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T. Nakano

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    MS 17 - Immunotherapy for Mesothelioma (ID 35)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 4
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      MS17.01 - Overview: Immunotherapy in Mesothelioma (ID 1922)

      14:20 - 14:40  |  Author(s): A.K. Nowak

      • Abstract
      • Presentation

      Abstract:
      Immunotherapy has recently confirmed its place as an important treatment strategy for a number of solid tumors, including melanoma and non-small cell lung cancer. Checkpoint blockade, in particular, has emerged as an ‘off-the-shelf’ immunotherapy which does not rely on known tumor antigens, costly and time-consuming individualised preparation of autologous tumor, or viral vectors. This overview will cover the history of immunotherapy in mesothelioma, recent reported clinical trials, trials in progress, and current cutting edge research with the potential for translation. Although mesothelioma is not classically considered immunogenic, there is abundant evidence that it is recognised by the immune system. Earlier studies described the relationship between tumour infiltrating lymphocytes and prognosis, occasional spontaneous remissions are seen, and there have been reports of low rates of responsiveness to a range of immunotherapies over the past 30 years. There is also a body of work demonstrating impaired immune responsiveness in people with mesothelioma and an immunosuppressive intratumoral milieu. Specifically, NK cell activity is reduced, CD4+ lymphocyte numbers are reduced, and dendritic cell function is impaired (Cornwall S, unpublished data), amongst other changes. Regulatory T cells and inhibitory cytokines within the tumour may contribute to an immunosuppressive milieu [1]. The presence of CD8+ infiltration within the tumour is a predictor of more favourable outcomes [2]. More recently, mesothelioma, in particular sarcomatoid subtype, was shown to overexpress PD-L1 and to predict poor prognosis [3] Historically, response rates below 20% have been seen in clinical trials of systemic and intrapleural interferons, generally accompanied by high toxicity [4]. Similarly, other cytokines such as Interleukin-2 or GM-CSF have shown either poor response rates, low feasibility, or excessive toxicity [5]. Gene therapy approaches have similarly shown very low response rates and are technically demanding [6]. More recent trials have focussed on antigen-specific approaches using the known tumor antigens mesothelin and WT-1, and the use of checkpoint blockade. Immunological checkpoints are inbuilt mechanisms that negatively regulate the size and duration of an immune response, both during induction of the T cell response and during the effector phase of the response, in tumor tissue. Their normal function is to prevent excessive and ongoing T cell activation which may lead to overwhelming autoimmunity. Many tumors, including mesothelioma, express ligands for these checkpoint molecules, allowing tumors to negatively regulate the anti-tumor immune response and thus evade elimination [3]. The expression of checkpoint molecules including Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and PD-1 on T cells, and the expression of ligands such as PD-L1 and PD-L2 on tumors, has allowed the development of antibody blockade which can prevent downregulation of the anti-tumor response by inhibitory signals, hence ‘taking off the brakes’ and facilitating a more effective host response to tumor. CTLA4 is expressed on T cells after activation, and counter-regulates the T cell activation which normally occurs when the co-stimulatory receptor CD28 is engaged. Whilst ligation of CTLA4 normally restricts ongoing T cell co-stimulation and activation, abrogating anti-tumour immunity[7], CTLA4 blockade using monoclonal antibody inhibitors can allow the endogenous anti-tumour response to proceed unopposed. The first report of a clinical trial of this drug class in mesothelioma was published by Calabro and colleagues in 2013 [8], with results showing some similarities to the first trials of CTLA4 blocking antibodies in melanoma. Durable partial responses were seen in two patients, with a further seven of 29 patients experiencing prolonged stable disease. The disease control rate was 31%, median progression free survival was 6·1 months, and almost 40% of participants were alive at two years. The phenomenon of early progression followed by a lengthy partial response was seen in one patient. The authors noted that the progression free survival and two year survival results were better than expected for this population, and although partial responses were uncommon they were long lasting. This study provided the rationale for the subsequent testing of tremelimumab in a large randomised phase II study in mesothelioma which has recently completed recruitment (NCT01843374). A recent presentation at the American Association for Cancer Research (AACR) reported on results from the mesothelioma cohort enrolled in the KEYNOTE-028 study. This trial used PD1 axis blockade with pembrolizumab in patients with mesothelioma selected to express the PD-L1 ligand. Of 25 patients treated, partial response was observed in 7 (28%) and stable disease in 12 (48%), giving a disease control rate of 76% with a tolerable toxicity profile. Many of the responses seen were profound and durable[9], highlighting the enormous potential of this approach in mesothelioma. Finally, mesothelin is highly expressed on mesothelioma cells, predominantly of the epithelioid subtype. A number of methods of targeting mesothelin are under development and clinical testing. The anti-mesothelin immunotoxin SS1P has been administered together with lymphodepletion using cyclophosphamide and pentostatin. Major responses were observed in a subset of patients in a small clinical trial (n=10), notably with some reports of immune pseudoprogression before eventual treatment response. Other treatments using mesothelin as a target include CRS-207, a live attenuated listeria monocytogenes strain which expresses mesothelin, and MORAb-009, a monoclonal antibody that targets mesothelin. Immunotherapy in mesothelioma remains very immature. Results of PD1 and/or PD-L1 blockade in larger numbers of treated patients are needed, and phase III studies will be important to define any benefits. Combinations of checkpoint blockade have shown outstanding efficacy in other cancer types and must be tested in mesothelioma. Underpinning these trials must be the search for biomarkers of treatment efficacy. Technologies such as tumor sequencing also have the potential to identify neoantigens with immunological reactivity in individual patients, an approach that could lead to the development of personalised vaccines, potentially in combination with other immunotherapies. References 1. Hegmans, J.P.J.J., et al., Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. European Respiratory Journal, 2006. 27(6): p. 1086-95. 2. Yamada, N., et al., CD8+ tumor-infiltrating lymphocytes predict favorable prognosis in malignant pleural mesothelioma after resection. Cancer Immunol Immunother, 2010. 59(10): p. 1543-9. 3. Mansfield, A.S., et al., B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol, 2014. 9(7): p. 1036-40. 4. Boutin, C., et al., Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer, 1994. 74(9): p. 2460-7. 5. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 6. Schwarzenberger, P., et al., Antitumor activity with the HSV-tk-gene-modified cell line PA-1-STK in malignant mesothelioma. Am J Respir Cell Mol Biol, 1998. 19(2): p. 333-7. 7. Pardoll, D.M., The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 2012. 12(4): p. 252-64. 8. Calabro, L., et al., Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol, 2013. 14(11): p. 1104-11. 9. Alley, E.W., et al., Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028, in Proc Am Assoc Cancer Res. 2015.

