Abstract
Small cell lung cancer (SCLC) is one of the deadliest cancer types in the world. Despite the high response rate to frontline platinum-containing doublets, relapse is inevitable for the majority of patients and the prognosis is poor. Topotecan, which has limited efficacy, has remained the standard second-line therapy for approximately three decades. Although SCLC has a high mutation burden, the clinical efficacy of immune checkpoint blockades (ICBs) in SCLC is far less pronounced than that in non-small cell lung cancer (NSCLC). Only atezolizumab in combination with chemotherapy improved overall survival over chemotherapy alone in the phase III CheckMate 133 trial and has recently received FDA approval as first-line therapy. Most studies concerning ICBs in SCLC are limited to early-phase studies and found that ICBs were not superior to traditional chemotherapy. Why is there such a large difference between SCLC and NSCLC? In this review, comparative analyses of previous studies indicate that SCLC is even more immunodeficient than NSCLC and the potential immune escape mechanisms in SCLC may involve the low expression of PD-L1 and the downregulation of major histocompability complex (MHC) molecules and regulatory chemokines. In consideration of these immune dysfunctions, we speculate that chemotherapy and radiotherapy prior to immunotherapy, the combination of ICBs with antiangiogenic treatment, and selecting tumor mutation burden in combination with PD-L1 expression as biomarkers could be promising strategies to improve the clinical efficacy of immunotherapy for SCLC.
Highlights
Worldwide, lung cancer is the leading cause of cancer incidence and mortality, with 2.1 million new cases and 1.8 million deaths estimated in 2018, representing 18.4% of the total cancer-related deaths [1]
Pembrolizumab in combination with standard chemotherapy resulted in significantly prolonged overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone among patients with squamous and nonsquamous non-small cell lung cancer (NSCLC) in KEYNOTE-407 and KEYNOTE-189 [68, 69]
These results indicated that the heavy tumor burden in Small cell lung cancer (SCLC) makes the immune system less functional than in NSCLC through IL-15 secretion and the CD47/SIRPα and Fas/FasL pathways
Summary
Lung cancer is the leading cause of cancer incidence and mortality, with 2.1 million new cases and 1.8 million deaths estimated in 2018, representing 18.4% of the total cancer-related deaths [1]. Suppressive immune features indicating a poor prognosis of SCLC include the frequency of CD14+HLA-DR-/low myeloidderived suppressor cells (MDSCs) [45], the C-reactive protein/albumin (CRP/Alb) ratio[46] and a higher Treg cell ratio in tumor infiltrates [47] These clinical evidence further illustrated the significance of the immune response and the possibility of immunotherapy for SCLC. Clinical outcomes of ICBs in NSCLC and SCLC Immune checkpoint blockades, including anti-CTLA4 antibody (ipilimumab), anti-PD-1 antibodies (pembrolizumab and nivolumab), and anti-PD-L1 antibodies (atezolizumab and durvalumab), have showed remarkable and durable responses across multiple cancer types and received FDA approval [21, 26, 30, 31]. First-line First, Reck et al conducted a randomized phase II trial to investigate ipilimumab in combination with chemotherapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
