Bystander Effects in Spatially Fractionated Radiation Therapy: From Molecule To Organism To Clinical Implications.

The standard of care for radiation therapy is numerous, low-dose fractions that are distributed homogeneously throughout the tumor. An alternative strategy under scrutiny is to apply spatially fractionated radiotherapy (high and low doses throughout the tumor) in one or several fractions, either alone or followed by conventional radiation fractionation . Spatial fractionation allows for significant sparing of normal tissue, and the regions of tumor or normal tissue that received sublethal doses can give rise to beneficial bystander effects in both cases. Bystander effects are broadly defined as biological responses that are significantly greater than would be anticipated based on the radiation dose received. Typically these effects are initiated by diffusion of reactive oxygen species and secretion of various cytokines. As demonstrated in the literature, spatial fractionation related bystander effects can occur locally from cell to cell and in what are known as "cohort effects," which tend to take the form of restructuring of the vasculature, enhanced immune infiltration, and development of immunological memory. Other bystander effects can take place at distant sites in what are known as "abscopal effects." While these events are rare, they are mediated by the immune system and can result in the eradication of secondary and metastatic disease. Currently, due to the complexity and variability of these bystander effects, they are not thoroughly understood, but as knowledge improves they may present significant opportunities for improved clinical outcomes.

Evidence for Early Stage Anti-Tumor Immunity Elicited by Spatially Fractionated Radiotherapy-Immunotherapy Combinations.

The combination of radiotherapy and immunotherapy may generate synergistic anti-tumor host immune responses and promote abscopal effects. Spatial fractionation of a radiation dose has been found to promote unique physiological responses of tumors, which might promote synergy with immunotherapy. To determine whether spatial fractionation may augment immune activity, whole-tumor or spatial fractionation grid radiation treatment (GRID) alone or in combination with antibodies against immune checkpoints PD1 and CTLA-4 were tested in an immunocompetent mouse model using a triple negative breast tumor (4T1). Tumor growth delay, immunohistochemistry and flow cytometry were used to characterize the effects of each treatment type. Whole-beam radiation with immune checkpoint inhibition significantly restrained tumor growth in the irradiated tumor, but not abscopal tumors, compared to either of these treatments alone. In mice that received spatially fractionated irradiation, evidence of abscopal immune responses were observed in contralateral tumors with markedly enhanced infiltration of both antigen-presenting cells and activated T cells, which were preceded by increased systemic IFNγ production and led to eventual tumor growth delay. These studies suggest that systemic immune activation may be triggered by employing GRID to a primary tumor lesion, promoting anti-tumor immune responses outside the treatment field. Interestingly, PD-L1 was found to be upregulated in abscopal tumors from GRID-treated mice. Combined radio-immunotherapy therapy is becoming a validated and novel approach in the treatment of cancer. With the potential increased benefit of GRID to augment both local and metastatic disease responses, further exploration of GRID treatment as a part of current standards of care is warranted.