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      MS17.02 - Immunotoxins and Mesothelin Antibody (ID 1923)

      14:40 - 15:00  |  Author(s): R. Hassan

      • Abstract
      • Presentation

      Abstract:
      Mesothelin is a tumor differentiation antigen that is highly expressed in several cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissue and its high expression in many solid tumors make it an attractive candidate for cancer therapy. Several drugs targeting mesothelin, including immunotoxins (SS1P, RO6927005), a chimeric monoclonal antibody (Amatuximab), an antibody drug conjugate (Anetumab Ravtansine), and a tumor vaccine (CRS-207), are in various stages of development to treat patients with mesothelin-expressing tumors. The first anti-mesothelin therapeutic agent to enter the clinic was the immunotoxin SS1P and it demonstrated that mesothelin could be successfully exploited as a target for cancer therapy and has led to a broad interest in developing different approaches for mesothelin immunotherapy treatment of solid tumors including malignant mesothelioma. Immunotoxins are targeted anti-cancer therapeutics that kill cancer cells by inhibition of protein synthesis using a cytotoxic bacterial toxin payload. In a phase I clinical trial SS1P had limited anti-tumor activity because it was immunogenic and patients develop antibodies to the drug limiting treatment efficacy. However, we have recently shown that co-administration of SS1P with a lymphocyte depleting regimen of pentostatin and cyclophosphamide can delay anti-drug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pre-treated mesothelioma patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and non-specific toxicity have been developed through protein engineering techniques. RO6927005 is a next generation anti-mesothelin PE-fusion protein that has been protein-engineered to maximally reduce its immunogenicity so that patients can receive multiple cycles of the drug. In pre-clinical studies RO6927005 has increased activity compared to SS1P against mesothelioma tumor cells directly obtained from patients as well as activity in mesothelioma tumor models either alone or in combination with chemotherapy. A phase I clinical trial of RO6927005 has just been initiated for patients with mesothelin expressing cancers including malignant mesothelioma. There are other antibody based therapeutics in advanced clinical development for treatment of malignant mesothelioma including amatuximab and anetumab ravtansine. In a phase II single arm trial of unresectable, chemotherapy naïve patients with pleural mesothelioma, amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Based on these results a registration front-line study of amatuximab with pemetrexed and cisplatin versus pemetrexed and cisplatin alone has been initiated for treatment of newly diagnosed patients with pleural mesothelioma. Anetumab Ravtansine (BAY 94-9343) is an antibody-drug conjugate in which a human anti-mesothelin monoclonal antibody is conjugated to the maytansinoid tublin inhibitor DM4. In preclinical studies it showed significant anti-tumor activity against mesothelioma cell lines as well as mesothelioma patient derived xenografts. Anetumab Ravtansine is currently being evaluated in patients with mesothelin expressing cancers who have failed standard therapies and represents a potential therapeutic option for treatment of patients with mesothelioma given the high and uniform expression of mesothelin in this tumor. Hopefully, these different approaches to exploit mesothelin for immunotherapy of malignant mesothelioma will result in new treatment options for these patients.

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      MS17.03 - DC Vaccination (ID 1924)

