Virtual Library

Start Your Search

B. Han

Moderator of

  • +

    MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • +

      MA04.01 - Non-Amplification Mutation of ERBB2 in EGFR-Mutated Lung Cancer (ID 6138)

      16:00 - 17:30  |  Author(s): K. Gowen, B. Halmos, R. Hoyer, W. Jeong, J. Suh, J. Elvin, J. Vergilio, S. Ramkissoon, S. Ali, A.B. Schrock, J. Sun, V. Miller, P.J. Stephens, J. Ross, L. Gay

      • Abstract
      • Presentation
      • Slides

      Background:
      Amplification of ERBB2 in EGFR-mutant lung cancers is a reported mechanism of acquired resistance to tyrosine kinase inhibitor (TKI) therapy. Comprehensive genomic profiling (CGP) of NSCLC tumors shows mutation of ERBB2, most often affecting the encoded HER2 receptor at residue S310, is also prevalent, particularly in the context of EGFR L858R.

      Methods:
      CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,887 consecutive cases of lung cancer. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes. Short variants (SV) include base substitutions or indels.

      Results:
      A total of 2,516 (16.9%) samples featured EGFR alterations, including amplification (amp) and SV. Of these, 2.9% (73/2,516) harbored alterations in ERBB2 (amp and/or SV). 18 samples (0.7%) harbored SV alterations in ERBB2, 14 of which were mutations at S310. ERBB2 S310 mutations were most often found with EGFR L858R. The ratio of observed to expected mutation at HER2 S310 in EGFR-mutated lung cancers was 2.12, and the ratio for HER2 S310 in combination with EGFR L858R was 5.03. The co-occurrence of HER2 S310 and EGFR L858R was highly significant (p<0.00005). The combination of EGFR and ERBB2 alterations was more common in women. The ratio of male:female patients with any lung cancer in this dataset was 1:1.1, whereas the ratio of male:female with any EGFR alteration was 1:1.7 and for both EGFR and ERBB2 alterations (amp or SV) was 1:3.4. Patients with a combination of EGFR and ERBB2 alterations have been shown to respond to treatment with the pan-ERBB inhibitor afatinib, or combinations of afatinib with the HER2-targeted therapy trastuzumab.

      Conclusion:
      Short variant alterations in ERBB2 may be an additional mechanism for tumors to acquire resistance to treatment with EGFR-targeted TKIs. Mutations at residue S310, in the extracellular domain of HER2, are the most common ERBB2 SV observed in EGFR-mutant lung cancer, and are significantly associated with EGFR L858R. The co-occurence of alterations in ERBB2 and EGFR is far more common in women than in men. Treatment with the pan-ERBB inhibitor afatinib, alone or in combination with agents targeting HER2, has been shown to benefit patients with lung cancer harboring mutations in both EGFR and ERBB2.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.02 - Neratinib ± Temsirolimus in HER2-Mutant Lung Cancers: An International, Randomized Phase II Study (ID 4302)

      16:00 - 17:30  |  Author(s): L. Gandhi, B. Besse, J. Mazieres, S. Waqar, A.B. Cortot, F. Barlesi, E. Quoix, G. Otterson, D. Ettinger, L. Horn, D. Moro-Sibilot, M.A. Socinski, K. Gold, J. Gray, A. Oton, R. Suk Heist, D. Costa, L. McCulloch, J. Bebchuk, R. Bryce, M.G. Kris

      • Abstract
      • Presentation
      • Slides

      Background:
      Combined inhibition of HER2 and mTOR is synergistic in models of HER2 (or ERBB2)-mutant lung cancers. PUMA-NER-4201 is an adaptive, multinational, randomized phase II study comparing the pan-HER inhibitor neratinib (Puma Biotechnology) ± the mTOR inhibitor temsirolimus in patients with advanced HER2-mutant lung cancers. In stage 1 of the study, neratinib + temsirolimus met predefined criteria for expansion into stage 2 [Besse et al. ESMO 2014].

