Immunotherapeutic approaches for small-cell lung cancer

Abstract

Immune-checkpoint inhibitors (ICIs) are approved in the first-line and third-line settings for patients with extensive-stage or relapsed small-cell lung cancer (SCLC), respectively. In the firstline setting, the addition of the anti-programmed cell death 1 ligand 1 (PD-L1) antibody atezolizumab to chemotherapy improves overall survival (OS). In patients with relapsed disease, data from nonrandomized trials have revealed promising responses, although a significant improvement in OS over that obtained with conventional chemotherapy was not achieved in a randomized trial in this setting. Substantial research interest exists in identifying predictive biomarkers that could guide the use of ICIs in patients with SCLC. PD-L1 expression is typically low or absent in SCLC, which has precluded its use as a predictive biomarker. Tumour mutational burden might have some predictive value, although blood-based measures of tumour mutational burden did not have predictive value in patients receiving atezolizumab plus chemotherapy in the first-line setting. After three decades, ICIs have finally enabled an improvement in OS for patients with SCLC; however, a substantial amount of research remains to be done, including identifying the optimal therapeutic strategy and predictive biomarkers. In this Review, we describe the available data on clinical efficacy, the emerging evidence regarding biomarkers and ongoing clinical trials using ICIs and other immunotherapies in patients with SCLC. Small-cell lung cancer (SCLC) accounts for ~15% of all lung cancers and ~30,000 deaths in the USA annually 1. Owing to the elusive pathophysiology of the disease, the poor prognosis of patients and minimal improvement in the effectiveness of therapies over the past decades, SCLC is a US National Cancer Institute-designated recalcitrant malignancy 2. With the FDA approval of carboplatin, etoposide and the anti-programmed cell death 1 ligand 1 (PD-L1) antibody atezolizumab as a first-line therapy, and the anti-programmed cell death protein 1 (PD-1) antibodies nivolumab and pembrolizumab as monotherapies in the third-line setting, immune-checkpoint inhibitors (ICIs) have entered the treatment

Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

“…Since SCLC has a very short survival time, new treatment strategies are urgently needed. The clinical efficacy of immunotherapies has been observed in patients with refractory or metastatic SCLC [12,[19][20][21][22][23]. The phase II KEYNOTE-158 study [21] showed that the PFS of pembrolizumab for relapsed SCLC was 2.0 months, the median OS was 9.1 months, and the one-year PFS and OS were 16.8% and 40.2%, respectively.…”

Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer

“…SCLC occurs primarily in heavy smokers, but despite the very high mutation burden (8–10) from SCLC genomes predicted to contribute an ample supply of neoantigens, SCLCs express low levels of major histocompatibility complex class I (MHC I) proteins to present tumor-specific antigens (11, 12). This could explain why, among various types of cancer, checkpoint-blockade immunotherapy (CBI) underperforms in SCLC (13, 14).…”

Cross‐Link‐Functionalized Nanoparticles for Rapid Excretion in Nanotheranostic Applications

“…P 3 -QDs-anti-CD8 and P 3 -ErNPs-anti-PD-L1 for Molecular Imaging of Immunotherapy Next, we explored P 3 -QDs for NIR-IIb molecular imaging. Despite the successful application of checkpoint blockade therapy in aw ide range of tumor types, [16] many patients fail to respond to the therapy, [17a] often associated with limited infiltration of CD8 + cytotoxic Tlymphocytes (CTLs). [17b,c] To investigate PD-L1 + tumor cells and CD8 + CTLs simultaneously in vivo,w ep erformed two-plex NIR-IIb molecular imaging using P 3 -QDs-anti-CD8 and ErNPs-anti-PD-L1 by detecting emission at % 1600 nm for both types of probes.The drastically different fluorescence lifetimes of P 3 -QDs and ErNPs were utilized to differentiate the two probes and their respective molecular targets for two-plex molecular imaging in the NIR-IIb window (see Supporting Information).…”