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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.

SUBMITTER: Menon H

PROVIDER: S-EPMC6727581 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Menon Hari H Chen Dawei D Ramapriyan Rishab R Verma Vivek V Barsoumian Hampartsoum B HB Cushman Taylor R TR Younes Ahmed I AI Cortez Maria A MA Erasmus Jeremy J JJ de Groot Patricia P Carter Brett W BW Hong David S DS Glitza Isabella C IC Ferrarotto Renata R Altan Mehmet M Diab Adi A Chun Stephen G SG Heymach John V JV Tang Chad C Nguyen Quynh N QN Welsh James W JW

Journal for immunotherapy of cancer 20190904 1

<h4>Background</h4>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.<h4>Methods</h4>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 a ...[more]

PMID: 31484556

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Project description:Caspase 3 (CASP3) has a key role in the execution of apoptosis, and many cancer cells are believed to disable CASP3 as a mechanism of resistance to cytotoxic therapeutics. Alongside, CASP3 regulates stress-responsive immunomodulatory pathways, including secretion of type I interferon (IFN). Here, we report that mouse mammary carcinoma TSA cells lacking Casp3 or subjected to chemical caspase inhibition were as sensitive to the cytostatic and cytotoxic effects of radiation therapy (RT) in vitro as their control counterparts, yet secreted increased levels of type I IFN. This effect originated from the accrued accumulation of irradiated cells with cytosolic DNA, likely reflecting the delayed breakdown of cells experiencing mitochondrial permeabilization in the absence of CASP3. Casp3-/- TSA cells growing in immunocompetent syngeneic mice were more sensitive to RT than their CASP3-proficient counterparts, and superior at generating bona fide abscopal responses in the presence of an immune checkpoint blocker. Finally, multiple genetic signatures of apoptotic proficiency were unexpectedly found to have robust negative (rather than positive) prognostic significance in a public cohort of breast cancer patients. However, these latter findings were not consistent with genetic signatures of defective type I IFN signaling, which were rather associated with improved prognosis. Differential gene expression analysis on patient subgroups with divergent prognosis (as stratified by independent signatures of apoptotic proficiency) identified SLC7A2 as a new biomarker with independent prognostic value in breast cancer patients. With the caveats associated with the retrospective investigation of heterogeneous, public databases, our data suggest that apoptotic caspases may influence the survival of breast cancer patients (or at least some subsets thereof) via mechanisms not necessarily related to type I IFN signaling as they identify a novel independent prognostic biomarker that awaits prospective validation.

Dataset Information

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

Publications

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

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