      Methods:
      Patients with stage IIIB/IV locally determined HER2-mutant cancers were randomized to receive oral neratinib 240 mg once daily ± intravenous temsirolimus 8 mg once weekly (escalated to 15 mg/week after a 3-week cycle if tolerated) with loperamide prophylaxis. Primary endpoint: overall response rate (RECIST v1.1). Secondary endpoints: duration of response, progression‑free survival, overall survival, toxicity assessments (NCI-CTCAE, v4.0). ClinicalTrials.gov: NCT01827267.

      Results:
      Of 62 randomized patients, 60 received ≥1 dose of neratinib: neratinib alone (n=17); neratinib + temsirolimus (n=43). Baseline characteristics: male/female 32%/68%; median age 66 years; never smokers 60%; adenocarcinoma 98%. HER2 (or ERBB2) mutation type: exon 20 insertions 93.5%; missense substitutions 3.2%; unspecified 3.2%. The most common HER2 allelic variant was A775_G776insYVMA. Exploratory biomarker analysis from available tumor and plasma samples will be presented at the meeting. Efficacy and safety results are shown in the table. With loperamide prophylaxis, the incidence of grade 3 diarrhea was 12% with neratinib and 14% with neratinib + temsirolimus, which lasted for a median duration of 1.5 (interquartile range, 1.0‒2.0) days and 4.0 (interquartile range, 2.0‒16.0) days, respectively. Figure 1



      Conclusion:
      Neratinib (240 mg/day) + temsirolimus (8 or 15 mg/week) produced responses lasting 2 to 18+ months in 19% of patients with HER2‑mutant lung cancers. Correlative data will be presented at the meeting. Diarrhea was manageable with loperamide prophylaxis.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.03 - Preliminary Results of a Phase II Study about the Efficacy and Safety of Pyrotinib in Patients with HER2 Mutant Advanced NSCLC (ID 6069)

      16:00 - 17:30  |  Author(s): S. Ren, C. Zhou, G. Gao, C. Su, X. Chen, F.Y. Wu, X. Li, C. Zhao, W. Cai

      • Abstract
      • Presentation
      • Slides

      Background:
      There is still an unmet need for targeted drugs in non small cell lung cancer (NSCLC) patients with HER2 mutation. Pyrotinib is an oral tyrosine kinase inhibitor targeting both HER-1 and HER-2 receptors. This phase II trial is designed to evaluate the safety and efficacy of pyrotinib in patients with HER2 mutant advanced NSCLC.

      Methods:
      A single arm prospective phase II trial was undergone to evaluate the efficacy and safety of Pyrotinib in patients with HER2 mutant advanced NSCLC in a single center of Shanghai Pulmonary Hospital, Tongji University(NCT 02535507). Pyrotinib was administrated 320mg or 400mg orally once a day. Next generation sequencing or ARMS was used to identify the patients with HER2 mutation. The primary endpoint was objective response rate and the secondary endpoints were side effect, progression free survival and overall survival.

      Results:
      From Jul 15 2015 to Jul 21, 2016, 11 patients with her2 mutated advanced NSCLC were enrolled into this study. Among them, the median age was 58 years old, 6 were male, 4 were smoker, ECOG PS 0/1/2 were 5/6 and all of them were adenocarcinoma. None of them received pyrotinib as the first line therapy and the median previous anti-cancer regimen was 2. 9 patients had the details variants of HER2 mutation including 7 with exon 20 776YVMA, 1 with exon 20 770AYVM and 1 with 2326G>ATTT. All of them evaluated the response, including 54.5% with partial response(6/11), 27.3% with stable disease(3/11) and 18.2% with progressive disease(2/11). 1 patient got response to pyrotinib after progressed from afatinib. 5 patients were still on the study and the median PFS was 6.2 months. Side effects were mild including 4 with grade I/II diarrhea, 2 with grade II fatigue, 2 with grade I rash and 1 with dispnea.

