We have shown in multiple preclinical tumor models that ionizing radiation therapy can convert tumors refractory to immune checkpoint inhibitors and other immune modulators into responsive ones. Importantly, the elicited antitumor T cells rejected not only the irradiated tumor but also nonirradiated spontaneous metastases or synchronous palpable tumors (abscopal effect), demonstrating the potential of radiation to generate systemically effective antitumor immune responses.
Investigations into the mechanisms underlying a successful response have highlighted a complex interaction between radiation and anti-CTLA-4 occurring at the priming and effector phase of the antitumor immune response. These data support a model whereby the irradiated tumor becomes a “live attenuated vaccine” resulting in marked expansion of a limited number of distinct T-cell clones within the tumor.
Our data also suggest that generation of an in situ tumor vaccine by radiation is regulated by the intrinsic tumor immunogenicity, the host immune system, and the radiation regimen employed. The interaction of these three compartments determines the levels of immune modulating mediators in the tumor microenvironment, including interferon type I, transforming growth factor-b, and adenosine, which in turn control the number and state of activation of intratumoral dendritic cells, and the magnitude of the induced T-cell response. Thus, while radiation offers the promise of a simple treatment to achieve individualized vaccination against each patient's own tumor, success is likely to be achieved by a personalized combination of the most effective radiation regimen and immune modulator(s).
We have recently shown in non-small cell lung cancer patients with chemotherapy-refractory metastatic disease that the synergy of radiotherapy and anti-CTLA-4 can be translated in the clinic (NCT02221739). Analysis of tumor and peripheral blood from responding and non-responding patients are beginning to provide clues to potential biomarkers and underlying mechanisms of response. Overall, local radiotherapy is showing the potential to be an ideal partner for immunotherapy. Because of its universal use in cancer treatment it is tempting to test standard of care radiotherapy in combination with any immunotherapy. However, rational use of radiation regimens and targeting of specific immune suppressive factors preexisting or elicited by radiation in a given tumor will be needed to truly reveal radiation's role in personalized immunotherapy.
Citation Format: Sandra Demaria. The future of combinations of immunomodulators with local radiation: toward a personalized immunotherapy approach. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY31-03.