MTE13.02 Basic Immunology for the Clinician

Abstract

Lung cancer remains the number one cause of cancer-related death worldwide. Cancer immunotherapy nowadays has become not only a growing field but also a fascinating area as recent clinical trials have improved both PFS and OS in first line and second line treatment for patients with advanced NSCLC. The idea of immunotherapy in cancer is to modify the host immune system, so cytotoxic T-cells (CTCs) can recognize tumor-associated antigens (TAAs) as abnormal and be destroyed by an immune response. For many decades, we have tried unsuccessfully many vaccines against different lung cancer antigens. It was thought at one point that lung cancer was a non immunogenic tumor very different from melanoma and kidney cancers. Whole-cell vaccines (e.g. belagenpumatucel-L) and antigen-specific vaccines (e.g., CIMAvax, MAGE-A3, L-BPL25) showed just promising results in clinical trials, but failed to significantly improve clinical outcomes.1-4 The major reason why vaccines failed in lung cancer was due to tumor escape mechanisms from host immune surveillance.5,6 One of this mechanisms was recently elucidated, checkpoint pathway. Lung cancer has been found to have high levels of CTLA-4 expression, programmed death-1 (PD-1), PD ligand 1 (PD-L1), B7-H3 and B7-H4 expression on tumor-infiltrating lymphocytes (TILs), and regulatory CD4+ T-cells (Tregs) suggesting that lung cancer is immunogenic. For many years, cancer immunology was centered on the adaptive immune system and T-cell activation. Stimulation of the T-cell response involves antigen presenting cells (APCs), or dendritic cells (DCs), expressing tumor antigens from the tumor microenvironment, which then bind to the T-cell receptor (TCR) on CD4+ or CD8+ T-cells. Meanwhile, B7-1/CD80, or B7-2/CD86 on the APC, bind to CD28 on the T-cell in a costimulatory fashion to stimulate tumor-antigen specific T-cells to proliferate. However, cross talk between APCs and T-cells at the immunological synapse is regulated very closely and can be attenuated. One of this attenuation signal is mediated by CTLA-4, which is also stimulated by CD80 and CD86. Although CTLA-4 and CD28 have the same ligands, CTLA-4 has a much higher affinity for them; hence, T-cell proliferation occurs despite the effects of CTLA-4 because of the intracellular location, short half-life and quick degradation of CTLA-4.7,8 Another example of a tumor immune checkpoint is PD-1 which binds B7-H1/PD-L1 and B7-DC/PD-L2.9 By using PD-1 inhibitors, we are able to remove the interaction between PD-1 receptor located in the T-cells and its ligand expressed in the tumor cells which cause inhibitory signaling over the T-cells. Hence, an immune response cannot be mounted. CTLA-4 has been studied in lung cancer in combination with platinum-based doublet (carboplatin/paclitaxel). Outcomes from that study were not enough to grant approval from regulatory entities. However, investigators found better response to CTLA-4 inhibition in patients with squamous cell histology; this population has higher percentage of TILs than their non-squamous counterparts. Why the combined therapy (chemotherapy plus ipilimumab) had limited effect remains unclear. Conversely, studies using PD-1 inhibitors pembrolizumab and nivolumab have shown OS advantage over docetaxel in second line therapy, and more recently, OS and PFS advantage in first line against chemotherapy when tumor cells expressed ≥ 50% of PD-L1.10 We also understand that PD-L1 is not the perfect predictive biomarkers so efforts are directed to discover more specific markers which can help us to tailor checkpoint inhibitors in lung cancer. The approval of nivolumab in NSCLC came from two phase III trials CheckMate 017 and CheckMate 057 which studied nivolumab vs docetaxel in second-line for squamous and non-squamous advanced NSCLC, respectively. The CheckMate 017 reached the “trifecta” proving that nivolumab was statistically superior to docetaxel for OS, PFS and response rate (RR). Interestingly, OS benefit was independent of PD-L1 expression. The CheckMate 057 showed OS and RR in favor of nivolumab. There was no difference in PFS between nivolumab and docetaxel in non-squamous NSCLC patients. In this study, PD-L1 expression levels at different cut-off matter for OS. For those patients who had ≥1%, ≥ 5%, and 10%, the hazard ratio (HR) for OS were 0.59 (p < 0.06), 0.43 (p < 0.001), and 0.40 (p < 0.001), respectively. In both studies, nivolumab was well tolerated and had better treatment-related adverse event profile. In case of pembrolizumab, it was KEYNOTE-010 study which proved OS advantage over docetaxel in second line therapy. Herein, pembrolizumab at a dose of 10 mg/kg and 2 mg/kg shown an OS of 12.7 months (HR 0.61; p < 0.001) and 10.4 months (HR 0.71; p < 0.001); OS for docetaxel was 8.5 months. Noteworthy, OS was better in patients whose tumors expressed PD-L1 ≥50%; these patients had an OS of 17.3 and 14.9 months when received pembrolizumab at 10 mg/kg and 2 mg/kg, respectively. Again, grade 3-5 treatment-related AEs were less common for both pembrolizumab doses than for docetaxel. Recently, press release on KEYNOTE-024 phase III study, reported OS in favor of pembrolizumab over platinum-based doublet in first-line therapy for advanced NSCLC patients with PD-L1 expression. The clinical results from KEYNOTE-024 may change the landscape of lung cancer treatment at first-line for advanced NSCLC. Also in development are the PD-L1 inhibitors which affect the interaction between PD-L1 and B7.1 and PD-1 receptor and PD-L2; the later interactions are not affected by PD-1 inhibitors. Atezolizumab and darvulumab have several phase III trials ongoing in first line for advanced NSCLC. Phase II trials for both compounds have shown promising results. The role of PD-L1 as predictive biomarker is still not well defined. PD-L1 expression is a dynamic process and it also varies as part of an adaptive immune resistance exerted by the tumor. There are other possible predictive biomarkers such as higher nonsynonymous mutation burden, molecular smoking signature, higher neo-antigenic burden, DNA repair pathway mutations, high levels of PD-L1 expression, T-helper type 1 gene expression, and others. There is no question that we must continue looking for a better predictive biomarker which can help us to determine the therapeutic benefit of PD-1/PD-L1 inhibitors. 1. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol. 24, 4721–30 (2006). 2. González G, Crombet T, Neninger E, Viada C, Lage A. Therapeutic vaccination with epidermal growth factor (EGF) in advanced lung cancer: analysis of pooled data from three clinical trials. Hum Vaccin. 3(1), 8-13 (2007). 3. Vansteenkiste J, Zielinski H, Linder A, et al. Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC). J Clin Oncol. 25(18S), 7554 (2007). 4. Palmer M, Parker J, Modi S, et al. Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer. Clin Lung Cancer. 3(1), 49-57 (2001). 5. Gross S, Walden P. Immunosuppressive mechanisms in human tumors: why we still cannot cure cancer. Immunology Letters. 116(1), 7–14 (2008). 6. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 3, 991–8 (2002). 7. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat immunol 3(7):611-618, 2002. 8. Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 13(18):5271-5279, 2007. 9. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. CancerI Immunol Immunother 56(5):739-745, 2007. 10. http://www.businesswire.com/news/home/20160616005393/en/Merck%E2%80%99s-KEYTRUDA%C2%AE%C2%A0-pembrolizumab-Demonstrates-Superior-Progression-Free-Survival. Access online September 20, 2016. lung cancer, checkpoint pathway, Immunotherapy, PD-L1