      Conclusion:
      Pyrotinib showed promising results about the ORR and PFS together with mild toxicity in patients with HER2 mutant advanced NSCLC, further multicenter large scale phase II study is initiated to validate the results in this study.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.04 - Discussant for MA04.01, MA04.02, MA04.03 (ID 7050)

      16:00 - 17:30  |  Author(s): T. Reungwetwattana

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.05 - P53 Non-Disruptive Mutation is a Negative Predictive Factor for OS and PFS in EGFR M+ NSCLC Treated with TKI (ID 5879)

      16:00 - 17:30  |  Author(s): J. Roeper, M. Netchaeva, A.C. Lueers, P. Regina, D. Sriba, K. Willborn, U. Stropiep, C. Hallas, M. Tiemann, N. Neemann, L.C. Heukamp, F. Griesinger, M. Falk

      • Abstract
      • Presentation
      • Slides

      Background:
      P53 mutations are common in lung cancer, and have also been described in EGFR mutated patients The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.

      Methods:
      484 patients diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing, hybrid cage next generation sequencing. P53 mutations were detected by Sanger Sequencing and either Miseq or hybrid cage NGS. Clinical characteristics including smoking status were available for more than 97%.

      Results:
      484 consecutive patients were studied. The overall EGFR M+ rate was 17.8% (86/484) in all patients, 84.9% (73/86) showing common mutations of exon 19 or 21. In 21/86 (24.4%) patients’ p53 analysis was not successful. P53 disruptive mutations were demonstrated in 24.6% (16/65) of successfully tested patients, and p53 non-disruptive mutation occurred in 27.7% (18/65) whereas p53 WT configuration was found in 47.7% (31/65). Median OS was 28 months in p53 disruptive mutation and 44 month in p53 WT compared to 23 months in p53 non-disruptive mutation (p<0.023). PFS on 1[st] line TKI therapy was 14 months in p53 disruptive mutation, 27 months in p53 WT and 10 months in p53 non-disruptive mutation (p<0.040). Similar results were shown in the EGFR common mutation subgroup. 11/16 (68.8%) patients with a disruptive p53 M+ and 25/29 (86.2%) patients with a p53 WT constellation achieved an objective response on the 1[st] line TKI therapy compared to 7/13 (53.8%) patients with a non-disruptive p53 status. The patients with an unknown p53 status achieved an objective response on the 1[st] line TKI therapy of 82.4.8% (14/17).

      Conclusion:
      Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 M+ status. P53 mutational status is predictive when disruptive and non-disruptive p53 M+ are differentiated. A p53 WT constellation has a positive effect on OS and PFS. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.06 - Signaling Networks in KRAS-Mutant Advanced NSCLC: A Complex Landscape Involving Immunoresponse, Inflammation and DNA Repair (ID 5768)

      16:00 - 17:30  |  Author(s): S. Baglivo, E. Baldelli, L. Crinò, V. Ludovini, R. Chiari, G. Metro, C. Bennati, A. Hodge, A. Siggillino, F.R. Tofanetti, T. Dong, L. Pistola, F. Bianconi, A. Sidoni, V. Minotti, E.F. Petricoin, M. Pierobon

      • Abstract
      • Presentation
      • Slides

      Background:
      KRAS is the most frequently mutated oncogene in Non-Small Cell Lung Cancer (NSCLC) and its role as prognostic and predictive biomarker remains widely debated. Unfortunately, KRAS direct targeting strategies have been unsuccessful and no approved target therapy exists for KRAS-mutant-NSCLC. This pilot study evaluated the activated signaling architecture of advanced NSCLC harbouring a KRAS mutation to better characterize the signaling network driving this subgroup of pulmonary malignancies.