      15:00 - 15:20  |  Author(s): J.G. Aerts

      • Abstract
      • Presentation
      • Slides

      Abstract:
      In recent years immunotherapy has become a new standard in the treatment of malignant diseases. Most clinical evaluated treatments like anti-PD1 aim to reactivate the cytotoxic T-cell response directed against the tumor (CTL-t ). A requirement for this treatment to be effective is the presence of CTL-t within the tumor as reviewed by us recently [Aerts, 2013]. CTL-t formation is dependent on a number of factors which are inhibited by tumor-derived factors and tumor-induced immune suppressive cells, precluding patients to respond to the PD-1 checkpoint blockade pathway. Knowing and bypassing these inhibition pathways of the tumor increases the number of responding patients. For instance, in melanoma it has been shown that combination treatment of anti-PD-1 and anti-CTLA-4 almost doubles the patients benefitting from checkpoint blockade inhibitors. However the number of inhibition pathways is diverse and also changeable according to the act – react principle. The blockade of one inhibitory pathway of the tumor may ultimately lead to the upregulation of another inhibitory pathway. This complex interplay inhibits the formation of new CTL-t and an exhaustion of the CTL-t present in the tumor. That is why cell based therapy, either with ex-vivo generated T-cells or stimulated dendritic cells (DC), precluding a number of inhibitory mechanisms in the patient is an alternative to increase the number of responding patients and thus the efficacy of immunotherapy. Mesothelioma is an aggressive neoplasm, with highly specific growth features making it a distinctive malignant tumor from other cancer types. One of the key immunological features in mesothelioma is the abundant immunosuppressive environment it is creating. There is a large infiltration of regulatory T-cells, immunosuppressive macrophages and myeloid derived suppressor cells (MDSC). Furthermore, the tumor milieu negatively influences immune activation for instance by the presence of hypoxic areas. , tumor metabolites (e.g. arachidonic acid), and suppressive cytokines and chemokines negatively influence the immune activation. Some early phase studies showed a possible clinical effect of immunotherapy in mesothelioma. For instance, checkpoint inhibition with anti-CTLA-4 and anti PD-1 in a subgroup of patients showed some benefit which is now further evaluated in larger studies in second and further line treatment [Calabro 2013, NCT01843374 results pending, NCT02399371 amongst others] . Although it can be questioned whether that is the right setting to determine clinical benefit in placebo controlled trials. Anti mesothelin antibodies also did show clinical efficacy which is now investigated further [Hassan 2010]. Cell based therapy may increase efficacy of immunotherapy also in mesothelioma. The choice of the tumor associated antigens (TAA) to induce a CTL-t is critical, considering the diverse and changing repertoire of TAA. Genetically altered T-cells, directed against mesothelin or Wilms tumour-1 (WT-1) have been developed and are tested in the clinic [NCT02414269 amongst others]. Also DC therapy, being the most powerful initiator of an immune response, is also tested. An advantage of DC, apart from the induction of a natural CTL-t activation, is the ability to load the DC with a pluripotent antigen mixture. DC therapy with an autologous tumor cell lysate demonstrated promosing results [Hegmans 2010] and an allogeneic tumor cell lysate is now tested as tumor associated antigen source in the clinic [NCT2395679]. In the patient stimulation of DC seems an attractive option and has been investigated but may be hampered by the immunosuppressive environment created by the tumor [Powell, 2006]. A new concept with in vivo activation of DC with mesothelin loaded listeria bacteria is now investigated in mesothelioma [NCT01675765]. DC treatment can also be optimized with the addition of different checkpoint activators or inhibitors [Lievense WCLC 2015] Apart from the immune activation strategies, investigations should focus on how to diminish the highly immunosuppressive effect of mesothelioma. Results of our trial on combination treatment with ex vivo matured DC loaded with autologous tumor cell lysate and regulatory T cell (Treg) depletion showed a reduction in circulation Treg [data submitted for publication]. We are in the field of a whole new changing treatment paradigm for mesothelioma. Immunotherapy will be one of the new treatment options. Much effort has to be invested to determine the optimal combination treatment for particular patients. Dendritic cell-based therapy seems an attractive option to generate a more robust immune response that can serve as a backbone for combination treatment.

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      MS17.04 - CTLA4 and PD-1 (ID 1925)

      15:20 - 15:40  |  Author(s): H.L. Kindler

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 14 - Biology 2 (ID 112)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 8
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      ORAL14.01 - Early Contrast Enhancement as a Non-Invasive Objective Biomarker of Pleural Malignancy (ID 1687)

      16:45 - 16:56  |  Author(s): S. Tsim, D.B. Stobo, G.W. Cowell, R. Woodward, J.E. Foster, K.G. Blyth

      • Abstract
      • Presentation
      • Slides

      Background:
      Despite imaging advances, differentiating pleural malignancy (PM) from benign pleural disease (BPD) remains challenging, particularly early-stage Malignant Pleural Mesothelioma (MPM), which can look similar to benign asbestos-related pleural effusion (BAPE). We report the diagnostic performance of a novel Magnetic Resonance Imaging (MRI) biomarker of PM - Early Contrast Enhancement (ECE).

      Methods:
      24 patients with suspected PM were recruited prospectively (January 2013-November 2014). All underwent contrast-enhanced Computed Tomography (CT) scanning and Thoracoscopy. 3-T Pleural MRI was performed prior to Thoracoscopy (median 4 (IQR 4–8) days). Imaging methodology was developed using patients 1-6. In 18 patients, T1-weighted 3D-spoiled-gradient-echo sequences were acquired coronally at baseline, 40 and 80 seconds and 4.5, 9 and 13.5 minutes after intravenous Gadobutrol contrast. Mean signal intensity (SI) of parietal pleura at each time-point was derived from 15 regions of interest placed by two respiratory physicians. ECE on the resulting SI/time curve was defined objectively as an early peak (at/before 4.5 minutes) and/or late fall in mean SI (Figure 1). CT and MRI scans were assessed for morphological features of PM by two thoracic radiologists. All analyses were blinded. Diagnostic performance was assessed using contingency tables. Inter- and intra-observer agreement was assessed using Cohen’s kappa statistic. Figure 1



      Results:
      Median patient age was 73 (IQR 70–80) years. 75% (n=18) were asbestos-exposed. ECE was present in 10/11 patients with PM (MPM (10); lung cancer (1)). The false negative case had MPM. 1 MPM case was initially diagnosed with BAPE but reclassified as MPM after developing progressive PM, consistent with their initial MRI result (ECE present). ECE was absent in 6/7 patients with BPD (BAPE (4), fibrothorax (2), TB (1)). The false positive case had TB. Table 1 summarises diagnostic performance.

