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J.P. Van Meerbeeck
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OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
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OA02.07 - Characterization of the Tumor Microenvironment and Investigation of Immune Checkpoint Expression in Malignant Pleural Mesothelioma (ID 4437)
12:05 - 12:15 | Author(s): J.P. Van Meerbeeck
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a role in protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints might help to identify new immunotherapeutic targets and their predictive and/or prognostic value.
Methods:
Immunohistochemistry (IHC) was performed on tissue samples of untreated (n=40) and chemotherapy-pretreated (n=14) MPM patients. Different subsets if immune cells were identified based on staining for CD4, CD8, FoxP3, CD68, CD45RO and granzyme B. The expression of the immune checkpoints TIM-3, LAG-3, PD-1 and its ligand PD-L1 was also investigated. The relationship between the immunological parameters and survival, as well as response to chemotherapy was analyzed using the R statistical software.
Results:
All patients had CD8+ tumor infiltrating lymphocytes (TILs), CD68+ histiocytes and macrophages and CD45RO+ T cells in their stroma, with CD8+ TILs being the predominant cell type of the immune infiltrate. Stromal CD4+ TILs were found in 75% of the untreated and 71% of the pretreated samples. A subset of those cells was also FoxP3+ and these CD4+FoxP3+ cells were positively correlated with stromal CD4 expression (p<0.001). Less than half of the samples showed positivity for granzyme B. Both, untreated and pretreated patients had PD-1+ TILs, while only 10% of the untreated patients also had PD-1+ tumor cells. PD-L1 positivity on lymphocytes and/or tumor cells was observed for more than half of the patients, with significant differences according to the histological subtype (p<0.001). Patients with a sarcomatoid histology showed the most PD-1 expression. TIM-3 was expressed in tumor cells, stromal lymphocytes and plasma cells, less often in pretreated samples compared to untreated samples. All samples were negative for LAG-3. After multivariate analysis stromal CD45RO expression was found to be an independent negative predictive factor for response to chemotherapy (p=0.017) and expression of CD4 and TIM-3 in lymphoid aggregates were good prognostic factors (p=0.008; p=0.001).
Conclusion:
Our data reveal the diversity of immune cells present in MPM and point to TIM-3 as a new target in mesothelioma. Administering chemotherapy before or together with PD-1/PD-L1/TIM-3 blocking agents may not be the best combination sequence and further research on the predictive value of CD45RO in the stroma might guide patient selection for chemotherapy.
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OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:H. Pass, N. Van Zandwijk
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 3
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OA22.05 - Breath Analysis by Gas Chromatography-Mass Spectrometry Can Be Used to Screen for Pleural Mesothelioma (ID 4845)
15:40 - 15:50 | Author(s): J.P. Van Meerbeeck
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is an asbestos-related tumour with poor prognosis. Since MPM is diagnosed at advanced stage due to non-specific symptoms and investigations, it is thought that only an early diagnosis will improve patient’s outcome. Breathomics allows to detect volatile organic compounds (VOCs) in breath which can be used as non-invasive biomarkers. Although we were able to discriminate MPM patients from controls using ion mobility spectrometry breathomics, we were not able to identify specific VOCs. Therefore, we aimed to identify VOCs in the breath of MPM persons and persons at risk with gas chromatography-mass spectrometry (GC-MS).
Methods:
Fourteen MPM patients, eighteen asymptomatic asbestos-exposed individuals, 16 individuals with benign asbestos-related diseases and fourteen healthy non-exposed persons were included. After 2 hours of fasting, participants breathed tidally for 5 minutes through a mouthpiece connected to a VOC filter. Subsequently, a full vital capacity was captured in a Tedlar bag of which 500 ml was immediately transferred on a Tenax[GR]-column. Samples were thermally desorbed followed by GC-MS analysis (Agilent 6890A–Thermo Focus DSQII). VOCs were manually selected in the chromatogram and standardised to an internal standard (toluene-d8). Only VOCs with a S/N-ratio>10 were used. Using SPSSv23, significant differences were searched and ROC-curves for discriminating MPM from all control groups were constructed. VOCs which had an AUC~ROC~>0.80 are reported.
Results:
114 VOCs were selected of which 17 were significantly different between MPM patients and controls. Of these, 7 had AUC~ROC~>0.80 and are possible markers for MPM diagnosis.Figure 1
Conclusion:
The large discriminative power and good sensitivity and specificity imply the possibility to use breath analysis for MPM screening. Therefore, persons exposed to asbestos with a positive test should be considered for follow-up in a cost-effective way, decreasing the need for CT-scans and radiation exposure in low-risk persons. Further work includes combining models for discrimination and validating these findings.