      Methods:
      Twenty Stage IV Formalin-fixed, paraffin-embedded (FFPE) NSCLCs were collected from chemo-naïve patients at S. Maria della Misericordia Hospital (Perugia, Italy). Ten tumors were KRAS-wild-type (KRAS-WT) and ten were KRAS-Mutant (KRAS-MUT). Whole-tissue lysates were obtained for all samples. Signaling network analysis was performed using the Reverse Phase Protein Array (RPPA) platform to quantitatively evaluate the expression/activation of 148 key proteins and phosphoproteins involved in cellular growth, survival, proliferation, apoptosis, autophagy, inflammation, invasion and cell motility. Wilcoxon Rank-Sum Test was used to compare the signaling architecture of KRAS-MUT and KRAS-WT tumours. All p-values <0.05 were considered significant. Non-parametric correlation analysis was performed to explore the signaling interconnection within each group of patients. Only correlations with p<0.0001 were considered significant.

      Results:
      This preliminary analysis revealed a statistically significant different activation level of 20 proteins between the KRAS-MUT and KRAS-WT samples. Five of the proteins that were statistically different in the KRAS-MUT group are involved in the inflammatory immunoresponse (ASK1 S83 p<0.01, Axl Y702 p=0.01, Stat2 Y690 p<0.01, Tyk2 Y1054/Y1055 p=0.01 and Twist p<0.01) and six in cell cycle control and DNA repair (ATM S1981 p=0.01; Bcl-xL p=0.03; Cleaved Caspase 3 D175 p=0.02; Histone H3 S10 p<0.01; p53 S15 p<0.01; p27 T187 p=0.04). The analytes that were statistically significant were all lower in the KRAS-MUT group compared to the WT (except for p27 T187 which decreased in the KRAS-MUT group compared to KRAS-WT). Pair-wise correlation analysis of the signaling proteins showed an overall more complex protein-protein interaction network and pathway activation (included AKT/mTOR signaling pathway) in the KRAS-MUT population with high number of statistically significant correlations compared to the KRAS-WT group.

      Conclusion:
      This pilot study indicated that the effect of KRAS mutation status on protein signaling in NSCLC was an alteration of the immunoresponse axis and DNA repair network. If validated in a larger cohort of patients, these results could have important clinical implications for stratification KRAS-MUT advanced NSCLC patients towards more efficacious targeted treatment and to identify new therapeutic targets based on multi-targets/multi-pathways KRAS inhibitory approach. (AIRC-supported study).

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.07 - Impact of Major Co-Mutations on the Immune Contexture and Response of KRAS-Mutant Lung Adenocarcinoma to Immunotherapy (ID 6343)

      16:00 - 17:30  |  Author(s): F. Skoulidis, Y.Y. Elamin, V. Papadimitrakopoulou, P. Tong, J. Wang, J. Lewis, W. Rinsurongkawong, C.T. Chu, E. Roarty, J. Zhang, H.T. Tran, J. Rodriguez-Canales, E.R. Parra, C. Behrens, H. Kadara, I. Wistuba, J. Heymach

      • Abstract
      • Presentation
      • Slides

      Background:
      Activating mutations in the KRAS proto-oncogene define a prevalent and clinically heterogeneous molecular subset of lung adenocarcinoma (LUAC). We previously identified three major subgroups of KRAS-mutant LUAC on the basis of co-occurring genetic events in TP53 (KP), STK11/LKB1 (KL) and CDKN2A/B (KC) and reported that LKB1-deficient tumors exhibit a “cold” tumor immune microenvironment, with reduced expression of several immune checkpoint effector/mediator molecules, including PD-L1 (CD274). Here, we extend these findings and examine the clinical outcome of co-mutation defined KRAS subgroups to therapy with immune checkpoint inhibitors.