      Table 1: Diagnostic performance and reproducibility of ECE, CT morphology and MRI morphology in pleural malignancy
      Sensitivity (%) Specificity (%) Negative Predictive Value (%) Positive Predictive Value (%) Inter-observer agreement Intra-observer agreement
      CT Morphology 90 50 80 69 0.753 Not done
      MRI Morphology 91 71 83 83 0.727 Not done
      MRI Early Contrast Enhancement 91 86 86 91 0.766 1.000


      Conclusion:
      ECE appears a sensitive and specific objective biomarker of PM, out-performing subjectively-defined CT and MR morphology. SI/time curves for ECE assessment can be generated reproducibly in patients with minimal pleural thickening, suggesting potential utility as a non-invasive biomarker for the early detection of MPM or low-volume metastatic PM.

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      ORAL14.02 - Clinical Significance of Soluble CD26 in Malignant Pleural Mesothelioma (ID 354)

      16:56 - 17:07  |  Author(s): N. Fujimoto, K. Ohnuma, K. Aoe, O. Hosono, T. Yamada, T. Kishimoto, C. Morimoto

      • Abstract
      • Presentation
      • Slides

      Background:
      There is no established diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein on the surface of many cell types that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 in patients with MPM.

      Methods:
      The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. Soluble CD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. To make a comparative review of the usefulness of sCD26, we determined serum and pleural fluid soluble mesothelin-related peptides (SMRP). SMRP was measured by the chemiluminescent enzyme immunoassay (CLEIA) based on 2-step sandwich method.

      Results:
      Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P=0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P=0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P=0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P=0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P=0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P=0.028). Median values of serum and pleural fluid SMRP in MPM patients were 0.43 and 15.37 mmol/l, respectively. Median value of pleural fluid SMRP in epithelioid MPM was 17.28 mmol/l. Median values of serum SMRP in SPE and pleural fluid SMRP in OPD were 0.90 and 0.43 mmol/l, respectively. Pleural fluid SMRP in MPM was significantly higher than in OPD (P=0.000) and serum SMRP in MPM was significantly higher than in SPE (P=0.000).

      Conclusion:
      Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM.

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      ORAL14.03 - Integrin Linked Kinase Pathway: A Potential Driver of Tumorigenesis of Malignant Pleural Mesothelioma (ID 2135)

      17:07 - 17:18  |  Author(s): A. De Rienzo, M.A. Archer, B.Y. Yeap, N. Dao, D. Sciaranghella, A.C. Sideris, A.G. Holman, Y.E. Wang, L. Croft, W.G. Richards, R. Bueno

      • Abstract
      • Slides

      Background:
      Identifying driver mutations assists with understanding molecular aspects of cancer and development of novel drugs. The genetics of malignant pleural mesothelioma (MPM) has primarily been to date described in terms of deletions of specific chromosomal regions with CDKN2A and NF2 most commonly mutated, and more recently, evidence for a role of BAP1. The current work suggests that activation of the Integrin Linked Kinase (ILK) pathway may be oncogenic in a subset of MPM.

      Methods:
      Whole-genome sequencing was accomplished for 10 tumor and matched normal genomic DNA samples using a Complete Genomics platform. Tumor and normal genomes were sequenced to at least 30-fold haploid coverage, with corresponding diploid coverage of at least 99.5%. Selected candidates single nucleotide variations (SNVs) were further characterized using PCR and Sanger sequencing to identify tumor-specific single nucleotide mutations. Potential driver genes were investigated in 147 additional MPM cases by targeted resequencing. Levels of transcripts were examined in an available expression data set (Affymetrix® Human Gene 1.1 ST Array). Association of mutation status and gene expression to clinicopathologic variables was explored statistically.

      Results:
      Among 146 single nucleotide variants (SNVs) mapping in amino acid coding regions of annotated exons and generating non-synonymous amino acid changes, 85 were confirmed to be tumor specific. Functional enrichments of genes affected by point mutations were performed utilizing Ingenuity Pathway Analysis to identify clusters of genes annotated in pathways potentially relevant to the biology of MPM. Mutations affecting genes involved in the Integrin Linked Kinase (ILK) pathway were the most significantly (p = 4.9e-5) enriched. Specifically, 5 of 10 sequenced MPM samples showed point mutations in at least one of 6 genes of this pathway (MYH9, MYH6, MYH10, PIK3C2A, RHOA, and TNFRSF1A). Re-sequencing analysis of 147 MPM tumors identified 40 SNVs in these genes among 31 MPM samples (21%). Thirty-five (88%) SNVs were present in both tumor and matching normal DNA samples. In 4 samples, tumor specific mutations were identified, 3 in MYH9 (1.4%) and 2 in RHOA (1.4%) both recently proposed as genes involved in tumorigenesis. Non-epithelioid tumors expressed significantly higher levels of MYH9 (p<0.001), RHOA (p<0.001), and MYH10 (p=0.001) compared to epithelioid tumors. RHOA was more highly expressed in men than women (p=0.001). The highest quartile of MYH9 and of RHOA expression was associated with higher gender-adjusted risk of death (HR=2.23 and HR=1.95, respectively) compared to the lower three quartiles (p<0.001) by multivariate analysis.

