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Kenichi Suda
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MA11 - Biomarkers of IO Response (ID 912)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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MA11.05 - Indoleamine 2,3-Dioxygenase Expression in Non-Small-Cell Lung Cancer: Analyses of Prevalence, Clinical Correlations and Prognostic Impact (ID 13309)
11:00 - 11:05 | Author(s): Kenichi Suda
- Abstract
- Presentation
Background
Indoleamine 2,3-dioxygenase-1 (IDO-1) is a cytosolic enzyme involved in the catabolism of tryptophan; IDO-1-related immune suppression is due to decreased tryptophan availability and to the generation of tryptophan metabolites, culminating in substantial suppression of T-lymphocytes. Here we investigate IDO-1 expression in a cohort of non-small-cell lung cancer (NSCLC) specimens, both in tumor cells and in immune infiltrate, with correlation of IDO-1 to PD-L1 expression, clinical patient demographics and outcomes.
a9ded1e5ce5d75814730bb4caaf49419 Method
A cohort of 1.200 NSCLC samples were obtained from 437 patients who underwent surgical lung resections at Austin Health, Melbourne, Australia. IDO-1 expression was evaluated by immunohistochemistry. Correlations were assessed using Spearman and Kendall tests. A Cox proportional hazards (PH) model was used to assess if overall survival (OS) was associated with IDO-1 positivity in univariate and multivariable settings.
4c3880bb027f159e801041b1021e88e8 Result
Samples from 437 patients were analyzed for IDO-1 expression, with 111 (25.4%) determined as positive (H-Score ≥ 1) and 326 patients (74.6%) as negative (H-Score: 0). IDO-1 expression was determined to be greater in tumor immune infiltrate, with 406 patients (93.8%) determined as positive, while just 27 (6.2%) were IDO-1 negative. There was a significant positive correlation between IDO-1 positive tumor cells and immune cells (0.2167, p < 0.001). Both continuous and binary versions of tumor H-Score showed a significant positive correlation with the amount of tumor immune infiltrate (0.1806 and 0.1698, p < 0.0001, respectively). None of the analyzed variables (age, sex, histology, stage, EGFR, KRAS and PD-L1 status) were found to display a significant correlation with IDO-1 positivity in tumor and immune cells. IDO-1 positivity in tumor cells was found to be significantly associated with OS in the univariate setting and in the multivariable model where variables age, sex, histology, stage, EGFR, KRAS and PD-L1 status were included [P-value = 0.009 and 0.021, respectively; HR: 0.72 (95% CI: 0.55-0.95)]. IDO-1 positivity in immune cells was found to be significantly associated with OS in the univariate setting and was borderline significant in the multivariable model [P-value = 0.006 and 0.053, respectively; HR: 0.798 (95% CI: 0.635-1.003)].
8eea62084ca7e541d918e823422bd82e Conclusion
To our knowledge, this is the most extensive analysis of IDO-1 expression in NSCLC patients reported in the literature. Our results suggest the possible prognostic role of IDO-1 expression in tumor and immune cells, highlighting the relevance of IDO-1 detection in tumor tissue. Since new compounds targeting IDO-1 are actually under investigation, the identification of potential prognostic and predictive biomarkers will be needed.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-41 - In Vitro Evaluation for Optimal MET-TKI Selection in Lung Cancers with MET Mutations Including Exon 14 Skipping (ID 12825)
16:45 - 18:00 | Author(s): Kenichi Suda
- Abstract
Background
MET exon 14 skipping mutation present in 3-5% of adenocarcinoma of the lung is an emerging driver gene alteration. Clinical responses of these tumors to MET-TKI have been reported. However, response rates are not very satisfactory compared with EGFR/ALK/ROS1 TKI. Therefore, it is necessary to create in vitro model system to understand sensitivity/resistance mechanism for various types of MET-TKI, to establish optimal treatment strategy.
a9ded1e5ce5d75814730bb4caaf49419 Method
We introduced MET exon 14 skipping mutation as well as Y1003F, D1010Y which had been also reported to be present in lung cancer, to mouse pro-B cell line, Ba/F3. Since Ba/F3 requires interleukin 3 (IL-3) for its growth, IL-3 independent growth of Ba/F3 indicates that transduced mutation is oncogenic. The growth inhibitory assays were then performed using 9 MET-TKIs that include all classes of MET-TKIs ; Type Ia (crizotinib), Type Ib (capmatinib, tepotinib, savolitinib and AMG337) , Type II (cabozantinib, merestinib and glesatinib) and Type III (tivantinib).
4c3880bb027f159e801041b1021e88e8 Result
Ba/F3 transfected with wild-type MET did not grow in the absence of IL-3, while all transfected with any of three mutated MET did so. In general, all type Ia/b / type II inhibitors were active for any of 3 MET mutations. Interestingly MET point mutations (Y1003F/D1010Y) were more sensitive to type Ib inhibitors except AMG337 than type II, while exon 14 skipping was likely to be more sensitive to type II inhibitors than type Ib compared with point mutations. IC50 / Cmax of cabozontinib was least for exon 14 skipping while that of capmatinib was least for Y1003F and D1010Y, suggesting most promising activity of these drugs (Table).
8eea62084ca7e541d918e823422bd82e Conclusion
We found that the MET exon 14 skipping, Y1003F, and D1010Y mutations were all oncogenic in Ba/F3 system. Several type I/II inhibitors especially cabozantinib and capmatinib are expected to be active for treating lung cancer patients with MET mutations.