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P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.03-028 - Wolf in Sheep's Clothing - Primary Lung Cancer Mimicking Benign Diseases (ID 3937)
14:30 - 14:30 | Author(s): J.P. Van Meerbeeck
- Abstract
Background:
Lung cancer is the biggest cancer killer and typically presents as mass or nodule, round or oval in shape. Recognition and diagnosis of these typical cases is often straightforward, whereas diagnosis of uncommon manifestations of primary lung cancer certainly is far more challenging. The aim of this pictorial essay is to illustrate the Computed Tomography (CT) and histopathology findings of uncommon manifestations of primary lung cancer with focus on these entities that mimic benign diseases.
Methods:
Cases presented were collected during the Multidisciplinary Thoracic Oncology Tumor Board between January 2014 and May 2016 and have histopathologic proof.
Results:
Lung cancer can mimic a variety of benign diseases, including infection, granulomatous disease, lung abscess, postinfectious scarring, mediastinal mass, emphysema, atelectasis and pleural disease. Previous history, clinical and biochemical parameters are certainly helpful and necessary in the assessment of these cases, but often aspecific and inconclusive. Whereas 18FDG-PET is the cornerstone in diagnosis and staging of lung cancer, it’s role in these uncommon manifestations is less straightforward since benign diseases, such as granulomatous and infectious diseases may also present with increased FDG-uptake. Chest CT is the imaging modality of choice and plays a central role in these cases. ‘Irregular air bronchogram sign’ in pneumonia-like lung cancer, ‘drowned lung sign’ in obstructive atelectasis and cortical bone erosion in lung cancer mimicking pleural disease are important signs that point to a malignant etiology. The stippled and eccentric morphology of calcifications in apical lesions aids in differentiating these lesions from postinfectious scarring. Mucinous tumours can mimic a pulmonary abscess and small cell lung cancer can typically present as mediastinal mass without parenchymal abnormalities. Lung cancer presenting with a miliary pattern or cavitating nodules can mimic granulomatous disease. Lung cancer presenting with cystic airspaces and ‘emphysema-like’ morphology is an uncommon entity in which early recognition is crucial since these tumors have an aggressive nature. Key imaging findings and tips and tricks for recognizing these uncommon faces of primary lung cancer will be discussed and illustrated.
Conclusion:
Primary lung cancer can mimic a wide variety of benign entities. Knowledge of these uncommon and atypical manifestations is crucial to avoid delay in diagnosis and treatment. A multidisciplinary approach in these cases is mandatory.
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P1.03-078 - Size Matters...but Don't Underestimate the Power of Morphology (ID 4181)
14:30 - 14:30 | Author(s): J.P. Van Meerbeeck
- Abstract
Background:
The detection of solitary pulmonary nodules has increased due to the widespread use of Computed Tomography (CT) and will increase even more in the future when lung cancer screening will be embedded in daily practice. In addition to the clinical information, size is one of the most important parameters to assess the likelihood of malignancy. Although there is a considerable overlap in imaging characteristics of benign and malignant solitary pulmonary nodules, the power of morphology –even in small nodules- should not be underestimated. The aim of this pictorial essay is to give an overview of the wide range of morphologic characteristics and to address the available evidence on sensitivity and specificity of these characteristics.
Methods:
Cases presented were collected during the Multidisciplinary Thoracic Oncology Tumor Board between January 2014 and May 2016. All malignant cases have histopathologic proof, whereas benign lesions were included when the benign nature was suggested after follow-up, negative PET-scan and/or multidisciplinary consensus.
Results:
With regard to margin characteristics, spiculation is highly suggestive of a malignant nature. It is the only feature that is incorporated as ‘morphologic’ variable in most risk prediction models. Other features however may also be strong indicators of malignancy. Lobulation, halo sign, pleural indentation, vascular convergence sign and pitfall sign are frequently encountered in malignant nodules. The nodule-bronchus relationship can give additional information regarding the nature of the nodule, with signs such as air bronchogram, bubble like lucencies and bronchus cutoff sign being indicative of a malignant nature. In cavitated nodules, a very thin wall might indicate a benign cause, whereas a very thick wall is more common in malignant nodules. Calcification is typically seen in benign nodules, but depending on the calcification pattern a malignant etiology cannot be excluded. The presence of fat is a relative reliable sign of benignity. Thin-section CT will enable detection of subtle findings. Nodules rarely present with only one characteristic and combination of findings can definitely increase the likelihood of a correct diagnosis.
Conclusion:
The management of solitary pulmonary nodules involves both clinical and imaging assessment. Although a great overlap exists in morphologic features of benign and malignant nodules, thorough knowledge and recognition of subtle morphologic findings will aid in early detection of nodules with a high likelihood of malignancy and will avoid unnecessary follow-up and delay in diagnosis and treatment.