      Conclusion:
      Tumor specific mutations in MYH9 or RHOA were found in six of 157 (3.8%) MPM patients. Interestingly, both MYH9 (22q13.1) and RHOA (3p21.3) reside in two chromosomal regions frequently deleted in MPM. Additional analysis is in progress to investigate the role of ILK pathway activation in MPM. These observations suggest that a sub-class of MPM may respond to therapy targeting the ILK pathway.

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      ORAL14.04 - Discussant for ORAL14.01, ORAL14.02, ORAL14.03 (ID 3332)

      17:18 - 17:28  |  Author(s): D.S. Schrump

      • Abstract
      • Presentation

      Abstract not provided

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      ORAL14.05 - Intracavitary Cisplatin-Fibrin After Resection of Malignant Pleural Mesothelioma (ID 1165)

      17:28 - 17:39  |  Author(s): I. Opitz, A. Kostron, O. Lauk, M. Meerang, M. Friess, G. Wuilleret, C. Bommeli, A. Jetter, B. Aeschlimann, D. Günther, R. Stahel, W. Weder

      • Abstract
      • Slides

      Background:
      Local tumor recurrence is very frequent after resection of malignant pleural mesothelioma (MPM). Intracavitary chemotherapy has been shown to be a promising approach to improve local tumor control. Here, we present the results of a phase-I-dose-escalation trial with intracavitary application of cisplatin-fibrin after surgical tumor resection.

      Methods:
      Altogether 12 patients (75% IMIG stage III-IV) were treated with 4 different dose levels of cisplatin (11, 22, 33 and 44mg/m[2] body surface area (BSA)). Eight patients of 22, 33 and 44mg/m[2] groups received previous induction treatment with intravenous cisplatin/pemetrexed. Cisplatin-fibrin was sprayed on the surface of chest wall, diaphragm, mediastinum and lung after pleurectomy/decortication (P/D). Blood was taken before surgery and at several time points after the treatment. Tissue sampling was conducted before and at 90 minutes after the administration. Cisplatin levels were measured by inductively coupled plasma sector field mass spectrometry.

      Results:
      Serum cisplatin kinetics and AUC0-120 are depicted in figure 1. Induction intravenous chemotherapy contributed to >50% of total serum cisplatin levels compared to cisplatin-fibrin (figure 1B). The median AUC0-24 of the 3 patients in the highest dose level (44mg/m[2]BSA) including predoses from induction chemotherapy reached 23h*µg/g, which is still below the suggested renal toxicity risk level, 25h*µg/g (Royer 2008). Our serum cisplatin AUC levels stayed far below levels reported after intrapleural perfusion (approx. 89h*µg/g (Ried 2013)). Local cisplatin concentration in tissues varied from 12-133 (median: 36.5µg/g) and did not seem to be dose dependent. No dose limiting toxicity due to cisplatin was observed. Major morbidity was observed in 4 patients (33%). 30day- and 90day-mortality was 0%. The median follow up after surgery was 11 months (range: 5-28 months). In 8 patients receiving 11, 22, 33 mg/m[2]BSA, relapse was detected after a median freedom from recurrence (FFR) of 8 months (95% confidence interval (CI): 1-14 months). In three patients with early IMIG stage (I and II), no sign of relapse was observed at 28, 8 and 6 months after the treatment (11, 44, 44 mg/m[2]BSA, respectively). The last patient (44mg/m[2]BSA) with IMIG stage III tumor currently shows no sign of recurrence at 5 months after surgery. Figure 1



      Conclusion:
      The administration of intracavitary cisplatin-fibrin as high as 44mg/m[2]BSA is safe after P/D, also in combination with induction chemotherapy. Tissue cisplatin concentration was high whereas no dose limiting toxicity due to systemic distribution was detected. A confirmation of the safety and efficacy of the highest dosage, 44 mg/m[2]BSA, in a phase II trial is warranted.

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      ORAL14.06 - MesobanK - an International Mesothelioma Tissue Bioresource - Now Open for Tissue Requests (ID 988)

      17:39 - 17:50  |  Author(s): R.C. Rintoul, D.M. Rassl, J. Gittins, J. Edwards, D.A. Fennell, R. Booton, N. Maskell, A. Chauhan, V. Hughes, S. Marciniak

      • Abstract
      • Presentation
      • Slides

      Background:
      Availability of quality assured, fully annotated mesothelioma tissue collected to rigorous standard operating procedures (SOPs) to facilitate basic and translational research is very limited. MesobanK, funded by the British Lung Foundation and the Mick Knighton Mesothelioma Research Fund, is a UK based bioresource to collect fresh tissue, blood, pleural fluid and anonymised linked clinical data to strict SOPs from patients with malignant pleural mesothelioma.

