Abstract
Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses.
Highlights
Immunotherapy has marked a revolution in the treatment of lung cancer
In order to correctly administer immunotherapy, the National Comprehensive Cancer Network (NCCN) and the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) guidelines strongly recommended that the expression of PD-L1 protein should be tested in patients [38,39]
In the CHECKMATE-227 clinical trial, the association of two different immunodrugs showed a similar improvement in progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients with at least 10 mutations per megabase [47] when compared to standard-of care chemotherapy; these results were irrespective of PD-L1 expression levels: ORR—45.3% versus 26.9%; median progression-free survival (mPFS)—7.2 months versus 5.5 months; HR for disease progression or death—0.58 (p < 0.001)
Summary
Immunotherapy has marked a revolution in the treatment of lung cancer. By manipulating the immune response to target tumour cells, disease control is achievable in subsets of lung cancer patients, resulting in prolonged survival, resistance after the initial response is not uncommon. Among ICIs, nivolumab and pembrolizumab target the checkpoint protein PD-1, whereas atezolizumab and durvalumab target PDL1, all approved by FDA for treatment of lung cancer patients. Beyond the expression of PD-L1, other biomarkers are under investigation to better stratify patients who may benefit from immune-checkpoint inhibitors (ICIs) (Table 1). One of these is represented by human leukocyte antigen class I (HLA-I). ALK: anaplastic lymphoma kinase; CNS: central nervous system; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EGFR: epidermal growth factor receptor; ICI: immune checkpoint inhibitor; NR: not reached; NSCLC: non-small cell lung cancer; OS: overall survival; PFS: progression free survival; TKI: tyrosine kinase inhibitor
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