      Methods:
      We conducted a single-institution analysis of clinical and molecular data (PCR-based next generation sequencing of panels of 50, 134 or 409 genes) prospectively collected from patients enrolled into the MD Anderson Lung Cancer Moon Shot GEMINI database. KRAS-mutant LUAC were separated into KP, KL and K (wild-type for TP53 and STK11) groups. The log- rank test and Fisher’s exact test were used for comparison of progression-free survival (PFS) and objective response rate (ORR) respectively between the groups. In addition, automated IF-based enumeration of lymphocyte subsets was performed in 40 surgically resected LUAC (PROSPECT cohort) with available whole exome sequencing data.

      Results:
      Among 229 patients with KRAS-mutant LUAC who consented to the protocol we identified 35 patients with metastatic disease (17 KP, 6 KL, 12 K) that received immunotherapy with nivolumab (N=29), pembrolizumab (N=3), nivolumab/urelumab (N=1) and durvalumab/tremelimumab (N=2) and had robust clinical outcome data. There was no impact of different KRAS alleles (G12C/G12V/G12D) on PFS (P=0.6149, log-rank test) or ORR to immune checkpoint inhibitors (P=0.88, Fisher’s exact test, 2x3 contingency table). In contrast, co-mutation defined KRAS subgroups exhibited significantly different median PFS to immunotherapy (KP: 18 weeks, KL: 6 weeks, K: 16 weeks, P=0.0014, log-rank test). Objective responses were observed in 9/17 (52.9%) KP and 3/12 (25%) K tumors compared to 0/6 (0%) KL tumors (P=0.049, Fisher’s exact test, 2x3 contingency table). In the PROSPECT cohort of surgically resected LUACs with available whole exome sequencing data, somatic mutation in STK11 was associated with reduced intra-tumoral densities of CD3+ (P=0.0016), CD8+ (P=0.0125) and CD4+ (P=0.0036) lymphocytes.

      Conclusion:
      Mutations in STK11/LKB1 are associated with an inert tumor immune microenvironment and poor clinical response of KRAS-mutant LUAC to immune checkpoint blockade. The mechanism that underlies this phenotype and strategies to overcome it are under investigation. The impact of additional co-mutations on the immune profile and response of KRAS-mutant LUAC to immunotherapy is also being explored.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.08 - Discussant for MA04.05, MA04.06, MA04.07 (ID 7078)

      16:00 - 17:30  |  Author(s): J. Molina

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.09 - RICTOR Amplification in Non-Small Cell Lung Cancer: An Emerging Therapy Target (ID 6177)

      16:00 - 17:30  |  Author(s): J. Ross, H. Cheng, R. Perez-Soler, J. Suh, D. Pavlick, S. Ali, A.B. Schrock, J. Elvin, J. Vergilio, S. Ramkissoon, D. Fabrizio, V.A. Miller, P.J. Stephens, L. Gay

      • Abstract
      • Presentation
      • Slides

      Background:
      Comprehensive genomic profiling (CGP) can discover novel therapy targets in NSCLC. Amplification of RICTOR, encoding a component of the MTORC2 complex, has recently been identified as a targetable alteration leading to clinical benefit.

      Methods:
      CGP was performed on hybridization-captured, adaptor ligation-based libraries for up to 315 cancer-related genes plus select introns from 28 genes frequently rearranged in cancer on 14,698 consecutive cases of NSCLC, comprising lung adenocarcinoma, squamous cell carcinoma (SCC) or NSCLC not otherwise specified (NOS). Tumor mutational burden (TMB) was determined on 1.1 Mb of sequenced DNA. All classes of genomic alterations (GA) were assessed simultaneously, including base substitutions, indels, rearrangements/fusions, and copy number changes.

