Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination

Abstract

Several inhibitors of programmed cell death-1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved as a form of immunotherapy for multiple cancers. Ionizing radiation therapy (RT) has been shown to enhance the priming and effector phases of the antitumor T-cell response rendering it an attractive therapy to combine with PD-1/PD-L1 inhibitors. Preclinical data support the rational combination of the 2 modalities and has paved way for the clinical development of the combination across a spectrum of cancers. In this review, we highlight the preclinical and clinical development of combined RT and PD-1/PD-L1 blockade to date. In addition to a comprehensive evaluation of available safety and efficacy data, we discuss important points of consideration in clinical trial design for this promising combination.

Keywords: Antitumor; Checkpoint inhibitor; Clinical trials; Immune response; PD-1; PD-L1; Preclinical; Radiation therapy.

Fig. 1

Proposed mechanisms of synergy between RT and PD-1/PD-L1 inhibitors. Emerging evidence demonstrates that immune modulation from PD-1/PD-L1 inhibitors and RT through nonredundant pathways contributes to synergistic antitumor activity, thereby forming the basis for the rationale combination of the two modalities. RT, radiation therapy; PD-1, programmed cell death 1 receptor; PD-L1, programmed death ligand 1; IFN-γ, interferon-γ; cGAS, cyclic GMP-AMP (cGAMP) synthase; STING, stimulator of interferon genes; MHC, major histocompatibility complex; TCR, T-cell receptor; TILs, tumor-infiltrating lymphocytes, Tregs; regulatory T cells; MDSCs, myeloid-derived suppressor cells