proportional hazard models. Human papillomavirus (HPV) and p16 testing was performed in 46 tumors. Findings were compared with Surveillance Epidemiology and End Results HNC (US-HNC) data. Results: This study represents the largest HIV-HNC series reported to date. HIV-HNC cases were more likely than US-HNC to be male (91% vs. 68%), younger (median age, 50 vs. 62 years), nonwhite (49% vs. 18%), and current smokers (61% vs. 18%). Median HIV-HNC survival was not appreciably lower than US-HNC survival (63 vs. 61 months). At diagnosis, most cases were currently on highly active antiretroviral therapy (77%) but had detectable HIV viremia (99%), and median CD4 was 300 cells per microliter (interquartile range = 167–500). HPV was detected in 30% of HIV-HNC and 64% of HIV-oropharyngeal cases. Median survival was significantly lower among those with CD4 counts ≤200 than >200 cells per microliter at diagnosis (16.1 vs. 72.8 months, P < 0.001). In multivariate analysis, poorer survival was associated with CD4 <100 cells per microliter [adjusted hazard ratio (aHR) = 3.09, 95% confidence interval (CI): 1.15 to 8.30], larynx/hypopharynx site (aHR = 3.54, 95% CI: 1.34 to 9.35), and current tobacco use (aHR = 2.54, 95% CI: 0.96 to 6.76). Conclusions: Risk factors for the development of HNC in patients with HIV infection are similar to the general population, including both HPV-related and tobacco/alcohol-related HNC.