Journal Thoracic Oncology

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Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 MESOTHELIOMA Isabelle Opitz Division of Thoracic Surgery, University Hospital Zurich, Zurich/Switzerland The rational of localized / intracavitary treatment is to eliminate microscopic residual disease (MRD) after macroscopic complete resection (MCR) for mesothelioma patients. The advantage of the treatment is that local effects can be enhanced whereas systemic side effects of the therapeutic agents applied might be reduced. Several approaches have been investigated over the past decades in preclinical and clinical trials, such as intracavitary chemotherapy (iCTX), immunotherapy (iIT), photodynamic therapy (PDT) and gene therapy (iGT). Intracavitary chemotherapy (iCTX) iCTX has been studied after mesothelioma resection, not only after extrapleural pneumonectomy (EPP) but also after (extended) pleurectomy/decortication ((e)P/D). The main therapeutic agent used is cisplatin. In some trials hyperthermia was additionally added with the aims to enhance the penetration of cisplatin into tissues and maximize its cytotoxicity in tumor cells [1]. Hyperthermic intrapleural perfusion had a maximum tolerated dose of 225-250 mg Cisplatin/m 2 BSA [2]. The morbidity ranges from 13 to 85% and the mortality from 0 to 29% [2, 3]. Some complications are related to renal toxicity which was the dose limiting adverse event [2]. Median survival time reaches up to 35.3 months in low-risk MPM patients receiving hyperthermic intraplueral cisplatin chemotherapy following MCR [4]. This treatment is only considered for well-designed clinical trials. In vivo preclinical model using intrapleural administration of cisplatin-mixed loaded to a fibrin carrier improved the local drug concentration and prolonged the exposure of tissue to high cisplatin concentration [5]. Our phase I dose escalation trial (INFLuenCe – Meso; see figure) has proven the safety of this treatment approach (manuscript in preparation). This treatment regimen is now being tested in a phase II trial (NCT01644994). In addition to chemotherapy, other substances have also been tested for intracavitary treatment. Recently, Tada, et. al. reported study plan for a phase I trial for intrapleural treatment with zoledronic acid, a third generation of bisphosphonates, in inoperable MPM, after having successfully proven the efficacy of zoledronic in a pre-clinical model [6]. Intracavitary immunotherapy (iIT) MPM is not a classical “immunogenic” tumor. Intrapleural instillation of cytokines such as interleukin (IL)-2, interferon (IFN)-α and IFN-γ provided a good control of malignant pleural effusion (MPE) and MPM with minimal toxicity [7, 8]. To prolong and increase local exposure of IFNs, recent studies implemented immuno-gene therapy approach using adenoviral vector expressing human IFNs. Four out of 10 patients with MPM and metastatic pleural effusions showed stable disease following a single dose of intrapleural adenoviral vector expressing IFN-β [9]. Nevertheless due to rapid production of neutralizing antibody against adenovirus, no improvement of gene transfer efficacy was achieved after the second dose [10]. The same research group conducted a clinical trial assessing the safety of adenoviral-mediated IFN-α2b in combination with chemotherapy. Recent data from this trial showed that the treatment is well tolerated and 25% of patients had partial response [11]. An intrapleural treament with re-directed T cells genetically engineered to express chimeric antigen receptor (CAR) that specifically recognizes tumor antigens is an attractive therapeutic option. A clinical phase I trial for intrapleural administration of fibroblast activation protein (FAP)-specific re-directed T cells is currently being conducted (NCT01722149). Photodynamic therapy (PDT) PDT is a light based cancer therapy. Most modern PDT applications involve three key components: a photosensitizer, a light source and tissue oxygen. The photosensitizing agent accumulates in tumor cells and is activated