Combining radiation and immunotherapy: a new systemic therapy for solid tumors?

Abstract

With the recent success of checkpoint inhibitors and other immunomodulating agents, there has been renewed interest in the combination of such agents with radiation. The biologic premise behind such a strategy is that the tumor-antigen release achieved by localized radiation will promote specific tumor targeting by the adaptive immune system, which can be augmented further by systemic immune-stimulating agents. In this manner, clinicians hope to induce a phenomenon known as the abscopal effect, whereby localized radiation results in immune-mediated tumor regression in disease sites well outside of the radiation field. Herein, we present a comprehensive overview of the early clinical and preclinical evidence behind this approach.

Figure 1

Schematic diagram outlining the antitumor activity and abscopal effect in combining checkpoint inhibitors with radiation-induced immune response. Radiation induces DNA damage and tumor cell death by promoting tumor cell expression of Fas and MHC class I; dying tumor cells release ATP, tumor antigens, and danger signals such as HMGB1 and calreticulin. Radiation also increases tumor cell expression of PD-L1 and secretion of TGF-β, and suppression of CD4⁺ Treg. Tumor antigens captured by antigen-presenting cells (APC) are processed and presented on MHC class I molecules in the draining lymph node to tumor antigen-specific T cells in conjunction with co-stimulation to promote activation and proliferation. CTLA-4 can bind B7-1 to downregulate T-cell activation. Activated CTLs leave the lymph node, follow inflammatory chemokines, and migrate to tumor sites. PD-L1 and PD-1 can interact to suppress CTL activation; various α–CTLA-4, α–PD-L1, and α-PD-1 mAbs have been developed and used successfully in cancer immunotherapies. CTL antitumor activity includes secretion of INFγ and TNF, suppression of myeloid derived suppressor cells (MDSC), expression of perforin and granzyme, and activation of Fas ligand-mediated tumor cell apoptosis.