Does Radiotherapy Lead to An In Situ Breast Cancer Vaccine?

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Preclinical studies suggest that radiotherapy’s pro-immunogenic effects might improve the antitumor efficacy of immune checkpoint inhibition.
Preclinical studies suggest that radiotherapy’s pro-immunogenic effects might improve the antitumor efficacy of immune checkpoint inhibition.
The following article features coverage from the San Antonio Breast Cancer Symposium (SABCS) 2017 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

Radiation causes the cytoplasmic accumulation of double-strand tumor DNA fragments that appear to serve as in-situ “vaccines,” facilitating an antitumor immune response outside of irradiated fields, according to a review of preclinical and early human trial data presented at the 2017 San Antonio Breast Cancer Symposium.1

Radiotherapy is a promising addition to cancer immunotherapy because of its ability to convert the irradiated tumor into an “individualized, in-situ vaccine,” said Silvia Formenti, MD, of Weill Cornell Medicine, in New York, New York.1

DNA damage repair (DDR) contributes to immune rejection of tumors, partly explaining the efficacy of platinum and radiotherapy combinations — potentially opening the door to precision radiotherapy and radioimmunotherapy, Dr Formenti said.

“Most breast cancers may require multiple immunotherapeutic interventions to become an in situ vaccine,” she added. “Radiation-induced DDR converges with the innate immune system, with a tumor-specific dose-threshold.”

Radiotherapy-induced cell death can induce T cell effects outside of the irradiated field. These abscopal effects are, however, “extremely rare,” due to immune-suppressive tumor microenvironments. Preclinical studies suggest that radiotherapy's pro-immunogenic effects might improve the antitumor efficacy of immune checkpoint inhibition. But the optimal radiation doses for combined immunoradiotherapy remain unclear.

In cell line research, mouse models, and early findings from pilot studies with human patients, carcinoma cells exposed to increasing radiation doses led to the release and accumulation of double-strand fragments of tumor DNA to a threshold level above which induction of the repair exonuclease 1 (Trex1) enzyme is triggered, Dr Formenti said.

There appears, however, to be a threshold radiation dose above which the vaccine-like abscopal immunogenicity of irradiated tumor tissue declines.

Trex1 induction by a single 20 Gy radiation dose downregulated interferon beta (IFNb) activation in a patient-derived non–small cell lung cancer (NSCLC) tumor xenograft.

The findings support the choice of 3 to 5 doses of 8 Gy each when radiotherapy is combined with immunotherapy, Dr Formenti said. Building on those findings, her team initiated a pilot clinical trial of radiotherapy in patients receiving ipilimumab for metastatic NSCLC.

Additional research is under way to begin to define optimal treatment fields and treatment sequencing.

Read more of Cancer Therapy Advisor's coverage of the San Antonio Breast Cancer Symposium (SABCS) 2017 meeting by visiting the conference page.

Reference

  1. Formenti, SC. Potential of radiation therapy to convert the tumor into an in situ vaccine. Oral Presentation at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX.
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