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Ignacio Gil-Bazo
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MS01 - Immunotherapy Resistance (ID 64)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Immuno-oncology
- Presentations: 4
- Now Available
- Moderators:Ignacio Gil-Bazo, Nuria Viñolas
- Coordinates: 9/08/2019, 10:30 - 12:00, San Francisco (2009)
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MS01.01 - Biological Mechanisms of Resistance (Now Available) (ID 3439)
10:30 - 12:00 | Presenting Author(s): Justin F. Gainor
- Abstract
- Presentation
Abstract
Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) axis have transformed the management of non-small cell lung cancer (NSCLC). Despite the dramatic and sometimes durable activity of these agents, a majority of patients will progress on therapy.1 Patients who experience a de novo lack of response to initial therapy are deemed as having primary (intrinsic) resistance. By contrast, acquired resistance refers to patients who initially achieve an objective response to therapy but eventually progress over time.
The mechanistic basis for primary versus acquired resistance to immune checkpoint inhibitors is still poorly defined. To date, studies into the biological mechanisms of resistance to immunotherapies have centered around preclinical studies and analyses of repeat biopsies obtained from patients at the time of disease progression.2 These efforts have been complemented by similar studies in other immuno-oncology settings (e.g., melanoma),3,4 since there is potential for shared biology underlying immunotherapy resistance across malignancies.
Both tumor cell-intrinsic and tumor cell-extrinsic factors have been implicated in mediating resistance to immunotherapies.2 In the setting of primary resistance, disease progression is commonly driven by a lack of neoantigens sufficient to illicit an initial immune response, commonly due to a low tumor mutation burden.5 Alternatively, tumors may actually harbor antigens capable of generating an immune response, but defects in antigen processing may ultimately limit the presentation of these antigens on the cell surface via MHC. Defective antigen presentation may be due to loss of beta-2 microglobulin (B2M), elimination of transporters associated with antigen processing (TAP) proteins, or downregulation of HLA.2,3 In addition, intrinsic resistance to immune checkpoint inhibitors may be due to altered oncogenic cell signaling (e.g., WNT/B-catenin pathway) and/or tumor de-differentiation with impaired antigen expression.
Molecular mechanisms of acquired resistance to checkpoint blockade likely include many of the same processes as those implicated in intrinsice resistance. Indeed, homozygous loss of B2M, which is required for stabilization of HLA on the cell surface, has been described in NSCLC at the time of acquired resistance to PD-1 pathway blockade.6 Additionally, neoantigen loss through elimination of specific tumor subclones (i.e., immunoediting), genetic alterations in interferon gamma (IFN) signaling, and upregulation of alternative checkpoints (e.g., TIM3) have also been purported to confer acquired resistance to checkpoint inhibitors.4,7,8 At present, the relative frequencies of these processes and the interplay among them within NSCLC and other malignancies remains to be defined.
Moving forward, it will be critical to pursue more in-depth preclinical and clinical studies of resistance to PD-1 pathway blockade in NSCLC. Just as insights into the molecular mechanisms of resistance to targeted therapy have transformed the therapeutic landscape for oncogene-driven tumors, it will be imperative for immuno-oncology to develop a framework for understanding resistance to checkpoint inhibitors and apply this framework to clinical development of next-generation immuno-onclogy agents. This is especially critical due to the sheer number of immuno-oncology combinations currently in clinical testing. Ultimately, knowledge of the mechanisms of resistance to immune checkpoint inhibitors may help better inform the rationale design of trials evaluating PD-1 inhibitor combinations.
References:
1. Garon EB, et al. J Clin Oncol 2019 Jun 2 [Epub ahead of print]. 2. Sharma P, et al. Cell 2017;168(4):707-23. 3. Sade-Feldman M, et al. Nat Commun 2017;8(1):1136. 4. Zaretsky JM, et al. NEJM 2016;375:819-29. 5. Rizvi NA, et al. Science 2015;348(6230):124-128. 6. Gettinger S, et al. Cancer Discov 2017:7:1420-35. 7. Anagnostou V, et al. Cancer Discov 2017;7(3):264-76. 8. Koyama S, et al. Nat Commun 2016;7:10501.
