Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY).

Slavisa Tubin,Michael Grusch,Eugen Hug,Seema Gupta,Piero Fossati,Barbara Peter-Vörösmarty,Samir N Khleif,Martin L Ashdown,Martin Hyden,Luka Brcic,Simone Negrini,Helmuth H Popper

doi:10.3390/cancers13010050

Abstract

Simple SummaryThis review presents and summarizes the key components and outcomes of a novel, unconventional radiation approach aimed to exploit immune-stimulatory radiation effects which, being added to direct radiation tumor cell killing, may improve the therapeutic ratio of radiotherapy. This technique, as a product of translational oncology research, was intentionally developed for the induction of immune-mediated bystander and abscopal effects in the treatment of unresectable bulky tumors which have much fewer therapeutic options and show poor prognoses after conventional treatments. This review offers insights into a unique unconventional radiotherapy technique which, due to its higher immunogenic potential, may improve the prognosis of patients affected by highly complex malignancies, providing additional opportunities for future research in terms of combining novel immuno-modulating agents with more modern radiotherapy approaches.Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher “immunogenic potential”. This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential.

Highlights

With the remarkable technological developments in the treatment planning and delivery, the modern high-precision, image-guided radiotherapy becomes one of the leading treatment options in cancer management
It has been shown that partial tumor irradiation is able to induce abscopal effects (AE) and bystander effect (BE) and antitumor immune responses
It has been shown that this tumoricidal BE is mediated by tumor necrosis factor (TNF)-α and TNF-related apoptosis-inducing ligand (TRAIL), secreted by the directly irradiated tumor cells [27,28,29,30]

Summary

Introduction

With the remarkable technological developments in the treatment planning and delivery, the modern high-precision, image-guided radiotherapy becomes one of the leading treatment options in cancer management. Based on the tumor volume and radiation dose used, for most of the treated lesions, local control rates of 80% or higher can be reached with an improvement of the overall survival, even for oligometastatic patients [1,2] These clinical outcomes cannot be reproduced by the patients with high-volume tumors even with most advanced radiotherapy techniques, which is especially true for patients with unresectable bulky tumors. In most of these cases, the delivery of an ablative radiation dose to the whole tumor by means of conventional radiotherapy is limited by surrounding tissue tolerance that makes a curative treatment demanding. Radiotherapy of largevolumes, which is the case for bulky tumors, might potentially bring another unfavorable aspect of radiation-induced lymphopenia

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