Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers

Abstract

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1) have been approved for a variety of malignant tumors and are widely used to treat patients with metastatic disease. However, the efficacy of PD-1 inhibitors is limited due to tumor heterogeneity, high tumor burden, and “cold” tumor microenvironment. Radiotherapy can improve the anti-tumor effects of PD-1/PD-L1 inhibitors in various ways. As a new radiotherapy method, stereotactic body radiotherapy (SBRT) or hypofractionated radiotherapy (HFRT) provides higher doses per fraction to the target lesions, thus achieving immune activation effects and overcoming tumor resistance to anti-PD-1/PD-L1 treatment, which significantly improves the local and distant control of tumors. However, for different metastatic situations, radiotherapy plays different roles in the combination therapy. In oligometastatic status, radiotherapy can be used as a local radical treatment aiming to eliminate cancers in cooperation with systemic PD-1 inhibitors. In other circumstances, like bulky metastasis or multiple metastatic tumors, radiotherapy can be used as adjuvant to systemic immunotherapy. This review focuses on the underlying mechanisms and optimization strategies for the combination of radiotherapy and anti-PD-1/PD-L1 therapy in metastatic disease.

Anti-PD-1 Immunotherapy Combined With Stereotactic Body Radiation Therapy and GM-CSF as Salvage Therapy in a PD-L1-Positive Patient With Refractory Metastatic Thyroid Hürthle Cell Carcinoma: A Case Report and Literature Review

“…The combination of radiotherapy and immunotherapy is one of the current research focuses, several cases have confirmed the synergistic effect of immunotherapy and radiation. RT plus ICIs can relieve the intratumoral immunosuppression, increase tumor immunogenicity and tumor antigens release and presentation, eventually induce systemic tumor control ( 34 ). Programmed death ligand-1 (PD-L1) expression and mismatch repair deficiency (or microsatellite instability high) are FDA-approved biomarkers that predict response to ICIs in solid tumors treatment ( 35 ).…”

Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial)

“…Interestingly, radiotherapy was found to enlarge the anti-PD1/PDL1 treatment effect by promoting different links in the immune response such as activation and recruitment of T cells, promotion of dendritic cells maturation, antigen exposure and upregulation of major histocompatibility complex molecules [ 25 , 26 ]. In addition, radiotherapy can also reduce tumor burden and reinvigorate exhausted T cells to strengthen the anti-PD1/PDL1 therapeutic efficacy [ 27 , 28 ]. Therefore, the combination of anti-PD1 with NCRT might lead to improvement in local remission and survival in LARC.…”

HIF-1α Inhibition Improves Anti-Tumor Immunity and Promotes the Efficacy of Stereotactic Ablative Radiotherapy (SABR)

“…Some investigators have asserted that DNA damage is the major mechanism for the cell death by SABR, while radiobiological principles show that DNA damage alone cannot account for the high efficacy of SABR. The recent accumulating pre-clinical and clinical evidence shows that SABR may eradicate tumor cells through a combination of three pathways: (i) Direct cell death via DNA double-strand breaks, (ii) Indirect cell death via vascular damages, and (iii) Anti-tumor immune response [11][12][13][14][15][16][17][18] (Figure 1). The relative importance of these pathways in eradicating tumor cells and controlling tumors depends on the radiation dose delivered and the tumor type.…”

“…SABR is highly effective because it indirectly kills many radioresistant hypoxic tumor cells by causing vascular occlusion [2][3][4][5][6]. The implication of anti-tumor immune response in the outcome of SABR is unpredictable since the immunogenicity of tumors before irradiation exposure significantly varies depending on tumor type, and high-dose irradiation is a double-edged sword regarding tumor immunity as it can cause both immune stimulation and immune suppression [11][12][13][14][15][16][17][18]. High-dose irradiation of tumors increases the anti-tumor immunity by stimulating practically all known pro-immunologic processes, beginning with the release of tumor-associated antigens (TAAs) from tumor cells and continuing to the final effector phase of killing target tumor cells by activated cytotoxic T-cells [11,12,15,17,18].…”