      Methods:
      1) To construct a tissue microarray (TMA) from 1000 cases of formalin fixed paraffin embedded pleural mesothelioma tissue linked to a clinical data set. Each case will have several cores taken to allow for tumour heterogeneity. 2) To collect 300 cases of fresh pleural mesothelioma tissue (5 samples per case), blood (whole blood, serum, plasma and buffy coat) and pleural fluid (supernatant and cell pellet) linked to a clinical data set. Longer term follow up and survival data will be provided by the UK National Cancer Registration Service. 3) To develop at least 20 new fully characterised and annotated mesothelioma cell lines. Governance MesobanK abides by all relevant UK and EU legislation regarding the collection of tissue and data. Mesobank is a member of the UK Confederation of Cancer Biobanks. Prioritisation for access to samples will be based solely on scientific merit. The project is managed by a dedicated project manager and overseen by a Steering Committee; an independent Scientific Advisory Board reviews anonymised applications for samples.

      Results:
      All required ethical permissions have been obtained. A secure, web-based multi-user database has been constructed for data collection. As of April 2015, 730 of the 1000 cases for the TMA have been acquired from UK pathology departments and the first part of the TMA construction is underway at the Cancer Research UK Cambridge Institute. In the first year of operation, 100 prospective cases have been banked and quality control to assess tumour percentage and necrosis in each sample is underway. Figure 1 shows weight of sample versus tumour percentage from the QC of the first 144 samples. Twenty six new cell lines have been developed and are currently being characterised. Figure 1



      Conclusion:
      Procurement of formalin fixed tissue for the TMA and fresh biospecimens is progressing well and MesobanK is now open for investigators to apply for tissue samples. Enquiries about tissue availability should be directed to [email protected]. An application form is available at www.mesobank.com. A cost contribution model has been developed to support on-going funding of MesobanK.

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      ORAL14.07 - Preclinical Investigation of the Therapeutic Potential of Nintedanib in Malignant Pleural Mesothelioma (ID 2655)

      17:50 - 18:01  |  Author(s): V. Laszlo, J. Ozsvar, M.A. Hoda, T. Klikovits, D. Lakatos, T. Garay, W. Berger, M. Grusch, W. Klepetko, F. Hilberg, B. Dome, B. Hegedus

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is a devastating malignancy with still rising incidence worldwide. Its aggressive biological behavior and therapy resistance result in a median overall survival (OS) of 9 to 17 months only. Currently, platinum-based chemotherapy in combination with antifolate agents is the standard front-line therapy for MPM and to date no molecularly targeted therapeutic approaches have been approved in the clinics. Nintedanib is an indolinone derivative that has been demonstrated to efficiently inhibit the activity of VEGFR, PDGFR and FGFR tyrosine kinase isoforms and thus to be capable to suppress angiogenesis and tumor growth. Here, we report the antitumor activity of nintedanib in MPM.

      Methods:
      21 MPM cell lines were treated with nintedanib and SRB assays were performed to determine the IC50 values for each cell line. 4 sensitive cell models were selected for further in vitro analysis: BrdU, TUNEL and clonogenic assays were performed to investigate the impact of the drug on the proliferation, apoptosis and colony formation capacity of MPM cells, respectively. The migratory activity of MPM cells was analyzed with 2D videomicroscopy. The downstream signaling of the target receptors was investigated by Western blot analysis. Drug interactions with cisplatin were assessed in the p31 MPM cell line and in its cisplatin-resistant subline (p31cis) by using the CalcuSyn software. The in vivo anti-MPM activity of nintedanib was studied in an orthotopic human MPM xenograft model in SCID mice. Tumor-bearing animals were treated with 50 mg/kg nintedanib daily, per os (PO) or intraperitoneally (IP) and followed for survival.

      Results:
      Nintedanib exerted a growth inhibitory effect on MPM cell lines in both short- and long-term viability assays. The inhibition of proliferation was observed in all MPM cell models analyzed, whereas significant apoptosis induction was only found in half of them. Migratory activity strongly decreased upon nintedanib treatment. Down-regulation of Erk1/2 phosphorylation was evident within 10 min of treatment and was present even after 24h. Nintedanib, however, had no inhibitory effect on the activation of Akt or S6. Additive, but no synergistic effect on cell viability was detected in the p31 and p31cis MPM cells when nintedanib was combined with cisplatin. In vivo, survival of PO-treated animals showed favorable trend (vs. PO control, log-rank test, p=0.059). Nintedanib significantly prolonged the survival of mice when it was administered IP (vs. IP control, log-rank test, p=0.0008).

      Conclusion:
      Our data suggest that nintedanib exerts antitumor activity in MPM both in vitro and in vivo and thus may represent a promising novel therapeutic option in this malignancy.