      Results:
      747 (5.0%) NSCLC featured RICTOR amplification (amp). There were 380 (51%) male and 367 (49%) female patients with a mean age of 64.1 years (range 18-88 years). The primary tumor was analyzed in 333 (45%) cases and a metastasis biopsy in 414 (55%) cases. Genes most frequently co-altered with RICTOR amp included TP53 (79.5%) and FGF10 (64.6%), which is located close to RICTOR on chromosome 5 and is frequently co-amplified. Several known oncogenes in NSCLC were mutated at significantly higher rates in tumors with RICTOR amp, including EGFR (22%), MET (8.4%), ERBB2 (7%), as well as FGFR1 (5%), FGFR3 (1.4%), and FGFR4 (1.6%). 42.2% of tumors with RICTOR amp did not harbor additional alterations in KRAS or genes indicated in the NCCN guidelines. KRAS GA were identified in 19.6% of RICTOR amp tumors, compared with 29.8% of all NSCLC, but this difference was not statistically significant. Mean TMB in RICTOR amp tumors was intermediate (14.9 mut/Mb), and is higher than the overall average for NSCLC (9.2 mut/Mb). The number of RICTOR-amplified tumors with high TMB (>20 mut/Mb) was 23%, higher than the rate for non-RICTOR amp NSCLC (12.9%). Examples of patients with RICTOR amplification within late stage NSCLC responding to MTOR inhibitors will be presented.

      Conclusion:
      RICTOR amplification, when compared to other non-EGFR known drivers of NSCLC, is a relatively frequent clinically relevant GA that has been shown to respond to MTOR inhibitors. The co-occurrence of RICTOR amplification with mutation of known oncogenic drivers suggests a possible mechanism of acquired resistance to therapy that should be explored further. Tumors with RICTOR amp more often have higher levels of TMB than other NSCLC. Further study of RICTOR amp as a therapy target NSCLC in a clinical trial setting appears warranted.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.10 - Lung Cancer Growth is Suppressed by CD26/DPP4-Inhibition via Enhanced NK Cell and Macrophage Recruitment (ID 6143)

      16:00 - 17:30  |  Author(s): J. Jang, F. Janker, S. Arni, Y. Yamada, W. Weder, W. Jungraithmayr

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of death among cancers. There is broad evidence that immune cells are involved in the growth and development of these malignancies. CD26/DPP4 (dipeptidyl peptidase 4) is a transmembrane glycoprotein, that is constitutively expressed on hematopoetic cells, but also found on lung epithelial and endothelial cells. We found previously that the activity of CD26/DPP4 of lung cancer patients at early stages is four times higher than in normal tissue. Here, we tested if CD26/DPP4-inhibition is able to modulate lung cancer growth in mice.

      Methods:
      An orthotopic lung tumor model was employed by sc. injections of the mouse lung cancer (Lewis Lung Carcinoma (LLC)) and a human lung adenocarcinoma cell line (H460). These were developed in mice C57BL6 (n=18) and CD1-nude mice (n=20) respectively. The CD26/DPP4-inhibitor Vildagliptin was given in drinking water of 50mg/kg daily dose. Tumor growth was evaluated by wet weight of tumor mass at 2 weeks. Histological assessments included TUNEL, immunohistochemistry (IHC) of CD3, B220, F4/80 and NKp46. IL-10, Arginase, IL-12, NKp46, NK1.1, IFN-g, Granzyme, and Perforin 1 were analyzed by RT-PCR. In vitro analysis of surfactant protein (SP) expression in LLC and H460 were performed by western blotting. For a proof of concept, macrophage ablation was performed by clodronate-liposome during Vildagliptin treatment.

      Results:
      Vildagliptin treatment significantly reduced the tumor growth of both, LLC and H460 in mice. IHC showed macrophages (F4/80+) and NK cells (NKp46+) to be significantly increased by Vildagliptin within tumors, while TUNEL stain and IHC of T- and B cell infiltration did not show any difference. Gene expression levels of anti-inflammatory markers (IL-10, and Arginase) were unchanged, while the pro-inflammatory cytokine IL-12 was significantly elevated. The NK cell markers NKp46, NK1.1, IFN-g, Granzyme and Perforin 1 were significantly upregulated within the tumor by Vildagliptin, indicating that inhibition of CD26/DPP4 recruits NK cells into the tumor. Furthermore, we found enhanced SP expressions in lung cancer cell lines by Vildagliptin treatment in vitro. Macrophage ablation with clodronate-liposome in Vildagliptin treated mice reversed the tumor size significantly.