by light of a specific wavelength to produce reactive singlet oxygen that mediates cellular toxicity. The tumor cells are killed through both apoptosis and necrosis and by damaging tumor vasculature. It may also induce inflammatory reaction capable of stimulating a tumor directed host immune response. The advantages of this treatment are that its efficacy is not influenced by chemo- or radio-resistance of tumor cells, that it can be repeated at the same site without compromising its efficacy and that it does not compromise the ability to administer other treatment modalities in patients with recurrent or residual disease. PDT should be combined with macroscopic complete resection due to limited depth of penetration. Localized inflammation and fluid accumulation after treatment can modestly extend hospital stay. PDT appears promising and may improve local control and potentially prolong survival in properly selected patients who are able to undergo MCR, with clinical outcomes appearing best when PDT is combined with lung-sparing definitive surgery [12]. Friedberg reported a median survival of 31.7 months (41.2 months in patients with epithelioid histological subtype), but the progression free survival was only 9.6 months [13]. Intracavitary gene therapy (iGT) Gene therapy is based upon transfer of genetic material, including complementary DNA, full-lengths genes, small interfering RNA or oligonucleotids into cells for therapeutic purposes. For sufficient gene delivery, adenovirus is the most widely used in clinical trials among a variety of viral and non-viral vectors. In addition to delivering cytokine expressing vectors or re-directed T cells (see iIT part), several different cancer gene therapy approaches are currently used including the so called suicide gene therapy wherein a neoplasm is transduced with a cDNA encoding for an enzyme rendering tumor cells sensitive to a benign agent by converting the product to a toxic metabolite. The Herpes Simplex Virus 1- thymidine kinase (HSVtk) gene encodes for an enzyme that converts ganciclovir, an antiviral drug, to its cytotoxic metabolite. Intrapleural adenovirus HSVtk/ganciclovir administration was safe in MPM and two patients survived >6.5 years. Nevertheless, due to the fact that transgenes HSVtk were only detected at the surface of tumor tissues, the authors suggested that the treatment efficacy may be a result of antitumor immune response stimulation [14]. MPM tumor genome is characterized by frequent mutations in tumor suppressor genes such NF2, BAP1 or p53, thus the delivery of tumor suppressor gene expressing vectors into tumor cells can serve as an attractive treatment approach. The delivery of adenovirus expressing p53 has been tested in clinical trials for lung cancer but did not show better clinical benefit over chemotherapy [15]. This may be due to limited transfection efficiency of the vector and the stimulation of neutralizing antibody, therefore an improvement of transfection is still needed for the further development of gene therapy.References: 1. Sugarbaker, P.H., et al., Update on chemotherapeutic agents utilized for perioperative intraperitoneal chemotherapy. Oncologist, 2005. 10(2): p. 112-22. 2. Richards, W.G., et al., Phase I to II Study of Pleurectomy/Decortication and Intraoperative Intracavitary Hyperthermic Cisplatin Lavage for Mesothelioma. J Clin Oncol, 2006. 24(10): p. 1561-1567. 3. de Bree, E., et al., Cytoreductive surgery and intraoperative hyperthermic intrathoracic chemotherapy in patients with malignant pleural mesothelioma or pleural metastases of thymoma. Chest, 2002. 121(2): p. 480-7. 4. Sugarbaker, D.J., et al., Hyperthermic intraoperative pleural cisplatin chemotherapy extends interval to recurrence and survival among low-risk patients with malignant pleural mesothelioma undergoing surgical macroscopic complete resection. J Thorac Cardiovasc Surg, 2013. 145(4): p. 955-63. 5. Lardinois, D., et al., Intrapleural topical application of cisplatin with the surgical carrier Vivostat increases the local drug concentration in an immune-competent rat model with malignant pleuromesothelioma. J Thorac Cardiovasc Surg, 2006. 