Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy

Abstract

Background Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor’s response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting. Methods A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1–20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (< 1 Gy total). Response rates, both defined as complete and partial responses as defined by RECIST criteria were used to compare lesion types. Results The 26 patients had a total of 83 lesions for comparison (38 receiving low-dose, 45 receiving no-dose). The average dose given to low-dose lesions was 7.3 Gy (1.1–19.4 Gy), and the average time to response was 56 days. Twenty-two out of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions ( P = 0.0001). The median change for longest diameter size for low-dose lesions was − 38.5% compared to 8% in no-dose lesions ( P < 0.0001). Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control (33 and 45 lesions respectively), 12 low-dose lesions (36%) responded without a corresponding response in their no-dose lesions; Conversely, two (4%) of the no-dose lesions responded without a corresponding response in their low-dose lesion ( P = 0.0004). Conclusions Low-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy. Electronic supplementary material The online version of this article (10.1186/s40425-019-0718-6) contains supplementary material, which is available to authorized users.

Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma

“…The post hoc analysis of our recently completed phase II trial of ipilimumab (anti-CTLA-4), in which stereotactic radiation therapy was given to lung or liver metastases, showed that tumors near the targets that received low-dose scatter radiation had significantly higher response rates (31%) compared with distant tumors that did not receive radiation (5%). 38 While both prior retrospective studies 16 38 and the present study provide exciting evidence for the therapeutic potential of L-XRT, a prospective randomized trial is warranted to confirm the role of L-XRT. In some of the patient cases we report here, there was regrowth of the tumors, suggesting delayed immune evasion.…”

“…To date, we have treated more than 25 patients on various trial arms with H-XRT, L-XRT, and immunotherapy to promote secondary tumor response. 16 Two representative cases from our recent prospective trial (NCT02710253) are demonstrated here ( figure 5A and online supplemental figure S9 ), followed by the tumor growth curves of nine patient cases that received RadScopal treatment from the same trial ( figure 5B and table 1). Patient 1 in figure 5A was a 54-year-old man with metastatic human papillomavirus-positive oropharyngeal squamous cell carcinoma who initially reported partial response to anti-PD1 therapy.…”

“…Lesions that received L-XRT showed an enhanced response rate of 36% while control lesions that received no L-XRT had only 4% response rate. 16 To understand the underlying mechanisms, we first established a lung adenocarcinoma one-tumor model transplanted in 129Sv/Ev mice and evaluated the optimal L-XRT dose per fraction that may correspond to this murine model. We found that giving two 1 Gy fractions on subsequent days was optimal for controlling tumor growth, while higher or lower doses of radiation did not prove efficacious, as higher doses especially could be deleterious to the immune cells.…”

“…In our recently published post hoc analysis of successful L-XRT-mediated abscopal responses, the dose-per-fraction intentionally prescribed ranged between 1 Gy and 2 Gy. 16 Therefore, a similar L-XRT dose and fractionation schedule was used in this study at the discretion of the treating radiation oncologist. While our collective clinical cases suggest a potential dosage strategy, evidence from further prospective trials is warranted before establishing the most optimal dosage and fractionation to elicit L-XRT-mediated abscopal responses.…”

Therapy-Induced Modulation of the Tumor Microenvironment: New Opportunities for Cancer Therapies

“…Yet the biological context remains to be proven that would favor multiple rounds of high-end ablative dose schedules in oligometastatic patient as advocated by some groups (49). Another concept of potential clinical relevance that has been put forward is the possibility that the immunomulatory effect of low-dose radiation for stromal modulation could favor T cell infiltration and enhance the immune response (47,50).…”