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MS01.02 - Treatment Determining Markers - What Have We Achieved so Far? (Now Available) (ID 3440)
10:30 - 12:00 | Presenting Author(s): Naiyer A Rizvi
- Abstract
- Presentation
Abstract
Progress has been made selecting patients for immune checkpoint blockade employing expression of PD-L1 however limitations exist with this approach. Increasing use of genetic markers has been incorporated into clinical trials and clinical practice. Beyond MSI testing, tumor mutation burden has gained increasing traction and prospective trials employing TMB are under way and will be reviewed. Additional unique sensitivity and resistance mutations are emerging and may be incorporated into our genetic analysis paradigm. Additionally genetic studies are now being performed with success on plasma ctDNA and emerging ctDNA analyses will be discussed.
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MS01.03 - Overcoming Resistance - Clinical Results? (Now Available) (ID 3441)
10:30 - 12:00 | Presenting Author(s): Ross Soo
- Abstract
- Presentation
Abstract
Overcoming resistance- clinical results.
The management of oncogene negative advancednon-small cell lunghas been transformed with the use of immune checkpoint inhibitors targeting programmed death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1). However, in a significant number of patients, either primary or acquired resistance has been observed. Primary resistance, usually defined as disease progression upon the first radiologic evaluation, represents an important clinical problem and has been reported in up to 20% of patients. Acquired resistance, defined as tumors with initial response following treatment but eventually develop disease progression, has been reported in approximately 20-40% of patients.
The mechanisms of primary and acquired resistance to immunotherapy are complex and are interdependent, involving alterations in immune cells, cytokines, metabolic and oncogene signaling pathways in the tumor cell and the tumor microenvironment. The usual treatment following progression on first line immune checkpoint inhibitor with or without a platinum doublet is single agent docetaxel or a platinum doublet +/- bevacizumab.
With an improvement in the understanding of the mechanisms of resistance to immune checkpoint inhibitors, to improve patients’ outcomes following resistance, strategies have been devised to tailor subsequent therapy according to the mechanism of resistance, including the use of therapies to increase antigenicity, enhance immune cell function, and modulate the tumor microenvironment.
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MS01.04 - Smoking and Immunotherapy (Now Available) (ID 3442)
10:30 - 12:00 | Presenting Author(s): Nise Yamaguchi
- Abstract
- Presentation
Abstract
Smoking disrupts the homeostasis of the innate and the adaptive immune system. Carcinogenic and pro-inflammation compounds of tobacco leaves and other chemicals present in cigarette interfere with the regulation of immunity in two opposing ways. Some compounds trigger chronic inflammation inducing cell damage and transformation; others inhibit apoptosis, a protective strategy against transformed cell proliferation. Smoking attenuates response by dendritic cells (DC), natural killer cells (NK), macrophages against transformed cells1. Smoking affects as well the adaptive immune cells, B lymphocytes, T helper cells, CD4+ / CD25+ regulatory T cells, and CD8+ T cells.[1]
Patients with NSCLC had low levels of serum bilirubin correlated with tumor progression and poor response to platinum-based chemotherapy[2]. Studies found that high normal levels of serum bilirubin indicated favorable prognosis in NSCLC and colorectal tumor.[3], [4] Bilirubin has anti-inflammatory, anti-oxidative, and anti-proliferative effects[5] and smoking decreased bilirubin in a cohort study using metabolomics profiling.[6] Zhang et al. reported that pretreatment with bilirubin correlated with overall survival (OS) in NSCLC patients with EGFR mutations.[7]
Epithelial to mesenchymal transition (EMT) is an important process of cell-transformation that facilitates metastases and smoking induced hypoxia, inflammation, and oxidative stress, culminating in malignancy and EMT.[8],[9] The effect of smoking on EMT also occurs in other cancer histologies. A study showed that the HDAC inhibitor MS-275 restores E-cadherin expression, reversing EMT, metastases, and invasion induced by smoking.[10], [11], 8