131(3): p. 697-703. 6. Tada, Y., et al., An intrapleural administration of zoledronic acid for inoperable malignant mesothelioma patients: a phase I clinical study protocol. Springerplus, 2016. 5: p. 195. 7. Astoul, P., et al., Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion. Chest, 1993. 103(1): p. 209-13. 8. Antoniou, K.M., E. Ferdoutsis, and D. Bouros, Interferons and their application in the diseases of the lung. Chest, 2003. 123(1): p. 209-16. 9. Sterman, D.H., et al., A phase I clinical trial of single-dose intrapleural IFN-beta gene transfer for malignant pleural mesothelioma and metastatic pleural effusions: high rate of antitumor immune responses. Clin Cancer Res, 2007. 13(15 Pt 1): p. 4456-66. 10. Sterman, D.H., et al., A phase I trial of repeated intrapleural adenoviral-mediated interferon-beta gene transfer for mesothelioma and metastatic pleural effusions. Mol Ther, 2010. 18(4): p. 852-60. 11. Sterman, D.H., et al., Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNalpha Combined with Chemotherapy. Clin Cancer Res, 2016. 22(15): p. 3791-800. 12. Simone, C.B., 2nd and K.A. Cengel, Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin Oncol, 2014. 41(6): p. 820-30. 13. Friedberg, J.S., et al., Radical pleurectomy and intraoperative photodynamic therapy for malignant pleural mesothelioma. Ann Thorac Surg, 2012. 93(5): p. 1658-65; discussion 1665-7. 14. Sterman, D.H., et al., Long-term Follow-up of Patients with Malignant Pleural Mesothelioma Receiving High-Dose Adenovirus Herpes Simplex Thymidine Kinase/Ganciclovir Suicide Gene Therapy. Clin Cancer Res, 2005. 11(20): p. 7444-7453. 15. Schuler, M., et al., Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol, 2001. 19(6): p. 1750-8. Keywords: malignant pleural mesothelioma, intracavitary chemotherapy, Intracavitary Immunotherapy, photodynamic therapy SC06: NOVEL THERAPIES IN MALIGNANT PLEURAL MESOTHELIOMA AND THYMIC MALIGNANCIES MONDAY, DECEMBER 5, 2016 - 14:30-15:45 SC06.04 IMMUNOTHERAPY OF MALIGNANT PLEURAL MESOTHELIOMA AND THYMIC MALIGNANCIES: THE END OF THE BEGINNING? Jan Van Meerbeeck Thoracic Oncology, Antwerp University Hospital, Edegem/Belgium The significant improvement in outcome observed with immune checkpoint S46 Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017
Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 inhibitors in advanced melanoma and NSCLC have triggered their use in mesothelioma and thymic tumours. Both tumours are characterized by an unmet need to improve their prognosis and an immunosuppressive environment induced by (i) the (over-)expression of checkpoint receptors, responsible for controlling and inactivating the immune system in order to avoid autoimmunity and prevent collateral tissue damage- and (ii) by a silencing of the antigen presenting function of dendritic cells by tumorderived soluble factors, leading to a defective induction of cytotoxic T– lymphocytes response [1]. The new paradigm consists of reactivating these silenced immune responses by either monoclonal antibodies or cell-based therapies. CTLA-4 is responsible for modulating central T-cell activation in the lymph nodes. Under physiological conditions, the immune inhibitory effect of CTLA-4 is involved in provoking an effective immune response without causing excessive damage to the normal surrounding tissue. However, tumor cells can stimulate abnormal expression of CTLA-4 by secreting TGF-beta, that induces CTLA-4 overexpression, resulting in a state of T-cell dysfunction whereby T-cells fail to proliferate and are no longer able to exert their effector functions. Tremelimumab and ipilimumab are selective monoclonal antibodies against CTL-A4 and block its binding to CD80 and CD 86, thereby enhancing T cell activity and anti tumor immunity. There are no known predictive factors for anti-CTL-A4 therapy in mesothelioma. After 2 phase 2 trials at different dose levels –which were negative for their primary endpoint, but nevertheless considered promising- DETERMINE compared