Immunotherapy in Extensive-Stage Small Cell Lung Cancer

Abstract

Small cell lung cancer (SCLC) remains a poorly understood disease with aggressive features, high relapse rates, and significant morbidity as well as mortality, yet persistently limited treatment options. For three decades, the treatment algorithm of SCLC has been stagnant despite multiple attempts to find alternative therapeutic options that could improve responses and increase survival rates. On the other hand, immunotherapy has been a thriving concept that revolutionized treatment options in multiple malignancies, rendering previously untreatable diseases potentially curable. In extensive stage SCLC, immunotherapy significantly altered the course of disease and is now part of the treatment algorithm in the first-line setting. Nevertheless, the important questions that arise are how best to implement immunotherapy, who would benefit the most, and finally, how to enhance responses.

Keywords: CTLA-4; PD-1; PD-L1; checkpoint inhibitors; immunotherapy; small cell lung cancer.

Figure 1

Factors affecting SCLC biology. Molecular Variables, Signaling Pathways, Transcription factors, Epigenetics, and Cell-surface Receptors. Evolving concepts in the understanding of SCLC include the following: The ubiquitous loss of TP53 and Rb1 involved mainly in the G1-S phase cellular cycle checkpoints; NEUROD1, ASCL1, and POUF2 expression as determinants of SCLC subtypes; Over-expression of AURKA involved in the G2-M checkpoint, and characterizing the MYC-driven NEUROD1 high SCLC-N subtype; Role of DNA damage response mediators such as Chk1, WEE1, ATM/ATR, as well as AURK; Role of epigenetics such as EZH2 and LSD1; Role of EZH2 influencing response to chemotherapy by alteration of SLFN11 and immune phenotype by effect on MHC-I presentation; Role of EZH2 in affecting ASCL1 expression responsible for SCLC-A phenotype through TGF-beta-SMAD pathway; Variable expression of chemokine receptors dependent on STING pathway; PD-L1 and DLL3 studied as targetable cell-surface receptors.