Synergistic effect of immunotherapy and radiotherapy in non-small cell lung cancer: current clinical trials and prospective challenges

Abstract

Lately, the success of ICIs has drastically changed the landscape of cancer treatment, and several immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for advanced non-small cell lung cancer (NSCLC). However, numerous patients are resistant to ICIs and require additional procedures for better efficacy results. Thus, combination therapy is urgently needed to strengthen the anti-tumor immunity. A variety of preclinical and clinical studies combining ICIs with radiotherapy (RT) have demonstrated that the combination could induce synergistic effects, as RT overcomes the resistance to ICIs. However, the underlying mechanism of the synergistic effect and the optimal arrangement of the combination therapy are indecisive now. Hence, this review was conducted to provide an update on the current clinical trial results and highlighted the ongoing trials. We also discussed the optimal parameters in clinical trials, including radiation dose, radiation fractionation, radiation target field, and sequencing of combination therapy. In this review, we found that combination therapy showed stronger anti-tumor immunity with tolerable toxicities in clinical trials. However, the best combination mode and potential biomarkers for the target patients in combination therapy are still unclear.

Keywords: combination; immune checkpoints; immunotherapy; non-small cell lung cancer; radiotherapy.

Figure 1.

Radiation activates the host immune system. Step 1. Release of neoantigen: Neoantigen increasing; Step 2. Neoantigen presentation: ATP/HMGB-1/CALR/IFN-I from tumor cells; Step 3. Proliferation and activation of dendritic cells and T cells: ATP/HMGB-1/CALR/IFN-I and CXCL10/CXCL 16 from tumor cells; Step 4. Recruiting of T cells to irradiated or unirradiated tumors: CXCL10/CXCL16 from tumor cells, increasing of VCAM-1 on endothelial cells; Step 5. Infiltration of T cells to tumors: CSF-1 from tumor cells, MDSC increasing; Step 6. Recognization and killing of tumor cells: PD-L1/MHC-1/NKG2D/FAS increasing on tumor cells. Vascular normalization: NO from macrophages.

Figure 2.

Sequencing modes of combination therapy. Sequential therapy: patients receiving ICI after CRT; Induction therapy: patients receiving CRT after a few cycles of ICI; Concurrent therapy: patients receiving CRT and ICI concurrently.