Smoking impairs lung cancer chemotherapy, requiring increased doses for patients who smoke. The polycyclic aromatic hydrocarbons (PAH) of smoke increases the synthesis of enzymes that metabolize many antineoplastic drugs. PAH increase clearance, requiring dose adjustments to reach toxicity levels of efficacy.[12] Smokers receiving irinotecan had increased clearance and lower exposure to therapeutic metabolites; and treatments with paclitaxel, docetaxel, irinotecan, and gemcitabine showed lesser neutropenia in smokers than in nonsmokers.12 Nicotine-derived nitrosamine ketones antagonizes cisplatin and carboplatin regimens by blocking apoptosis.[13],[14],[15]
Erlotinib blocks the receptor for tyrosine-inhibiting epidermal growth activation (EGFR) and is metabolized by CYP3A4 and, by CYP1A2 and CYP1A1.[16] Smoking accelerates drug catabolism, decreasing erlotinib plasma concentrations and survival rates in NSCLC. Retrospective analysis of 88 patients NSCLC receiving erlotinib or pemetrexed showed better progression-free survival (PFS) with erlotinib in never smokers than in former smokers (3.5 versus 2.7 months, p = 0.005)[17] and smokers with squamous histology receiving erlotinib lived longer than former smokers.[18] A study on the efficacy of second-line docetaxel and erlotinib in NSCLC patients with smoking history versus never smokers shoed decreased overall survival (hazard ration [HR] 3.61 [1.77–7.4], p = 0.0005) in the erlotinib arm.[19]
Nicotine affected EGFR/AKT/ERK pathways, preventing/decreasing erlotinib action in NSCLC, promoting tumor growth in the PC9 xenograft model. [20]
[1] Qiu F. et al. (2016) Impacts of cigarette smoking on immune responsiveness: up and down or upside down? Oncotarget, 2017, Vol. 8, (No. 1), pp: 268-284.
[2] Song Y-J. et al. (2018) Direct bilirubin levels are prognostic in non-small cell lung cancer. Oncotarget, 2018, Vol. 9, (No. 1), pp: 892-900.
[3] Li N, et al. Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer. Cancer Epidemiol. 2015; 39:763–8. https://doi.org/10.1016/j.canep.2015.06.007.
[4] Zhang Q, et al. Nomograms incorporated serum direct bilirubin level for predicting prognosis in stages II and III colorectal cancer after radical resection. Oncotarget. 2017; 8:71138–46. https://doi.org/10.18632/oncotarget.11424
[5] Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis. 2000; 21:361–70.
[6] Wen CP et al. (2015) The ability of bilirubin in identifying smokers with higher risk of lung cancer: a
large cohort study in conjunction with global metabolomics profiling. Clin Cancer Res. 2015; 21:193–200. https://doi.org/10.1158/1078-0432.CCR-14-0748.
[7] Zhang Y, et al. Pretreatment direct bilirubin and total cholesterol are significant predictors of overall survival in advanced non-small-cell lung cancer patients with EGFR mutations. Int J Cancer. 2017; 140:1645–52. https://doi.org/10.1002/ijc.30581.
[8] Milara, J.; Peiró, T.; Serrano, A.; Cortijo, J. Epithelial to mesenchymal transition is increased in patients with
COPD and induced by cigarette smoke. Thorax 2013, 68, 410.
[9] Dasgupta, P.; Rizwani,W.; Pillai, S.; Kinkade, R.; Kovacs, M.; Rastogi, S.; Banerjee, S.; Carless, M.; Kim, E.;
Coppola, D.; et al. Nicotine induces cell proliferation, invasion and epithelial to mesenchymal transition in a
variety of human cancer cell lines. Int. J. Cancer 2009, 124, 36–45.
[10] Sohal, S.S.; Walters, E.H. Role of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD). Respir. Res. 2013, 14, 120.
[11] Ibidem 10.
[12] O’Malley et al. Effects of Cigarette Smoking on Metabolism and Effectiveness of Systemic Therapy for Lung Cancer. J Thorac Oncol. 2014;9: 917–926.
[13] Xu J, Huang H, Pan C, Zhang B, Liu X, Zhang L. Nicotine inhibits apoptosis induced by cisplatin in human oral cancer cells. Int J Oral Maxillofac Surg 2007;36:739–744.
[14] Zeng F, Li YC, Chen G, et al. Nicotine inhibits cisplatin-induced apoptosis in NCI-H446 cells. Med Oncol 2012;29:364–373.
[15] Zhang J, Kamdar O, Le W, et al. Nicotine induces resistance to chemotherapy by modulating mitochondrial signaling in lung cancer. Am J Respir Cell Mol Biol 2009;40:135–146.