tremelimumab to placebo as second line treatment in MPM [2]. No difference in outcome was reported, but an increased class specific toxicity in the patients treated with tremelimumab. The PD-1-PD-L1 axis is responsible for controlling peripheral T-cell activation at the tumor site. Overexpression of PD-L1 is thought to induce immune tolerance. In MPM, PD-L1 expression by immunohistochemistry was reported in 20-70% of formalin-fixed paraffin embedded mesothelioma, in 70% of thymic carcinomas and in 23% of thymomas [1,3]. In mesothelioma, PD-L1 expression overexpression is more common in non-epitheloid histology, is associated with a significantly worse survival. PD-L1 expression is furthermore considered a –weak- predictive factor for the activity of immune checkpoint inhibitors in NSCLC, besides mutagenic load and the formation of neo-epitopes. Several anti PD-(L)1 antibodies are registered and/or in development for use in other tumour types. Promising phase 2 trial results in mostly pretreated mesothelioma patients are summarized in the table [4-6]. Expression level of PD-L1 did not correlate with response in either trial. Checkpoint inhibitors in mesothelioma Trial Drug Phase Line N DETERMINE (2) KEYNOTE 28 (4) NIVOMES (5) JAVELIN (6) Subtype Ep: 83% all PDL1+ Tremelimumab Pembrolizumab Nivolumab Avelumab 3 2/3 382 2 2 25 ORR/ DCR (%) PFS 4.5/31.7 2.8 m 28/76 49.4% @ 6m 2 NR 18 NR 27/49 NR 1b 2-5 53 Ep: 83% 9.4/56.6 17.1 w Dendritic cells (DC), obtained by leukapheresis, can be loaded with synthetic peptides coding for parts of tumor-associated antigens, a lysate of tumor material of the patient itself (autologous dendritic cell-therapy) or with other sources of tumor-specific antigens (allogeneic dendritic cell-therapy). Wilms’ tumor 1 (WT1) is an ideal candidate for a tumor selective cancer vaccine in cancers expressing WT1, such as MPM. Two vaccines have investigated this approach. Vaccination with autologous DC’s, electroporated with mRNA encoding the WT1 antigen was evaluated in 10 patients with mesothelioma not progressing after platinum/ pemetrexed-based chemotherapy [7]. Biweekly intradermal vaccinations were administered for an intended period of 6 months, followed by monthly or bimonthly injections. DC vaccination was well-tolerated: no systemic toxicity was recorded; local reactions at the injections sites occurred in all patients, but were mild and self-limiting. At a median follow-up of 22.7 months, 6 patients are alive, 4 have died and 1 year survival rate is 90% from start of treatment, suggesting that adjuvant DC-based immunotherapy provides a clinical benefit. In a pilot trial in pretreated MPM, the multivalent native and synthetic WT1 peptide vaccine Galinpepimut-S was well-tolerated and CD4/8 immune responses were generated. After completing multimodality therapy, 40 mesothelioma patients were randomized to receive maintenance Montanide and GM-CSF with or without Galinpepimut-S [8]. There were no serious treatment related adverse events. Based on a pre-specified futility analysis, accrual was stopped. Median PFS from randomization was 11.4 months in the experimental arm vs. 5.7 months in the control arm (HR 0.69). Similarly, median overall survival (OS) from randomization was 21.4 months in the Galinpepimut-S arm vs. 16.6 months in the control arm (HR 0.52). In the subgroup with R0 resection, median OS was 39.3 months in the Galinpepimut-S and 24.8 in the control arm (p = 0.04). A confirmatory adequately powered randomized adjuvant study is awaited. In the European DENIM trial, patients not progressing after 1 st line platinum-pemetrexed chemotherapy will be randomized between standard follow up and a maintenance treatment consisting of 5 injections of DC’s, pulsed with an allogeneic lysate obtained from 5 well-characterized clinical grade human malignant mesothelioma cell lines. Cell-based immunotherapy carries high expectations but remains cumbersome and labour-intensive. Anti-CTL-A4 antibody-based immunotherapy in mesothelioma has so far failed to deliver the expected improvement in outcome. Whether