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

Hari Menon, Dawei Chen, Rishab Ramapriyan, Vivek Verma, Hampartsoum B Barsoumian, Taylor R Cushman, Ahmed I Younes, Maria A Cortez, Jeremy J Erasmus, Patricia de Groot, Brett W Carter, David S Hong, Isabella C Glitza, Renata Ferrarotto, Mehmet Altan, Adi Diab, Stephen G Chun, John V Heymach, Chad Tang, Quynh N Nguyen, James W Welsh, Hari Menon, Dawei Chen, Rishab Ramapriyan, Vivek Verma, Hampartsoum B Barsoumian, Taylor R Cushman, Ahmed I Younes, Maria A Cortez, Jeremy J Erasmus, Patricia de Groot, Brett W Carter, David S Hong, Isabella C Glitza, Renata Ferrarotto, Mehmet Altan, Adi Diab, Stephen G Chun, John V Heymach, Chad Tang, Quynh N Nguyen, James W Welsh

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.

Keywords: Abscopal effect; Immunotherapy; Low-dose radiotherapy; Metastatic cancer; Stereotactic ablative radiation therapy.

Conflict of interest statement

ICG, MA, JVH and DSH have received research grants from Bristol-Myers Squibb. JWW, ICG, JVH, and DSH also receive research funding from Merck. MA receives research funding from Novartis and Lilly. DSH and JWW are founders and have ownership interest in OncoResponse and MolecularMatch. All other authors declare no conflicts of interest. JWW reports research support from GlaxoSmithKline, Bristol Meyers Squibb, Merck , Nanobiotix, Mavu Pharma and Checkmate Pharmaceuticals. JWW serves on the scientific advisory board for RefleXion Medical, MolecularMatch, OncoResponse, CheckMate, Mavu Pharmaceuticals, Alpine Immune Sciences. He is co-founder of Healios Oncology, MolecularMatch, and OncoResponse and serves as an advisor to Astra Zeneca, Merck, MolecularMatch, Incyte, Aileron and Nanobiotix. JWW has the following patents; MP470 (amuvatinib), MRX34 regulation of PDL1, XRT technique to overcome immune resistance. MD Anderson Cancer Center has a trademark for RadScopalTM.

Figures

Fig. 1
Fig. 1
Low-dose radiation improves abscopal responses based on RECIST criteria. a, the percentage of lesions showing a clinical response based on RECIST criteria (CR/PR) was 53% (20 of 38) in low-dose lesions compared to 18% (8 of 45) no-dose lesions, ***P < 0.001. b, the median change for the sum of the longest diameter for low-dose lesions was − 38.5% (range − 100 to 68%) compared to 8% (range − 75 to 132%) in no-dose lesions, ****P < 0.0001. c, the percentage of lesions responding according to radiation dose. *P < 0.05. d, of the lesions from 22 patients with both no-dose (n = 45) and low-dose (n = 33) lesions, 12 lesions (36%) had low-dose-only responses at 6 months, and two (4%) had no-dose-only responses. e, Waterfall plot of no-dose tumor responses in patients having both lesion types. f, Waterfall plot of low-dose tumor responses in patients having both lesion types. g, Waterfall plot of low-dose tumors receiving 5–10 Gy in patients having both lesion types. h, Waterfall plot of low-dose tumors with NSCLC histology
Fig. 2
Fig. 2
Representative scans from a patient receiving scatter radiation to a low-dose lesion. Scans from a 20-year-old patient with fibrolamellar hepatocellular carcinoma who was given ipilimumab and sequential radiation to the lung
Fig. 3
Fig. 3
Representative scans from a patient receiving intentional low-dose radiation. Scans from a 69-year-old patient with Merkel cell carcinoma with previous disease progression on atezolizumab and bevacizumab who was given low-dose radiation to an involved inguinal node. An area receiving no radiation in the right adrenal gland developed a metastasis 3 months later, which was subsequently treated and shown to have improved radiographically as well
Fig. 4
Fig. 4
Visual representation of two uses of radiation and how low-dose radiation and high-dose radiation affect the immune cell cycle. High-dose radiation is beneficial in directly killing primary tumor cells (1), which allows antigen release (2) and leads to T-cell priming (3). Immunotherapy decreases T-cell exhaustion and enhances lymphocyte trafficking to secondary tumors (4). Low-dose radiation, by contrast, modulated the tumor stroma and enhances infiltration of natural killer (NK) cells and T cells into secondary tumor sites (5), leading to enhanced immune-cell recognition of tumor cells (6) and resulting in ongoing tumor cell killing (1) and antigen release (2). Abbreviations: DAMPs, danger-associated molecular patterns; MHC1, major histocompatibility complex 1; ICOS, the immune checkpoint ‘inducible co-stimulator’; MDSCs, myeloid-derived suppressor cells; Tregs, T regulatory cells; TGF-β, tumor growth factor-beta; TAMs, tumor-associated macrophages

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