      Conclusion:
      The Inhibition of CD26/DPP4 decreased lung cancer growth in primary models of mouse and human lung cancer and increased inflammatory macrophages and NK cell cytotoxicity within those tumors. Furthermore, an increased expression of SP by Vildagliptin treatment in lung cancer cell lines suggests that surfactant production in lung cancer activates macrophages to fight against lung cancer via the recruitment of macrophages and NK cells.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.11 - Mechanistic Insights into CAR T-Cell Efficacy in the Treatment of Heterogenous Antigen Expressing Lung Adenocarcinoma (ID 6039)

      16:00 - 17:30  |  Author(s): A. Morello, M. Zeltsman, A.J. Bograd, D. Jones, P.S. Adusumilli

      • Abstract
      • Presentation
      • Slides

      Background:
      Our laboratory has translated (NCT02414269, NCT02792114) mesothelin (MSLN), a cancer-antigen, targeted chimeric antigen receptor (CAR) T-cell therapy to solid tumors including for lung adenocarcinoma (ADC) patients. The goal of this study is to investigate the anti-tumor efficacy of MSLN CAR T cells against lung ADC with heterogenous MSLN expression, and further develop mechanistic insights to potentiate the therapy.

      Methods:
      Human CAR T cells transduced with M28z, MSLN CAR with CD28 costimulation, were tested in vitro (cytotoxicity by [51]Cr release assay, proliferation, cytokine secretion, LFA-1/ICAM-1 [lymphocyte function associated antigen-1/intercellular adhesion molecule 1] adhesion assay, and flow cytometry) and in vivo (tumor and T-cell bioluminescence imaging [BLI], survival) against low-, high- or a mixture (50:50 or 70:30) of MSLN-expressing A549 human lung ADC.

      Results:
      MSLN CAR T cells demonstrate antigen-intensity dependant cytotoxicity against both low- and high- MSLN-expressing A549 cells with additive bystander cytotoxicity against [51]Cr-labelled low-MSLN A549 cells in the mixture both in vitro (Figure Panel A) and in vivo (22 days delay in tumor progression by low-MSLN A549 cells). Flow cytometry demonstrated ICAM-1 overexpression on low-MSLN A549 cells when treated with effector cytokine-rich supernatant collected by exposure of CAR T cells to high-MSLN A549 cells (Panel B), LFA-1 expression by MSLN-activated CAR T cells (Panel B). Activated CAR T cells adherence to ICAM-Fc coated plates compared to controls (Panel C). LFA-1/ICAM-1 expression promoted adherence of antigen-activated CAR T cells to low antigen-expressing tumor cells (Panel D), which is inhibited in the presence of LFA-1 blocking antibody (Panel E). Figure 1



      Conclusion:
      We provide a mechanistic reason for the antigen-specific, bystander efficacy of CAR T cells against low-antigen expressing lung cancer cells. Strategies to augment LFA-ICAM interactions between CAR T cells and cancer cells can effectively translate mesothelin-targeted CAR T-cell therapy against heterogenous antigen-expressing solid tumor, lung cancer.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA04.12 - Discussant for MA04.09, MA04.10, MA04.11 (ID 7012)

      16:00 - 17:30  |  Author(s): A. Ryska

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.