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      ORAL14.08 - Discussant for ORAL14.05, ORAL14.06, ORAL14.07 (ID 3331)

      18:01 - 18:11  |  Author(s): H.L. Kindler

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MINI 24 - Epidemiology, Early Detection, Biology (ID 140)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI24.10 - Discussant for MINI24.06, MINI24.07, MINI24.08, MINI24.09 (ID 3428)

      17:35 - 17:45  |  Author(s): T. Nakano

      • Abstract
      • Presentation

      Abstract not provided

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    MINI 25 - Trials, Radiation and Other (ID 142)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI25.03 - Potent Anti-Mesothelioma Activity by the Novel Naftopidil Analogue HUHS1015; Preclinical Evidence for Treatment (ID 2733)

      16:55 - 17:00  |  Author(s): T. Nakano

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is usually a fatal neoplasm, and current therapeutic interventions are far from satisfactory. Naftopidil, an α1-adrenoceptor antagonist, is used clinically for the treatment of benign prostate hypertrophy, and has been found to reduce the incidence of prostate cancer and to inhibit prostate cancer cell proliferation via G1 cell cycle arrest. Recently, naftopidil has been demonstrated to induce apoptosis in mesothelioma cells by activating caspase-8 and the effector caspase-3 independently of α1-adrenoceptor suppression. Hence, a more potent naftopidil analogue, HUHS1015, was synthesized. The current study evaluates the inhibitory effect of HUHS1015 on malignant mesothelioma cell proliferation in preclinical models and assesses whether HUHS1015 can be the basis for new drug for the treatment of MPM.

      Methods:
      We treated the human MPM cell lines MSTO-211H, NCI-H28, NCI-H2052 and NCI-H2452 with HUHS1015, and evaluated cell viability using the MTT method. Additionally, NCI-H2052 tumor xenograft models in BALB/c-nu/nu mice were utilized to investigate anti-mesothelioma activity in vivo.

      Results:
      HUHS1015 reduced the viability of MPM cells more potently than cisplatin or paclitaxel at concentrations higher than 30 μM, and the drug induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. The effect of HUHS1015 on the expression of Bcl-2 family mRNAs in MSTO-211H and NCI-H2052 cells was tested using real-time RT-PCR. Puma, Hrk, and Noxa mRNAs were up-regulated in both cell lines. In the NCI-H2052 mouse xenograft models, HUHS1015 strongly suppressed tumor growth.

      Conclusion:
      These results indicate that HUHS1015 may be an effective anticancer drug candidate for the treatment of MPM. HUHS1015 induces apoptosis of MPM cells through modulation of a mitochondrial pathway, and future clinical investigations with this drug are warranted for mesothelioma.

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    P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P1.08-012 - Immunohistochemistry as Prognostic Markers for Malignant Pleural Mesothelioma (ID 1663)

      09:30 - 09:30  |  Author(s): T. Nakano

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy of the mesothelium. Several previous studies reported the prognostic ability of immunohistochemistry markers. But there are few reports adjusted for confounding appropriately.

      Methods:
      A retrospective cohort study was performed using epithelial and biphasic MPM patients treated in two tertiary hospitals in Japan between 2007 and 2014. Candidate prognostic factors were as follows: age; gender; performance status; stage; treatment modality; NLR (neutrophil lymphocyte ratio); calretinin expression; D2-40 expression; WT1 (Willms’ tumor 1). The primary outcome was overall survival (OS). The log-rank test and the Cox proportional hazards model were used for analyses to detect prognostic factors. We defined p<0.05 was statistically significant.

      Results:
      Total 371 patients comprised 309 epithelioid, 62 biphasic subtype of MPM. Median OS was 12.9 months. On univariate analysis all variables except for WT1 were associated with OS. On multivariate Cox proportional regression analysis PS (1<), Stage (II<), treatment modality, NLR (3<=), D2-40 negative expression were associated with shorter OS.

      Conclusion:
      Positive expression of D2-40 were associated with longer OS of epithelial and biphasic MPM. Further studies are warranted.

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    P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 3
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      P3.08-006 - NF2 Mutations in Malignant Pleural Mesothelioma Synchronous with Acoustic Neuroma: Disease-Causing Mutation or Chance Effect? (ID 2562)

      09:30 - 09:30  |  Author(s): T. Nakano

      • Abstract
      • Slides

      Background:
      Patients with neurofibromatosis type 2 (NF2) are predisposed to schwannomas and meningiomas. Somatic NF2 mutation has also been reported in patients with sporadic schwannomas and a variety of cancers. In particular, approximately 35–40% of patients with malignant pleural mesothelioma (MPM) carry inactivating mutations of NF2. In addition to NF2, BRCA1-associated protein-1 (BAP-1) has also been identified as a key genetic alteration in mesothelioma. Recently, a new familial cancer syndrome associated with germline mutations in BAP1 was proposed, which includes MPM, ocular melanoma, and other cancers. However, NF2 mutations do not usually cause mesothelioma synchronous with schwannoma. We here report two cases of MPM synchronous with vestibular schwannomas and analytical finding on NF2 mutations

      Methods:
      Case 1 was a 65-year-old man with epithelioid MPM. A unilateral acoustic neuroma was resected in 2010 because the patient experienced progressive hearing loss in the right ear since 2000. In April 2012, right pleural fluid was detected on chest X-ray and a thoracoscopical examination was performed. Epithelioid MPM was diagnosed pathologically. Case 2 was a 72-year-old man with epithelioid MPM synchronous with unilateral acoustic neurinoma. The patient presented with DOE and hearing loss in the left ear that had progressed over the past month. Chest X-ray showed pleural effusion, and a biopsied specimen with thoracoscopy revealed epithelioid MPM. Brain MRI and CT showed a mass that was highly suspected to be acoustic neurinoma between the left cerebellopontine angle and the opening of the internal acoustic meatus. We performed whole-exome sequencing on DNA in tumor tissue and blood and immunohistochemical analysis of NF2 gene encoding protein merlin.