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P1.13-42 - Activity of Novel HER2 Inhibitor, Poziotinib, for HER2 Exon 20 Mutations in Lung Cancer and Mechanism of Acquired Resistance (ID 12717)
16:45 - 18:00 | Author(s): Kenichi Suda
- Abstract
Background
Oncogenic HER2 mutations are present in 2-4% of adenocarcinoma of the lung. However, clinical trials of HER2 inhibitors such as afatinib or neratinib has been unsatisfactory. Recently, a novel HER2 inhibitor, poziotinib has been developed and clinical trial results are being expected. Here, we evaluated poziotinib in comparison with pre-existing TKIs using Ba/F3 system. We also derived resistant clones against poziotinib and investigated their resistant mechanism.
a9ded1e5ce5d75814730bb4caaf49419 Method
We introduced three common HER2 mutations into Ba/F3 cells (i.e. G776delinsVC (VC), A775_G776insYVMA (YVMA) and P780_Y781insGSP (GSP)) which account for 13, 72, 9% of HER2 mutations in human lung cancer, respectively. We defined sensitivity index (SI) as an IC90divided by trough concentration of a given drug at the recommended dose for humans in the literature, as a surrogate for drug activity in humans. Poziotinib activity was compared with 8 TKIs (afatinib, osimertinib, erlotinib, neratinib, lapatinib, dacomitinib, irbinitinib, and AZ5104). In addition, we created resistant clones by exposing poziotinib in the presence of N-ethyl-N-nitrosourea (ENU) and HER2 secondary mutations were searched.
4c3880bb027f159e801041b1021e88e8 Result
All drugs but lapatinib showed the highest activity against VC (Table). In contrast, YVMA was most resistant in all but neratinib and poziotinib. For most common YVMA, poziotinib was the only drug that had SI of less than 10 (Table). Furthermore, poziotinib was most potent for VC and GSP except dacomitinib for GSP (Table). We established 19 poziotinib-resistant clones, all of which harbored C805S secondary mutation of the HER2 gene homologous to C797S of the EGFR gene.
Ctrough [nM] YVMA VC GSP Afatinib 69 28 5.4 12 Dacomitinib 166 20 4.4 6.6 Erlotinib 2969 337 22 98 Osimertinib 400 40 4.5 30 Neratinib 100 11 11 28 Lapatinib 516 133 117 91 Poziotinib 20 6.0 2.7 10 Irbinitinib 520 34 33 16 AZ5104 50 60 8.0 48
8eea62084ca7e541d918e823422bd82e Conclusion
Poziotinib showed the most potent activity against HER2 exon 20 mutations. We also found that secondary C805S HER2 mutation was the common mechanism of acquired resistance, which most likely inhibit covalent binding of poziotinib with HER2.
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P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.04-13 - The Immune Checkpoint, HVEM Contribute to Immune Escape in Non Small Cell Lung Cancer of Lacking PDL1 Expression (ID 13116)
16:45 - 18:00 | Author(s): Kenichi Suda
- Abstract
Background
Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
A TMA of 527 resected NSCLC samples and 53 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems（AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 22C3 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used.
4c3880bb027f159e801041b1021e88e8 Result
HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was18.6%(77/415) and 45.3%(24/53) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, P=0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, P=0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p=0.706) and PD-L1 expression (median 45 vs 48 months, p=0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.232, p=0.002, Figure 1A) in patients with NSCLC and also have a negative correlation in NSCLC cell lines(r=-0.055, p=0.764,Figure 1B).
8eea62084ca7e541d918e823422bd82e Conclusion
HVEM was found to be overexpressed in patients of NSCLC with advanced disease or lymph node metastasis and has a negative co-relationship with PD-L1 expression, while, it did not have a prognostic role in patients with NSCLC.
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P2.04-15 - Heterogeneity and Correlation Between Immune Markers in Lung Cancers: Analysis of Treatment-Naïve Lesions (ID 11288)
16:45 - 18:00 | Presenting Author(s): Kenichi Suda
- Abstract
Background
Immunotherapies are becoming a new standard of care for patients with lung cancers. Although a few immune-checkpoints are currently used as therapeutic targets and/or as predictive biomarkers, the complex correlation between immune-checkpoints is not well understood. Expression level of immune-checkpoint molecules is affected by numerous factors including tumor cells themselves, patients’ immunological characteristics, tumor microenvironment (metastatic sites), and previous treatments. To effectively investigate correlations of immune-checkpoints across multiple lesions, we analyzed gene expression data obtained from treatment-naïve autopsied patients.
a9ded1e5ce5d75814730bb4caaf49419 Method
Our cohort of 5 lung cancer patients included thirty specimens of both primary and metastatic lesions. RNA sequencing reads were mapped to the hg19 reference genome using the TopHat/Cufflinks workflow and transcripts were quantified using the FPKM method. Expression data for immune-checkpoints and total numbers of detected mutations were compared.
4c3880bb027f159e801041b1021e88e8 Result
We observed substantial inter-tumor heterogeneity in immune-checkpoint expression between lesions obtained from each patient. No consistent correlation was found by comparison of primary vs. metastatic lesions or between primary vs. specific metastatic sites. Evaluation of immune-checkpoints expressed by tumor cells and/or antigen presenting cells revealed a positive correlation between GAL9 and PD-L2 (R = 0.79) and GAL9 and HVEM (R = 0.69; Figure 1A). We also observed a strong correlation between these markers when lesions obtained from each patient were correlated to each other (Figure 1B and C). Comparisons between immune-checkpoints expressed by immune cells identified a positive correlation between PD-1 and LAG3 (R = 0.77). No correlation was found between immune-checkpoint expression and mutation burden.
8eea62084ca7e541d918e823422bd82e Conclusion
We observed substantial inter-tumor heterogeneity in immune-checkpoints expression in each patient. We also found several positive correlations between immune-checkpoints which were consistent within the small cohort of patients. Further functional evaluation is warranted.
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