[16] Ling J, Johnson KA, Miao Z, et al. Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug Metab Dispos 2006;34:420–426.
[17] Zugazagoitia J, Puente J, González-Larriba JL, et al. Erlotinib versus pemetrexed for pretreated non-squamous non-small cell lung cancer patients in clinical practice. Oncology 2013;84:255–264.
[18] Chiang CL, Tsai CM, Chou TY, et al. Erlotinib in patients with advanced lung squamous cell carcinoma. Cancer Chemother Pharmacol 2013;71:203–208.
[19] Krawczyk P, Kowalski DM, Wojas-Krawczyk K, et al. The qualification of docetaxel or erlotinib for second-line therapy should be based on clinical and molecular predictive factors. Chemotherapy 2012;58:60–69.
[20] Li H, Wang S, Takayama K, et al. Nicotine induces resistance to erlotinib via cross-talk between 1nAChR and EGFR in the non-small cell lung cancer xenograft model. Lung Cancer 88 (2015) 1–8.
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Author of
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EP1.03 - Biology (ID 193)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.03-33 - CD26/DPP4 as a Novel Prognostic Marker for Lung Adenocarcinoma (Now Available) (ID 1734)
08:00 - 18:00 | Author(s): Ignacio Gil-Bazo
- Abstract
Background
CD26/dipeptidyl peptidase 4 (DPP4) is a transmembrane exopeptidase expressed on various malignancies in conjunction with activity of epithelial-mesenchymal transition (EMT). We found previously that the activity of CD26/DPP4 in human lung adenocarcinoma is four times higher than in normal lung tissue and the inhibition of CD26/DPP4 decreased the growth of lung tumors in experimental models. These data prompted us to analyze the expression of CD26/DPP4 and EMT markers in samples from non-small cell lung cancer patients to unravel a function of CD26/DPP4 as a prognostic marker and potential therapeutic target for lung cancer.
Method
We employed multi-organ tissue micro array (TMA) of non-small cell lung cancer patient samples from two institutions, University Hospital Zurich and Dongsan Medical Center. To identify CD26/DPP4 and EMT markers (Ecadherin, Vimentin, beta-Catenin, Elastin, Periostin, and Versican), immunohistochemistry (IHC) on TMA was performed. Three pathologists scored the intensity IHC from zero to six in a blinded manner. The cohort consisted of 1126 patients (adenocarcinoma: 593; squamous carcinoma: 443; others (large cell carcinoma, adeno-squamous carcinoma): 90). The overall survival rate of patients was considered as a measure of prognosis. To identify a correlation between CD26/DPP4 and EMT related protein expression in lung cancer the Pearson correlation coefficient test was applied.
Result
CD26/DPP4 IHC scores revealed that adenocarcinoma expresses significantly higher amount of the protein compared to normal lung or squamous carcinoma or others (p=0.035, p<0.0001, p<0.0001 respectively). In adenocarcinoma, patients with high CD26/DPP4 score (4-6) showed the worst overall survival compared to patients scoring low (1-3) or zero. The correlation analysis of CD26/DPP4 with EMT markers in adenocarcinoma showed that the epithelial marker Ecadherin was negatively correlated (p=0.001), while mesenchymal proteins Vimentin, beta-Catenin, Elastin were positively correlated with CD26/DPP4 (p=0.03, 0.01, and 0.001 respectively). Periostin and Versican showed no correlation with CD26/DPP4 expression.
Conclusion
The expression of CD26/DPP4 was significantly higher in adenocarcinoma among non-small cell lung cancers and associated with worse survival of patients. Furthermore, the expression of CD26/DPP4 was significantly correlated with the EMT status. We therefore deem CD26/DPP4 to be a novel prognostic marker for lung adenocarcinoma. In consideration with CD26/DPP4 expression of these cancer samples, inhibition of CD26/DPP4 can potentially improve lung cancer patients’ survival.