this also applies to anti- PD-(L)1 monoclonal antibodies remains to be seen from ongoing and future trials. A low mutational burden and the limited formation of neo-epitopes under chemotherapy, -both considered important predictive factors for immune checkpoint therapy- are the challenges for this approach. As in other tumour types, studying a combination of different checkpoint inhibitors either with or without chemotherapy or with anti-angiogenic agents is of interest [9]. In thymic tumours, the presence or risk of developing immunemediated paraneoplastic syndromes is of particular concern. This could be an argument to prioritize checkpoint inhibitors in thymic carcinomas[10]. References 1: Marcq E et al. Targeting immune checkpoints: new opportunity for mesothelioma treatment? Cancer Treatm Rev 2015; 41(10):914 2:Kindler HL et al. Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): Results from the global, double-blind, placebo-controlled DETERMINE study. J Clin Oncol 2016; 34 (suppl): abstr 8502 3: Katsuya Y et al. Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma. Lung Cancer. 2015;88(2):154 4: Alley EW et al. Single- Agent Pembrolizumab for Patients with Malignant Pleural Mesothelioma. J Thorac Oncol 2015; 10(9) supplement 2: abstr O11.03 5: Quispel-Janssen J et al. NIVOLUMAB IN MALIGNANT PLEURAL MESOTHELIOMA (NIVOMES): AN INTERIM ANALYSIS. Proc IMiG 13, Birmingham 2016; abstr MS 04.07 6: Hassan R et al. Avelumab in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity and PD-L1 expression. J Clin Oncol 2016; 34(suppl): abstr 8503 7: Berneman ZN et al. Dendritic cell vaccination in malignant pleural mesothelioma: A phase I/II study. J Clin Oncol 2014; 32:5s: abstr 7583 8: Zauderer MG et al. Randomized phase II study of adjuvant WT1 vaccine (SLS-001) for malignant pleural mesothelioma after multimodality therapy. J Clin Oncol 2016; 34 (suppl): abstr 8519 9: Anonymous. Nivolumab Monotherapy or Nivolumab Plus Ipilimumab, for Unresectable Malignant Pleural Mesothelioma (MPM) Patients (MAPS2). Available at: https://clinicaltrials.gov/ct2/show/NCT02716272 10: Anonymous. MK-3475 in Patients With Thymic Carcinoma. Available at: https:// clinicaltrials.gov/ct2/show/NCT02364076 Keywords: thymic tumours, Mesothelioma, Immunotherapy, check point inhibitors SESSION SC07: NEW CHALLENGES FOR LUNG CANCER: WATERPIPES AND E-CIGARETTES MONDAY, DECEMBER 5, 2016 - 16:00-17:30 SC07.03 CONNECTIONS OF NICOTINE TO CANCER AND ITS INFLUENCE ON CANCER TREATMENT Sergei Grando University of California, Irvine/CA/United States of America There is a growing evidence of direct contributions of nicotine to cancer onset and growth. The list of cancers reportedly connected to nicotine is expanding and presently includes small-cell and non-small-cell lung carcinomas, as well as head and neck, gastric, pancreatic, gallbladder, liver, colon, breast, cervical, urinary bladder and kidney cancers. The mutagenic and tumour-promoting activities of nicotine may result from its ability to damage the genome, disrupt cellular metabolic processes, and facilitate growth and spreading of transformed cells. The nicotinic acetylcholine receptors (nAChRs), which are activated by nicotine, can activate several signaling pathways that can have tumorigenic effects, and these receptors might be able to be targeted for cancer therapy or prevention. There is also growing evidence that the unique genetic makeup of an individual, such as polymorphisms in genes encoding nAChR subunits, might influence the susceptibility of that individual to the pathobiological effects of nicotine. The emerging knowledge about the carcinogenic mechanisms of nicotine action should be considered during the evaluation of regulations on nicotine product manufacturing, distribution and marketing. Keywords: Cancer, Nicotinic acetylcholine receptor, nicotine SESSION SC08: IASLC-ESTS JOINT SYMPOSIUM: THE BORDERLINE PATIENT MONDAY, DECEMBER 5, 2016 - 16:00-17:30 Copyright © 2016 by the International Association for the Study of Lung Cancer S47
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