ESTRO 2020 Abstract book
S41 ESTRO 2020
Median survival times were 22.5 days in untreated control, 30 days by aPD1 monotherapy, and 36 days by SRS 10 Gy alone. After SRS and aPD-1 together, the median survival was not reached up to 60 days with 75% of mice being alive with a complete imaging and pathological response at the end of the study duration. IHC and gene expression arrays showed that tumor growth by itself induced a dramatic increase in both the CD8+ T-cells and tumor-infiltrating phagocytic cells, associated with increased serum INF-γ level, and elevated expression of CD86 (a marker of dendritic cells/macrophages). All these early increases were abolished by 10 Gy radiation. However, CD8+ cells and CD86 were increased again in the group treated with combined SRS and aPD1. When the T-cells were blocked, the median survival fell to 35 days. Similarly, when the macrophage influx was blocked by CSF1R, the mouse survival was reduced to 45 days, indicating the role of both T-cells and macrophage in this treatment. Conclusion Combined SRS and aPD1 significantly improved GBM tumor control and survival. Both CD8+ and CD86+ cells play a major role mediating the tumor response. The findings indicate that the local anti-tumor immune response against GBM may be a unique mechanism, distinct from the abscopal (distant) effects. OC-0086 A sarcoma hypoxia signature (nanoString® assay) validates in the phase III VorteX radiotherapy trial L. Forker 1 , B. Bibby 1 , L. Yang 1 , J. Irlam 1 , H. Valentine 1 , P. Shenjere 2 , J. Wylie 3 , M. Leahy 4 , P. Gaunt 5 , L. Billingham 5 , M. Robinson 6 , A. Choudhury 1 , C. West 1 1 University of Manchester, Translational Radiobiology, Manchester, United Kingdom ; 2 The Christie NHS Foundation Trust, Histopathology, Manchester, United Kingdom ; 3 The Christie NHS Foundation Trust, Clinical Oncology, Manchester, United Kingdom ; 4 The Christie NHS Foundation Trust, Medical Oncology, Manchester, United Kingdom ; 5 University of Birmingham, Cancer Research UK Clinical Trials Unit, Birmingham, United Kingdom ; 6 University of Sheffield, Academic Unit of Clinical Oncology, Sheffield, United Kingdom Purpose or Objective Soft tissue sarcomas (STS) are a rare group of tumours encompassing ~50 malignant, heterogeneous subtypes. Localised disease is managed with surgery ± radiotherapy. Neoadjuvant radiotherapy response is varied and despite high metastatic recurrence rates, there is no definite overall survival benefit from the addition of systemic chemotherapy. Each subtype is very rare; therefore, biomarkers of adverse biological features present across subtypes might be more successful in selecting high-risk patients for clinical trials. Tumour hypoxia is associated with poor radiotherapy response and metastasis. We previously derived a 24-gene STS hypoxia signature that was prognostic in two independent cohorts. The study aims were (1) signature validation in a new whole transcriptome cohort (2) assay development for pre- treatment biopsies (3) assay validation. Material and Methods Three cohorts were used (1) VorteX n=203 (2) single centre retrospective n=165 (3) MCRC Biobank n=28. VorteX was a randomised phase III trial comparing radiotherapy volumes in adults with localised extremity STS. Validation cohorts included mainly high-risk patients (85% high-grade). Whole transcriptome RNA-sequencing data (Illumina HiSeq4000) were generated from fresh frozen tumour samples for VorteX. Two targeted assays (Taqman® array cards and nanoString®) were compared in formalin-fixed, Proffered Papers: Proffered papers 3: Sarcoma
(p<0.001), resulting in 38% long-term tumour remission, Figure 2. Based on preliminary results of the ImmunoSABR phase 1 trial (NCT02086721), 15 Mio IU L19-IL2 are safe after SABR. Treatment response was seen in 50% of patients with PFS and OS of >2 years. A phase 2 trial (NCT03705403) has been approved by the medical ethical board and is currently recruiting patients.
Conclusion Our results suggest that radiotherapy would better synergize with immunocytokines than checkpoint inhibitors, and that triple combination with aPDL1 is able to make a tumour immune-permissive. Combining the knowledge gained from the successful phase 1 trial and pre-clinical evidence we expect prolonged PFS and OS in the multicentric ImmunoSABR phase 2 trial. OC-0085 Fractionated Radiosurgery plus Check Point Blockade is a Novel Paradigm for Treating Glioblastoma S. Ryu 1 , A. Stessin 1 , M. Clausi 1 , T. Duong 2 , S. Thirks 3 1 Stony Brook University, Department of Radiation Oncology, Stony Brook, USA ; 2 Stony Brook University, Department of Radiology, Stony Brook, USA ; 3 Stony Brook University, Department of Pharmacology, Stony Brook, USA Purpose or Objective We have shown that fractionated radiosurgery (fSRS) with simultaneous differential dosing of 32 Gy (to enhancing tumor) and 24 Gy (to flair abnormality) in 4 fractions improved the local control of recurrent glioblastoma (GBM). Although immunotherapy improved outcome in many tumor types, CHECKMATE 143 showed no benefit of adding checkpoint inhibitors to the standard GBM treatment. We carried out experiments to develop a new strategy of in-situ vaccination effect to control the GBM tumor by fSRS combined with immune checkpoint inhibitor. Material and Methods Orthotopic GL261 glioma cells implanted to the forebrain in immunocompetent B57 mice. The tumor diameter becomes 2-3 mm on day 10 post-implantation. Total of 46 tumor-bearing mice were randomized to treatment groups of 1) untreated tumor control, 2) RS 10 Gy on day 10 post- implantation, 3) anti-PD-1 (aPD1) mouse nivolumab 10 mg/kg i.p. on days 10, 12, and 14 post-implantation, and 4) combination of SRS and aPD1. Survival time was measured. At time points of 11, 15, 30 days, and death, the whole brain samples were prepared for multiplex IHC, flow cytometry, and western blot and gene expression assay by RNA extraction to examine the dynamics in immune effector cells and the signatures. The mice were imaged with 9.4 Tesla MRI scan to measure the tumor size and to identify the predictive imaging biomarkers. Results
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