Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges

Abstract

Management of small cell lung cancer (SCLC) has not changed over the last decades. In more recent years, alterations of DNA repair machinery and other molecular pathways have been identified in SCLC and preclinical data suggest that dysregulation of these pathways might offer new therapeutic opportunities.While immune checkpoint inhibitors (ICIs) have had a major impact on the clinical outcome of several solid tumors, including non-small cell lung cancer, the potential role of ICIs is currently under investigation in SCLC and some promising data are available. However, several clinical and biological hurdles have to be overcome and predictive markers are still eagerly needed. Knowledge of molecular pathways specifically involved in SCLC growth and treatment resistance is essential for a more rational planning of new combinations including ICIs.The present manuscript summarizes the current clinical evidence on immunotherapy in SCLC, describes the molecular bases underlying treatment resistance and discusses the potentialities and the rationale of different therapeutic combinations.

Keywords: Combination therapy; Enhancer of zeste homolog 2; Immune checkpoint inhibitors; Immunotherapy; Small cell lung cancer; Tumor microenvironment.

Fig. 1

Molecular landscape of SCLC. SCLC cells are characterized by ubiquitous loss of TP53 and Rb1 (dotted lines), the main G1-S cellular cycle checkpoints. SCLC cells depend on G2-M cell cycle checkpoint, that may be influenced by Aurora kinase A over-expression, characterizing the Myc-driven “variant” subtype of SCLC) and by Chk1-WEE1 axis. Chk1 is activated by Ataxia telangiectasia Mutated (ATM)/Ataxia telangiectasia and Rad-3 related protein (ATR) pathway upon chemo-induced DNA double strand break. After its activation, Chk1 can induce G2 cell cycle arrest through the phosphorylation of WEE1. Activated Chk1 can also up-regulate PD-L1 expression through the activation of the Signal Transducer and Activator of Transcription 1–3 (STAT1–3) mediated regulation of Interferon regulatory factor 1 (IRF1). Signaling pathways involving Enhancer of zeste homolog 2 (EZH2), an epigenetic modifier inducible both by immunotherapy and cytotoxic agents, also seem crucial in SCLC. EZH2 activity is required for the acquisition of an immunosuppressive phenotype, down-regulating antigen presentation process (resistance to immune-therapy), and also for an enhanced chemo-resistance property, through the inhibition of Schlafen family member 11 (SLFN11), a negative regulator of homologous repair machinery (HRM)

Fig. 2

New combination strategies. Mechanisms of action of drugs that are being studied for new combination strategies in small-cell lung cancer. Panel a: utomilumab triggers CD137, a co-stimulatory receptor expressed on activated immune cells and it is studied in combination with avelumab; trilaciclib is a CDK4/6 inhibitor and it is studied with platinum/etoposide and atezolizumab; SGI110 contrasts the role of EZH2, by interfering with DNA methylation and it is under evaluation in combination with durvalumab. Panel b: another promising strategy is to associate immune checkpoint inhibitor, such as Ipilimumab, to immune stimulatory agents. INCAGN01876 is a monoclonal antibody that activates Glucocorticoid-induced TNF-receptor-related protein (GITR), a T cell co-stimulatory receptor involved in the immunological synapsis able to enhance T cell responsiveness to weakly immunogenic tumor-associated antigens. INCAGN01949, another antibody that targets and stimulates OX40, a T cell co-stimulatory receptor that potentiates TCR signalling