Radiation dose and checkpoint blockade immunotherapy: unanswered questions

We wish to compliment Andrew Sharabi and colleagues 1 Sharabi AB Lim M DeWeese TL Drake CG Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015; 16: e498-e509 Summary Full Text Full Text PDF PubMed Scopus (515) Google Scholar on their well written and comprehensive Review. However, we believe that the discussion on radiation dose would benefit from further clarification of the statement, “Overall, hypofractionated radiation at a dose of 5–20 Gy per fraction is thought to be better than conventionally fractionated schemes of 1·8–2·2 Gy fractions”. This insight is largely derived from specific animal models. For various reasons, extrapolation of radiation dose effects from animal to human studies is not straightforward, not least of which being the exponential absolute differences in numbers of irradiated cells. Moreover, unlike human patients, animals are seldom irradiated every day for a period of weeks because of logistical and cost issues. Therefore, dose per fraction might, in many studies, serve as a proxy for total dose and overall levels of cell death. In human patients, this is commonly achieved with conventionally fractionated radiation. These important differences notwithstanding, results from animal models have suggested that low dose per fraction radiation might be more effective at recruiting T-cells to a tumour microenvironment than at high doses. 2 Klug F Prakash H Huber PE et al. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective t cell immunotherapy. Cancer Cell. 2013; 24: 589-602 Summary Full Text Full Text PDF PubMed Scopus (666) Google Scholar Ultimately, examination of existing preclinical dose comparisons do not provide a clear answer. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergyCheckpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. Full-Text PDF