Emerging therapeutic strategies for enhancing sensitivity and countering resistance to programmed cell death protein 1 or programmed death‐ligand 1 inhibitors in non–small cell lung cancer

• Published in: Cancer Vol. 129; no. 9; pp. 1319 - 1350
• Main Authors: Villaruz, Liza C., Blumenschein, George R., Otterson, Gregory A., Leal, Ticiana A.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2023
• Subjects: Apoptosis; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung - pathology; Cell death; drug resistance; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Immunotherapy - adverse effects; Inhibitors; Ligands; Lung cancer; Lung Neoplasms - pathology; Metastases; Mortality; neoplasm; Non-small cell lung carcinoma; non–small cell lung cancer; Oncology; Patients; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor; programmed cell death protein 1; programmed death‐ligand 1; Proteins; Sensitivity enhancement; Small cell lung carcinoma; tumor escape; Tumor Microenvironment; non-small cell lung cancer; programmed cell death protein 1; immunotherapy; neoplasm; programmed death-ligand 1; drug resistance; tumor escape
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.34683

The availability of agents targeting the programmed cell death protein 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) immune checkpoint has transformed treatment of advanced and/or metastatic non–small cell lung cancer (NSCLC). However, a substantial proportion of patients treated with these agents do not respond or experience only a brief period of clinical benefit. Even among those whose disease responds, many subsequently experience disease progression. Consequently, novel approaches are needed that enhance antitumor immunity and counter resistance to PD‐(L)1 inhibitors, thereby improving and/or prolonging responses and patient outcomes, in both PD‐(L)1 inhibitor‐sensitive and inhibitor‐resistant NSCLC. Mechanisms contributing to sensitivity and/or resistance to PD‐(L)1 inhibitors in NSCLC include upregulation of other immune checkpoints and/or the presence of an immunosuppressive tumor microenvironment, which represent potential targets for new therapies. This review explores novel therapeutic regimens under investigation for enhancing responses to PD‐(L)1 inhibitors and countering resistance, and summarizes the latest clinical evidence in NSCLC. Novel therapeutic approaches are required to enhance antitumor immunity and counter resistance to programmed cell death protein 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) inhibitors in non–small cell lung cancer (NSCLC). This study explores emerging approaches currently under investigation for enhancing responses to PD‐(L)1 inhibitors and countering resistance and reviews the latest clinical evidence in NSCLC.