Radiotherapy and Immunotherapy—A Future Partnership towards a New Standard

Abstract

The impressive results in terms of survival brought by immune checkpoint inhibitors (ICI) in metastatic malignant melanoma and the transformation of this disease with a poor prognosis into a chronic disease even with long-term survival cases have opened horizons for a new era in cancer treatments. Later, therapy with CTLA-4 and PD-1/PD-L1 inhibitors became standard in other solid tumors, especially in relapsed and metastatic settings. The PACIFIC clinical trial revolutionized the concept of consolidation immunotherapy after the favorable response to curative chemoradiotherapy in non-small cell lung carcinoma (NSCLC). Two new effects will govern the future of the immunotherapy–radiotherapy association: the local “in situ” vaccination effect and the systemic remote “abscopal” response. Even if stereotactic body irradiation (SBRT) or stereotactic radiosurgery (SRT) seems to be more effective in generating the synergistic effect, the PACIFIC trial demonstrates the role of conventional irradiation in combination with chemotherapy in modulating the host’s immune response. Thus, the radiotherapy–chemotherapy–immunotherapy triad may become the future standard in locally advanced disease. The different mechanisms of producing immune-mediated cell death and the indirect role of augmenting the immune effect induced by radiotherapy make the old theories related to the therapeutic sequence, fractionation, doses, and target volumes as well as the protection of healthy tissues to be re-evaluated. The new concept of immuno-radiotherapy in synergistic association has as its physiopathological substrate the dual immunosuppressive and enhancement of antitumor response to irradiation, including the activation of the immune effectors in the tumor microenvironment (TME). The choice of sequential treatment, a hypofractionated irradiation regime, and the possible omission of lymph node irradiation with the limitation of lymphopenia could tilt the balance in favor of the activation and potentiation of the antitumor immune response. The selection of therapeutic targets chosen for the combination of immunotherapy and associated radiotherapy can be conducted based on the classification of tumors in the three immune phenotypes that characterize “cold” and “hot” tumors from the point of view of the response to therapy.