      Results:
      Both patients were diagnosed with synchronous acoustic neurinoma and epithelioid MPM. NF2 gene mutations were identified in both tumors of MPM and acoustic neurinoma in Case 1. And in Case 2, diagnosis of acoustic neurinoma was depended on typical findings of brain MRI/CT, for which surgical resection was not performed because of advanced stage of MPM. Tumor tissue of MPM in Case 2 showed positive result of NF2 mutation. Both patients had a history of asbestos exposure.

      Conclusion:
      Although the role of NF2 mutation as a possible disease-causing mutation in MPM and synchronous occurrence with schwannoma remain unclear, both cases showed the possible role of NF2 mutation in asbestos-related neoplasm. We will show the pedigree of the patients’ families.

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      P3.08-014 - COMMAND: A Phase 2 Randomized, Double-Blind, Study of Defactinib (VS-6063) as Maintenance Therapy in Malignant Pleural Mesothelioma (ID 2847)

      09:30 - 09:30  |  Author(s): T. Nakano

      • Abstract

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung. Median OS with frontline chemotherapy of pemetrexed/cisplatin (pem/cis) is ~12 months. There is no established second line therapy. Pem/cis has been shown to enrich cancer stem cells (CSCs) in tumors. Focal adhesion kinase (FAK) inhibitors have been found to decrease CSCs in mesothelioma models. The use of a FAK inhibitor in a maintenance setting after frontline chemotherapy may therefore extend survival of MPM patients. Furthermore, approximately 40% of MPM tumors exhibit disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Mesothelioma cell lines that lack merlin are more sensitive to FAK inhibitors than those with wild type merlin. This Phase 2 study will determine if defactinib (VS-6063), an oral inhibitor of FAK, provides superior clinical benefit compared with placebo as maintenance treatment in patients with MPM following frontline pem/platinum therapy.

      Methods:
      COMMAND is a multinational, randomized, double-blind, placebo-controlled trial. Approximately 370 patients with PR or SD following ≥4 cycles of frontline pem/platinum therapy will be enrolled. Patients will receive defactinib 400 mg BID or matched placebo. Randomization will be stratified by merlin status, as determined by immunohistochemistry. Primary endpoints include OS and PFS. An adaptive enrichment design at the interim analysis (projected to occur in Q2 2015) may restrict patients to those with low merlin protein expression if greater benefit is observed among this subpopulation. Secondary endpoints include patient-reported outcomes, objective response and safety and tolerability. The study is currently enrolling across 15 countries. Clinical trial: NCT01870609.

      Results:
      Not applicable

      Conclusion:
      Not applicable

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      P3.08-015 - Naftopidil Is Effective in the Treatment of Malignant Pleural Mesothelioma (ID 2732)

      09:30 - 09:30  |  Author(s): T. Nakano

      • Abstract
      • Slides

      Background:
      Naftopidil, an antagonist of the α1A/1D-adrenoceptor, was developed as a drug for the treatment of benign prostate hyperplasia and hypertension, and has recently been shown to exert antitumor activity in a variety of cancers. We previously discovered that naftopidil induces apoptosis of malignant pleural mesothelioma (MPM) cells in an α1-adrenoceptor-independent manner, as this was not reproducible using other α1-adrenoceptor-inhibitors such as prazosin. The present study was conducted to assess whether naftopidil is useful for the treatment of MPM.

      Methods:
      Cell viability of cultured NCI-H2052 human cells was evaluated using MTT. TUNEL staining was performed to detect in situ DNA fragmentation as a marker of apoptosis using an in situ apoptosis detection kit. Caspase activity was measured using a caspase fluorometric assay kit. NCI-H2052 cells were treated with naftopidil (100 μmol/L) and were subcutaneously inoculated into the right flank of BALB/c-nu/nu mice under pentobarbital-induced general anesthesia. Naftopidil was diluted with a physiological salt solution and injected intraperitoneally twice a week, starting 1 week after inoculation; the salt solution alone was used in control mice. The longer (L) and shorter (S) lengths of the induced tumors were measured using calipers, and tumor volume (V) was calculated according to the following equation: V = (L × S[2]) × 1/2.

      Results:
      Naftopidil reduced NCI-H2052 cell viability in a concentration-dependent manner and significantly increased the number of TUNEL-positive NCI-H2052 cells compared to untreated cells. Naftopidil activated caspase-3 and -8, but not caspase-9. Naftopidil did not affect the expression of FasL protein in NCI-H2052 cells. Notably, however, it did significantly increase the concentrations of extracellular FasL protein in a bell-shaped, time-dependent manner. Intraperitoneal injection of naftopidil significantly inhibited NCI-H2052 xenograft tumor growth compared to tumors in control mice. All mice injected with naftopidil survived 8 weeks after the first injection, and the drug had no effect on their mean weight.

      Conclusion:
      The results of the present study suggest that naftopidil induces apoptosis of NCI-H2052 cells by stimulating the secretion of FasL, a ligand of the death receptor Fas. This in turn activates caspase-8 and the effector caspase-3, leading to the inhibition of NCI-H2052 xenograft tumor growth in vivo. This supports the concept that naftopidil could be developed as a therapeutic agent for the treatment of malignant pleural mesothelioma.

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