Author of

  • +

    MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • +

      MA08.04 - Discussant for MA08.01, MA08.02, MA08.03 (ID 6975)

      11:00 - 12:30  |  Author(s): B. Han

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P1.05 - Poster Session with Presenters Present (ID 457)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Early Stage NSCLC
    • Presentations: 1
    • +

      P1.05-019 - Two Inflammatory Biomarkers MDC/CCL22 and BLC/CXCL13 Are Independently Associated with the Significant Risk of Early Stage Lung Adenocarcinoma (ID 3966)

      14:30 - 15:45  |  Author(s): B. Han

      • Abstract
      • Slides

      Background:
      This prospective study was designed to investigate the association between multiple inflammatory biomarkers in circulation and the risk for early stage lung adenocarcinoma.

      Methods:
      We measured 10 inflammatory biomarkers in 228 early stage lung adenocarcinoma patients and 228 age, sex and smoking matched healthy controls by using the Luminex bead-based assay.

      Results:
      Only two biomarkers were significantly associated with early stage lung adenocarcinoma risk after Bonferroni correction: the multivariate odd ratio or OR (95% confidence interval or CI) was 0.29 (0.16-0.53) for MDC/CCL22 (P<0.0001) and 4.17 (2.23-7.79) for BLC /CXCL13 (P<0.0001) for the comparison of 4[th] quartile with 1[st] quartile. When analysis was restricted to never smokers (196 patients/196 controls), MDC/CCL22 and BLC/CXCL13 were still significantly associated with early stage lung adenocarcinoma risk (OR; 95% CI; P: 0.37; 0.21-0.66; P<0.0001 for MDC/CCL22 and 2.78; 1.48-5.22; P =0.001 for BLC/CXCL13). Additionally, significance persisted after restricting analysis to 159 stage IA lung adenocarcinoma patients and 159 matched controls for MDC/CCL22 (OR; 95% CI; P: 0.37; 0.21-0.66; <0.0001) and BLC/CXCL13 (2.78; 1.48-5.22). Furthermore, elevated BLC/CXCL13 was associated with a 2.90-fold (95% CI: 1.03-8.17; P=0.037) increased risk of subcentimeter lung adenocarcinoma, and there was an increasing trend for BLC/CXCL13 with the progression of subcentimeter lung adenocarcinoma.

      Conclusion:
      Our findings demonstrated that MDC/CCL22 and BLC/CXCL13 were independently associated with the significant risk of early stage lung adenocarcinoma, and this association persisted even in non-smokers and in stage IA patients. Moreover, BLC/CXCL13 was identified to play a carcinogenic role in the progression of lung adenocarcinoma.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
    • +

      P2.01-082 - Transcriptional Profiling Identified the Anti-Proliferative Effect of Mitofusin-2 Deficiency and Its Risk in Lung Adenocarcinoma (ID 6011)

      14:30 - 15:45  |  Author(s): B. Han

      • Abstract

      Background:
      Mitofusin-2(MFN2) was initially identified as a hyperplasia suppressor in hyper-proliferative vascular smooth muscle cells of hypertensive rat arteries, which has also been implicated in various cancers. There exists a controversy in whether it is an oncogene or exerting anti-proliferative effect on tumor cells. Our previous cell cycle analysis and MTT assay showed that cell proliferation was inhibited in MFN2 deficient A549 human lung adenocarcinoma cells, without investigating the changes in regulatory network or addressing the underlying mechanisms.

      Methods:
      We performed expression profiling in MFN2 knock-down A549 cells. Furthermore, we compared the expression profiling of a cohort consisting of 61 pairs of tumor-normal match samples from The Cancer Genome Atlas(TCGA).

      Results:
      The expression profiling in MFN2 knock-down cells suggested that cancer related pathways were among the most susceptible pathways to MFN2 deficiency. Next, we teased out the specific pathways to address the impact that MFN2 ablation had on A549 cells, as well as identified a few genes whose expression level associated with clinicopathologic parameters. In addition, transcriptional factor target enrichment analysis identified E2F as a potential transcription factor that was deregulated in response to MFN2 deficiency. Figure 1 Figure 2





      Conclusion:
      The anti-proliferative effect of MFN2 deficiency and its risk in lung adenocarcinoma were found by transcriptional profiling.