A combination of radiotherapy with local and systemic immunotherapy may be clinically beneficial for treating some types of tumors. There is an urgent need, however, for the development of clinical trials to explore this novel treatment regimen, according to an article published in Trends in Cancer. Novel immunotherapies are entering clinical practice at an accelerating rate, but clinicians are not sure how to best combine them with radiotherapy.1

“Local tumor radiotherapy has shown the ability to enhance responses to immune checkpoint inhibitors, similar to ipilimumab, nivolumab, pembrolizumab, and Toll-like receptor agonists, such as imiquimod. This includes other agents not yet approved, but under investigation for human use, in several pre-clinical models of cancer, including breast, colorectal, brain, melanoma, lung and prostate,” said lead study author Sandra Demaria, MD, professor of radiation oncology and pathology at Weill Cornell Medicine in New York, New York.

She said that early data show a benefit with a combination of radiotherapy and immunotherapies in patients with melanoma, non-small cell lung cancer (NSCLC) and some lymphoid malignancies. Dr Clinical trials are ongoing in other cancer types as well, and producing some rather encouraging results in preliminary reports. Responses were seen with the combination of radiation and anti-PD-1 in tumor types where responses to anti-PD-1 alone had not been significant in some patients with ovarian cancer and small intestinal adenocarcinoma.

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“As of now, data suggest that the use of radiation in patients during immunotherapy appears to be generally safe and to benefit patients beyond local control of their tumor. Treating physicians should evaluate the patients for abscopal responses, but more data are needed before the combination treatment can be recommended as a standard of care,” Dr Demaria told Cancer Therapy Advisor.

To use radiation with the purpose of generating anti-tumor immune responses, there is a need to better understand the mechanisms involved. Dr Demaria said there are many unanswered questions about whether greater immune responses are triggered by high- or low-dose radiation, given once or several times, and if different tumors respond differently to the varying fractionation regimens.

“Unfortunately, in most clinical studies the radiation is given based on the physician preference or the standard of care used for palliation, which may not produce the desired effects,” said Dr Demaria. “We need to do more work and think critically when designing clinical studies. This is a multidisciplinary topic and it should be based on a novel partnership among immunologists/immunotherapists and radiation oncologists.”

According to Dr Demaria, this process is not unique to radiation. Other cancer treatments, such as chemotherapy and targeted therapies, are being used for patients receiving immunotherapy. Clinicians still don’t know how these treatments interact.

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Raquibul Hannan, MD, PhD, assistant professor of radiation oncology at the University of Texas (UT) Southwestern in Dallas, said the synergistic approach of radiation and immunotherapy is both promising and exciting. This applies particularly to stereotactic ablative radiotherapy (SABR) and stereotactic body radiation therapy (SBRT).

“We are calling the approach of strategically combining SABR and immunotherapy i-SABR, and we have 3 ongoing clinical trials, NCT01896271 and NCT01818986, which were designed to answer this question about which cancer sites and immunotherapies are responsive to this strategy,” Dr Hannan told Cancer Therapy Advisor. “Multiple new immunotherapies are changing the standards of care for melanoma, lung, head and neck, bladder and renal cancers.”

The benefits, however, may not be limited only to those malignancies. Dr Hannan said that many more sites are being evaluated to determine those that are even minimally responsive to an immunotherapy/radiotherapy combination. “Wherever there is response, there is a possibility of radiation therapy to boost that response. When there is no response, there is an opportunity for radiation to initiate a response. This is due to the fact that radiation initiates a tumor-specific response and the tumor specificity is lacking in the checkpoint inhibitor immunotherapies,” said Dr Hannan. “It is through clinical trials that we will identify which sites are more responsive to this i-SABR strategy. In my opinion, melanoma and RCC will be the first, but certainly not the only sites where this strategy will prove to be synergistic.”


1. Demaria S, Coleman CN, Formenti SC. Radiotherapy: changing the game in immunotherapy. Cancer Cell. 2016;2:286-294.