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MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
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MA17.11 - High Sensitivity to PD-1 Blockade Therapy After Ld1 Depletion in KRAS-Driven Lung Cancer Through CD8+/CD3+ Tumor Infiltration and PD-L1 Induction (Now Available) (ID 2562)
15:45 - 17:15 | Author(s): Ignacio Gil-Bazo
- Abstract
- Presentation
Background
PD-1/PDL-1 inhibitors are approved for non-small cell lung cancer (NSCLC). However, many patients do not benefit and therapeutic combinations are under investigation. We have previously described Id1, involved in proliferation, angiogenesis and immunosuppression, as a prognostic factor in lung adenocarcinoma (LUAD) (Ponz-Sarvise, Clin Cancer Res 2011), Id1’s role in lung cancer metastasis (Castanon, Cancer Letters 2017) and more recently shown that Id1 sustains mutant KRAS-driven progression and metastasis in NSCLC (Roman, Cancer Res 2019).
In a previous syngeneic murine lung cancer model with depleted levels of Id1 using Id1-/- and Id1 wildtype C57BL/6 mice inoculated with Lewis Lung Carcinoma (LLC), we tested a combined therapeutic strategy targeting PD-1 and Id1, showing impaired tumor growth and increased survival (Gil-Bazo, presented at WCLC 2018).
Here we study a combined strategy targeting PD-1 and Id1 in a KRAS-mutant murine LUAD model and the immune-related mechanisms involved.
Method
First, a correlation between Id1 and PD-L1 mRNA expression was studied in mutant and wild-type KRAS LUAD cohorts from The Cancer Genome Atlas data set (TCGA).
Secondly, a syngeneic tumor model using Balb/c mice through subcutaneous injection of KRAS-mutant LUAD (Lacun3) cells and Id1-silenced Lacun3 (Id1sh) cells. In vitro, proliferation was measured in both cell lines through MTS assays. IFNg-induced PD-L1 expression in both cell lines and flow cytometry was used to evaluate its mechanistic effects on the immune response.
After tumor cells injection, mice were treated with an anti-PD-1 (RMP-1-14) monoclonal antibody or PBS, i.p. Tumor volumes according to Id1 status in tumor cells and the treatment administered were quantified. Vectra 3.0™ multispectral microscopy was used to characterize the tumor associated immune cells in paraffin-embedded tissues from our previous syngeneic murine lung cancer model using Id1-/- and Id1 wildtype C57BL/6 mice inoculated with LLC in which the combined blockade had been reported as effective. Immune marker antibodies were used to study expression of CD3, CD4 and CD8.
Result
An inverse, moderate and statistically significant correlation between Id1 and PD-L1 expression in mutant and wild-type KRAS LUAD cohorts from TCGA was found in both cohorts (-0.367 and -0.351, respectively, p<0.001), indicating that Id1 depletion may lead to PD-L1 expression induction.
In vitro assays showed that Id1 silencing reduced Lacun3 cells proliferation (p<0.001). Up-regulation of surface PD-L1 expression occurred in Id1sh cells, but not in Lacun3 cells, after receiving IFNg (p=0.0022). Mechanistically, in the syngeneic murine model, Id1 inhibition in the injected cells, combined with anti-PD-1 treatment, significantly induced a tumor growth impairment (p<0.001). An intense CD8+ and CD3+ immune cell infiltration was observed in LLC Id1-/- C57BL/6 mice treated with anti-PD1 (p<0.05 for CD3+ TILS), compared the control groups, possibly explaining the dramatic tumor growth impairment previously shown on the treated animals.
Conclusion
Id1 silencing may induce PD-L1 overexpression according to in silico and in vitro results. Id1 and PD-1 combined blockade in our KRAS-mutant syngeneic murine LUAD model significantly impaired tumor growth, compared to each strategy alone. A significantly increased CD3+ and CD8+ tumor infiltration and IFNg-induced PD-L1 tumor expression after the combined blockade may explain these findings.
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YI04 - Basics of Immunology (ID 110)
- Event: WCLC 2019
- Type: Young Investigator Session
- Track: Young Investigators
- Presentations: 1
- Now Available
- Moderators:Noemi Reguart, Julie R Brahmer
- Coordinates: 9/08/2019, 13:30 - 15:00, Dublin (1997)
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YI04.01 - PD-L1: Basics of Biology (Now Available) (ID 3708)
13:30 - 15:00 | Presenting Author(s): Ignacio Gil-Bazo
- Abstract
- Presentation
Abstract not provided
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