Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose?

Abstract

Recent evidence indicates that ionizing radiation can enhance immune responses to tumors. Advances in radiation delivery techniques allow hypofractionated delivery of conformal radiotherapy. Hypofractionation or other modifications of standard fractionation may improve radiation’s ability to promote immune responses to tumors. Other novel delivery options may also affect immune responses, including T-cell activation and tumor-antigen presentation changes. However, there is limited understanding of the immunological impact of hypofractionated and unique multifractionated radiotherapy regimens, as these observations are relatively recent. Hence, these differences in radiotherapy fractionation result in distinct immune-modulatory effects. Radiation oncologists and immunologists convened a virtual consensus discussion to identify current deficiencies, challenges, pitfalls and critical gaps when combining radiotherapy with immunotherapy and making recommendations to the field and advise National Cancer Institute on new directions and initiatives that will help further development of these two fields.This commentary aims to raise the awareness of this complexity so that the need to study radiation dose, fractionation, type and volume is understood and valued by the immuno-oncology research community. Divergence of approaches and findings between preclinical studies and clinical trials highlights the need for evaluating the design of future clinical studies with particular emphasis on radiation dose and fractionation, immune biomarkers and selecting appropriate end points for combination radiation/immune modulator trials, recognizing that direct effect on the tumor and potential abscopal effect may well be different. Similarly, preclinical studies should be designed as much as possible to model the intended clinical setting. This article describes a conceptual framework for testing different radiation therapy regimens as separate models of how radiation itself functions as an immunomodulatory ‘drug’ to provide alternatives to the widely adopted ‘one-size-fits-all’ strategy of frequently used 8 Gy×3 regimens immunomodulation.

Hypofractionated Radiotherapy Upregulates Several Immune Checkpoint Molecules in Head and Neck Squamous Cell Carcinoma Cells Independently of the HPV Status While ICOS-L Is Upregulated Only on HPV-Positive Cells

“…Notably, a hypofractionated RT scheme of 5x3.0Gy was very effective in terms of inducing cell death and modulating immune checkpoint molecules on the surface of HNSCC cells, and partly also on a mRNA level. This should be considered when designing new multimodal tumor therapies with adapted RT protocols [40]. However, as current studies are carried out with rather small patient cohorts and little is known about long-term effects, especially with regard to normal tissue tolerance [38], additional preclinical research in this area is needed.…”

“…So far, no significant disadvantages in terms of local control, overall survival and quality of life have been found [38,39], and there is evidence that intensifying the treatment by either altering RT fractions or adding concurrent therapies might even improve the outcome in patients [38]. The optimal radiation dose and fractionation for combination of RT with ICM still has to be identified [40]. In order to do so, knowledge about early alterations of the immune phenotype of HNSCC tumor cells following RT with a distinct fractionation approach is mandatory.…”

Intersection of Two Checkpoints: Could Inhibiting the DNA Damage Response Checkpoint Rescue Immune Checkpoint-Refractory Cancer?

“…However, while chemotherapy reduces the systemic tumor burden, it also weakens the anti-tumor immune response (as lymphocytes are sensitive to cytotoxic agents), making this an approach that may not be suitable for all tumor types [ 37 , 38 ]. Combining radiation with ICI has been widely tested with some notable areas of success [ 39 , 40 , 41 , 42 , 43 ], although it may be immunosuppressive in some settings. Adding radiotherapy to immune therapy in ICI-resistant patients has generally not yielded a synergistic clinical benefit for unirradiated tumors despite very promising data in animal models and some early, promising clinical studies [ 39 , 44 , 45 , 46 ].…”

“…Targeting tumor cells with low-dose, conformal radiotherapy and an ATRi, which is selectively cytotoxic in rapidly dividing cells, may reduce the burden of MCC without suppressing systemic immunity which is critical for controlling MCC. Using radiotherapy, particularly hypofractionated regimens which are often considered more immunogenic [ 42 , 110 ], to effect DNA damage and potentiate ICI has been heavily explored over the past decade. The addition of an ATRi may help to potentiate the pro-inflammatory effects of radiation rather than its immunosuppressive properties [ 102 ].…”

Immune radiobiology

“…The main concept is to exploit the immunogenic potential of IR to jumpstart host immune responses with the ultimate goal to raise the tail of cancer patient survival curves treated with immunotherapies [ 2 , 4 ]. The rationale for the use of IR as an immune adjuvant originates from extensive preclinical studies demonstrating that IR elicit an immunogenic cell death (ICD) and a type I interferon (IFN-I) response to generate antigen specific T cell killing [ 2 ].…”