Immunotherapy in extensive small cell lung cancer

Abstract

Small cell lung cancer which constitutes about 15% of lung cancers is pathobiologically and clinically distinct from non small cell cancer. Histologically it is characterized by small cells with scant cytoplasm, absent or inconspicuous nucleoli, extensive necrosis, and expresses neuroendocrine markers. It is on a spectrum of neuroendocrine cancer that extend from typical carcinoids to large cell to small cell cancer. Clinically it behaves in a more malignant fashion with a rapid doubling time, early metastasis. They respond rapidly to cytotoxic treatment however tend to develop resistance soon. Immunotherapy with checkpoint inhibitors take advantage of PD 1 ligand-receptor axis between the tumor and T cells or CTLA4 on T cells which when engaged lead to inhibition of T cells. This inhibition helps tumors to evade immune surveillance. Checkpoint inhibitors break this axis by either binding to PD 1 ligands or PD 1 to CTLA4, thereby preventing tumors to evade the immune systems. This has led to remarkable responses in tumors. The immune related adverse effects can be severe however are experienced at much lower rates as compared to cytotoxic chemotherapy. Recently, CheckMate 032 has shown impressive response rates with Nivolumab and Nivolumab/Ipilimumab in relapsed small cell cancer. IMpower 133, a phase 3 trial showed that addition of Atezolizumab to Carbo/Etoposide led to a significant survival benefit in treatment naive extensive small cell cancer. This review will summarize recent developments and ongoing studies of immune therapy in extensive small cell cancer in addition to a brief summary of immune therapy landscape of Non small cell lung cancer. Investigational approaches to immune therapy have also been delineated.

Overexpressed immunoglobulin-like transcript (ILT) 4 in lung adenocarcinoma is correlated with immunosuppressive T cell subset infiltration and poor patient outcomes

“…For example, the complex immunosuppressive factors in TME including Tregs and inhibitory checkpoint molecules can restrict T cell infiltration and killing ability, which are critical for tumor eradication [21]. Moreover, tumor intrinsic features including deficient PD-L1 expression, low mutation burden, mismatch repair protein and mutated driver-genes also imparied ICB efficacy [5]. Among all the factors, lack of PD-L1 expression in tumor cells and/or reduced TILs in the stroma are main contributors to ICB resistance, as was widely accepted in the Tumor Immune Microenvironment (TIME) classification [22].…”

“…Among all the factors, lack of PD-L1 expression in tumor cells and/or reduced TILs in the stroma are main contributors to ICB resistance, as was widely accepted in the Tumor Immune Microenvironment (TIME) classification [22]. Much effort has been made to overcome these limitations, e.g., development of novel checkpoint targets, engineered T cells, tumor vaccines, targeting other immunocytes, optimizing the predictive biomarkers, and exploring combination strategies [5,23]. Here we (See figure on previous page.)…”

“…However, the objective response rate of single PD-1/PD-L1 inhibitors in lung cancer is merely 20% [4]. Except for the inadequate patient selection and tumor intrinsic hypoimmunogenicity, the complex immunosuppressive microenvironment, which contains inhibitory immunocytes, cytokines and metabolites as well as decreased TIL number and functionality, presents a major hurdle to T cell immunity and effective ICB therapy [5,6]. Therefore, the development of novel immunotargets and treatment are urgently needed to break the suppressive barrier in anti-tumor immunotherapy.…”

Prognostic and Clinicopathological Value of Programmed Cell Death Ligand1 Expression in Patients With Small Cell Lung Cancer: A Meta-Analysis

“…The PD-1/PD-L1 checkpoint inhibitors, as an important part of immunotherapy, show promising effects in patients with SCLC as the first-line treatment ( 27 ). The IMpower133 trial showed that first-line atezolizumab plus chemotherapy prolongs the median OS (12.3 vs. 10.3 months, p = 0.007) and median progression-free survival (5.2 vs. 4.3 months, p = 0.02) compared with those following standard chemotherapy alone in patients with extensive-stage SCLC ( 7 ).…”

Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Small Cell Lung Cancer

“…Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers [2] with 6.0 cases per 100,000 individuals in 2014 [3]. SCLC is strongly associated with exposure to tobacco and grows rapidly, with early widespread metastases and frequent brain involvement [4, 5]. This disease subtype is also associated with high mutation rates, including rare oncogenic drivers and inactivation of the TP53 and RB1 tumor suppressor genes [6].…”