Combining radiation, immunotherapy, and antiangiogenesis agents in the management of cancer: the Three Musketeers or just another quixotic combination?

Abstract

With the advent of new cancer therapies in the last few years, the goals of reducing disease burden and improving quality of life are frequently achieved. Yet despite the advances seen with numerous monotherapies, a multimodality approach that targets different aspects of tumor biology may yield the greatest clinical benefit for patients with late-stage disease. Many such strategies have been employed with varying degrees of success. The addition of immunotherapy to standard-of-care radiation therapy has shown evidence of efficacy in some preclinical models and in the clinical setting. However, exploiting these two modalities safely and effectively remains an ongoing challenge. It is feasible that the addition of another therapeutic modality could further enhance the antitumor effects of these treatments. The recent addition of angiogenesis inhibitors to the cancer treatment armamentarium represents an attractive option, especially since these agents have been shown to be most effective when combined with other therapies. This review examines preclinical and clinical data on the interaction between immunotherapy and radiation, and discusses the potential synergy between these two modalities and angiogenesis inhibitors.

Fig. 1

Antigen release from dying tumor cells can activate immune responses—irradiation induces death of cancer cells. As these cells die, they are taken up by professional antigen presenting cells. These antigen presenting cells then travel to regional lymph nodes where they present antigen to T cells, initiating or potentiating an antitumor immune response. Activated tumor-specific T cells can then traffic to areas of tumor to participate in immune-mediated tumor killing.

Fig. 2

Anti-angiogenic agents can increase radiation sensitivity—the use of antiangiogenic agents can normalize tumor vasculature which increases tumor perfusion while decreasing interstitial pressure. The increased oxygen content in the formerly hypoxic tumor gives rise to elevated reactive oxygen species (ROS) upon irradiation, leading to increased DNA damage, mitotic catastrophe, and ultimately, cell death.

Fig. 3

Angiogenesis inhibitors can increase tumor responses to immunotherapy—angiogenesis inhibitors cause regression of existing vessels, prevent new vessel formation, and normalize tumor vasculature. This results in increased blood flow, oxygenation, and glucose required by infiltrating lymphocytes.

Fig. 4

The combined use of radiation, immunotherapy, and angiogenesis inhibitors—by normalizing blood flow and lowering intratumoral pressure, angiogenesis inhibitors enable T cells to gain efficient access to the tumor, while increasing the necessary components for effective T-cell function at the tumor site. Furthermore, by reducing hypoxia, antiangiogenic agents allow for optimization of radiotherapy, thereby providing the immune system with a rich supply of tumor antigens while modulating tumor-cell phenotype for enhanced T-cell killing.