Immunotherapy for small cell lung cancer: the current state and future trajectories

Discover Oncology Review Immunotherapy for small cell lung cancer: the current state and future trajectories Min Qiang1 · Hongyang Liu1 · Lei Yang1 · Hong Wang1 · Rui Guo2 Received: 1 April 2024 / Accepted: 21 June 2024 © The Author(s) 2024  OPEN Abstract Small cell lung cancer (SCLC) constitutes approximately 10% to 15% of all lung cancer diagnoses and represents a pressing global public health challenge due to its high mortality rates. The efficacy of conventional treatments for SCLC is suboptimal, characterized by limited anti-tumoral effects and frequent relapses. In this context, emerging research has pivoted towards immunotherapy combined with chemotherapy, a rapidly advancing field that has shown promise in ameliorating the clinical outcomes of SCLC patients. Through originally developed for non-small cell lung cancer (NSCLC), these therapies have extended new treatment avenues for SCLC. Currently, a nexus of emerging hot-spot treatments has demonstrated significant therapeutic efficacy. Based on the amalgamation of chemotherapy and immunotherapy, and the development of new immunotherapy agents, the treatment of SCLC has seen the hoping future. Progress has been achieved in enhancing the tumor immune microenvironment through the concomitant use of chemotherapy, immunotherapy, and tyrosine kinase inhibitors (TKI), as evinced by emerging clinical trial data. Moreover, a tripartite approach involving immunotherapy, targeted therapy, and chemotherapy appears auspicious for future clinical applications. Overcoming resistance to post-immunotherapy regimens remains an urgent area of exploration. Finally, bispecific antibodies, adoptive cell transfer (ACT), oncolytic virus, monotherapy, including Delta-like ligand 3 (DLL3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT), as well as precision medicine, may present a prospective route towards achieving curative outcomes in SCLC. This review aims to synthesize extant literature and highlight future directions in SCLC treatment, acknowledging the persistent challenges in the field. Furthermore, the continual development of novel therapeutic agents and technologies renders the future of SCLC treatment increasingly optimistic. Keywords Immunotherapy · Small cell lung cancer (SCLC) · Combined therapy · Bispecific antibodies · ACT· Oncolytic virus · DLL3 · TIGIT 1 Introduction Lung cancer has emerged as a predominant global health challenge, representing the second most frequently diagnosed malignancy and the principal cause of cancer-related mortality in 2020. Specifically, it accounted for approximately 11.4% of all cancer diagnoses and 18% of all cancer-related deaths [1]. Lung cancer can be classified into two distinct subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) [2]. * Rui Guo, ; Min Qiang, ; Hongyang Liu, ; Lei Yang, ; Hong Wang, | 1Cancer Center, The First Hospital of Jilin University, Changchun, China. 2Clinical Laboratory, The First Hospital of Jilin University, Jilin University, Changchun, China. Discover Oncology (2024) 15:355 | https://doi.org/10.1007/s12672-024-01119-5 Vol.:(0123456789) Review Discover Oncology (2024) 15:355 | https://doi.org/10.1007/s12672-024-01119-5 SCLC constitutes approximately 10–15% of all lung cancer cases and is associated with high mortality rates [3]. SCLC derives its nomenclature from the microscopic observation of its small, oval-shaped cellular morphology. This malignancy is distinguished by its rapid proliferative kinetics and its propensity for swift metastasis to distant sites. Notably, therapeutic options remain limited and largely ineffective upon disease recurrence [4, 5]. According to the differential expression levels of specific genes, SCLC subtypes are classified as follows: those with elevated achaete-scute homolog 1 (ASCL1) expression are designated SCLC-A; those with increased neurogenic differentiation factor 1 (NEUROD1) expression fall under SCLC-N; elevated POU class 2 homeobox 3 (POU2F3) expression delineates SCLC-P; and those with heightened yes-associated protein 1 (YAP1) expression are classified as SCLC-Y. These taxonomical distinctions underscore the inherent heterogeneity of SCLC and pave the way for the development and application of subtype-specific targeted therapies [6]. Owing to the complex landscape of tumor heterogeneity in SCLC, there is a pressing imperative to identify and validate additional biomarkers. This endeavor is not merely an academic exercise, but serves to stratify the patient population most amenable to immunotherapeutic interventions. It also facilitates more rigorous evaluation of immunotherapeutic efficacy, thereby enhancing the precision of therapeutic regimens in SCLC [7–9]. Clinically, SCLC is categorized into two stages: limited-stage and extensive-stage. The malignancy is characterized by its aggressive nature and poor prognosis. The majority of patients are diagnosed with extensive-stage disease at the time of initial presentation [10]. The term "extensive-stage" denotes that the malignancy has metastasized beyond the lungs to other regions of the body. Standard treatment modalities for SCLC commonly incorporate a regimen of chemotherapy and radiation therapy, with surgical intervention considered in select cases. Over the past decade, chemotherapy has persisted as the cornerstone for both first- and second-line therapies across the spectrum of SCLC [11]. In this context, limited-stage small cell lung cancer (LS-SCLC) predominantly relies on a treatment strategy of radiotherapy coupled with chemotherapy. For extensive-stage small cell lung cancer (ES-SCLC), chemotherapy serves as the principal therapeutic approach. Specifically, a combination of etoposide with either cisplatin or carboplatin has remained the standard chemotherapy regimen for ES-SCLC for over three decades [12]. While initial treatment often results in some degree of remission for patients with SCLC, the propensity for disease relapse and progression is high, and therapeutic options following relapse are limited. Consequently, the 5-year survival rate remains suboptimal, which OS is only about 2%. Despite minimal advancements in overall survival (OS) over the years, contemporary literature has increasingly focused on the promise of immunotherapy. Immune checkpoint blockages (ICBs), particularly programmed cell death protein 1/programmed death-ligand 1 (PD-1/ PD-L1) inhibitors such as atezolizumab and durvalumab, are currently the subject of rigorous investigation (Table 1) [13]. The advent of immunotherapy has marked a seminal shift in the treatment landscape for SCLC, achieving for the first time an OS exceeding 1 year and ushering SCLC into the immunotherapeutic era [14]. Nonetheless, PD-1 inhibitors have not achieved a significant breakthrough in the treatment of SCLC. Insights from the IMpower133 and CASPIAN trials indicate that PD-L1 monoclonal antibodies have demonstrated incremental advancements [15] (...truncated)