Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy

Stereotactic body radiotherapy (SBRT) is known to induce important immunologic changes within the tumor microenvironment (TME). However, little is known regarding the early immune responses within the TME in the first few weeks following SBRT. Therefore, we used the canine spontaneous tumor model to investigate TME responses to SBRT, and how local injection of immune modulatory antibodies to OX40 and TLR 3/9 agonists might modify those responses. Pet dogs with spontaneous cancers (melanoma, carcinoma, sarcoma, n = 6 per group) were randomized to treatment with either SBRT or SBRT combined with local immunotherapy. Serial tumor biopsies and serum samples were analyzed for immunologic responses. SBRT alone resulted at two weeks after treatment in increased tumor densities of CD3+ T cells, FoxP3+ Tregs, and CD204+ macrophages, and increased expression of genes associated with immunosuppression. The addition of OX40/TLR3/9 immunotherapy to SBRT resulted in local depletion of Tregs and tumor macrophages and reduced Treg-associated gene expression (FoxP3), suppressed macrophage-associated gene expression (IL-8), and suppressed exhausted T cell-associated gene expression (CTLA4). Increased concentrations of IL-7, IL-15, and IL-18 were observed in serum of animals treated with SBRT and immunotherapy, compared to animals treated with SBRT. A paradoxical decrease in the density of effector CD3+ T cells was observed in tumor tissues that received combined SBRT and immunotherapy as compared to animals treated with SBRT only. In summary, these results obtained in a spontaneous large animal cancer model indicate that addition of OX40/TLR immunotherapy to SBRT modifies important immunological effects both locally and systemically.

Prospective Randomized Phase II Study of Stereotactic Body Radiotherapy (SBRT) vs. Conventional Fractionated Radiotherapy (CFRT) for Chinese Patients with Early-Stage Localized Prostate Cancer

Background: Stereotactic body radiotherapy (SBRT) has potential radiobiologic and economic advantages over conventional fractionated radiotherapy (CFRT) in localized prostate cancer (PC). This study aimed to compare the effects of these two distinct fractionations on patient-reported quality of life (PRQOL) and tolerability. Methods: In this prospective phase II study, patients with low- and intermediate-risk localized PC patients were randomly assigned in a 1:1 ratio to the SBRT (36.25 Gy/5 fractions/2 weeks) or CFRT (76 Gy/38 fractions/7.5 weeks) treatment groups. The primary endpoint of variation in PRQOL at 1 year was assessed by changes in the Expanded Prostate Cancer Index Composite (EPIC) questionnaire scores and analysed by z-tests and t-tests. Results: Sixty-four eligible Chinese men were treated (SBRT, n = 31; CFRT, n = 33) with a median follow-up of 2.3 years. At 1 year, 40.0%/46.9% of SBRT/CFRT patients had a >5-point decrease in bowel score (p = 0.08/0.28), respectively, and 53.3%/46.9% had a >2-point decrease in urinary score (p = 0.21/0.07). There were no significant differences in EPIC score changes between the arms at 3, 6, 9 and 12 months, but SBRT was associated with significantly fewer grade ≥ 1 acute and 1-year late gastrointestinal toxicities (acute: 35% vs. 87%, p < 0.0001; 1-year late: 64% vs. 84%, p = 0.03), and grade ≥ 2 acute genitourinary toxicities (3% vs. 24%, p = 0.04) compared with CFRT. Conclusion: SBRT offered similar PRQOL and less toxicity compared with CFRT in Chinese men with localized PC.