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P1.04 - Poster Session with Presenters Present (ID 456)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Pulmonology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.04-028 - Collection of ICHOM-Defined Patient-Reported Outcome Measures (PROMs) during Routine Lung Cancer Treatment: A Pilot Study (ID 5476)
14:30 - 14:30 | Author(s): J.P. Van Meerbeeck
- Abstract
Background:
PROMs -including symptoms, health related quality of life, well-being and functional status- are commonly measured in clinical trials. They are used in a variety of ways, including therapy decisions on individual patient level or research into disease progression. Optimizing how patients feel is a goal of good oncology practice and a quality performance indicator of care. Therefore it is important to implement the collection of PROMs during routine lung cancer treatment without disturbing the routine workflow. The International Collaboration on Health Outcomes Measures (ICHOM) has proposed a standard set of uniform PROMs for lung cancer (Mak et al, ERJ 2016).
Methods:
A pilot study is set up to establish an operational workflow and to identify trouble shooting to the collection of PROMs in standard of care. Self-reporting by the patient is conducted via a web-based interface using questionnaires and individual case-mix variables according to the ICHOM standard set. At baseline, during treatment and in follow up patients receive electronic invitations. Computer-inexperienced patients have the opportunity to complete paper forms.
Results:
A gap analysis was done and a swim lane algorithm constructed which will be presented at the meeting. From February 2016 onwards, 24 patients were screened of whom 11 consented. The other 13 patients were screen failures because of language barrier, previous therapy start or mental confusion. From the enrolled patients, 2 are currently in follow up and 5 patients choose to complete PROMs on paper forms. Updated results on compliance and outcome in 50 patients will be brought at the meeting.
Conclusion:
Participants’ profile reflect a tertiary setting hospital with many referrals and patients, unable to complete the PROM’s. To optimize the inclusion rate, several adaptations in the implementation workflow have been introduced. Although the registration of PROMs is not very time-consuming, real-time monitoring requires a user-friendly online tool and dedicated staff. Lessons from this pilot study will be applied when rolling out other ICHOM standard sets.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-093 - Exo-ALK Proof of Concept: Exosomal Analysis of ALK Alterations in Advanced NSCLC Patients (ID 5471)
14:30 - 14:30 | Author(s): J.P. Van Meerbeeck
- Abstract
Background:
A subset of NSCLCs (approx. 5%), present alterations in ALK gene. This produces abnormal ALK proteins that induce cells to grow and spread. Different generation of ALK inhibitors are available for targeted therapy and their indication depends on the detection of ALK alterations in the tissue. Thus, it is mandatory to develop new techniques that allow us to demonstrate ALK alterations in peripheral blood. The purpose of this study is to analyze the feasibility to determine ALK alterations in exosomes (Exo-ALK) in NSCLC patients and determine the sensitivity and specificity of the technique.
Methods:
This study is performed in blind in a cohort 19 NSCLC with and without known alterations of ALK in tumoral tissue. ALK-positive tissue samples were identified by FISH or IHQ and patients were included independently of stage and time of disease. Exosomal RNA is isolated by exoRNeasy Serum/Plasma (Qiagen) and retrotranscripted by ProtoScript II First Strand cDNA Synthesis kit. The ALK gene present in the exosomes was determined by NGS and bioinformatic analysis by OncoDNA. Samples and data from patients included in the study were provided by the Biobank of the University of Navarra and were processed following standard operating procedures approved by the Ethical and Scientific Committees, were provided also by UZA Biobank and by the University of Naples Federico II.
Results:
The analyzed samples have been 16 ALK-EML4 tissue positive patients and 3 ALK-EML4 tissue negative, defined in this case by FISH. After analysis, we have been able to detect 9 positive ALK-EML4 patients, 8 negative samples and 2 samples where the RNA was degraded. Looking at the clinical data, the 9 positive samples detected in the exosomal RNA were positive also for ALK-EML4 translocation in the tissue, and comparing the 8 negative samples, 3 were tissue negative and 5 tissue positive. These data show a specificity of 64% and a specificity of 100%. No correlation has been found comparing naïve patients with treated patients.
Conclusion:
Exosomes are raising as one of the most promising tools to understand the tumor due to their stability in the blood and their similarity to the cells of origin. Our preliminary results show a high specificity and sensitivity for a proof of concept analysis. Further studies with a bigger number of patients and a crossvalidation analysis are required, but as we represent in this abstract, exosomes can represent an important tool for the clinical management of this specific NSCLC population.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-027 - Randomized Phase II Study of Anetumab Ravtansine or Vinorelbine in Patients with Metastatic Pleural Mesothelioma (ID 5671)
14:30 - 14:30 | Author(s): J.P. Van Meerbeeck
- Abstract
Background:
Mesothelioma is a rare but aggressive cancer with a poor prognosis. Mesothelin is a cell surface protein that is highly expressed in mesothelioma and other epithelial cancers. Anetumab ravtansine (BAY 94-9343), a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DM4, has shown encouraging efficacy in mesothelioma patients in a phase I study. To further explore the possible benefit of antibody-drug conjugate therapy for mesothelioma, we initiated a randomized, open-label, active-controlled, phase II trial to evaluate the efficacy and safety of anetumab ravtansine in patients with metastatic pleural mesothelioma (MPM) overexpressing mesothelin and who have previously progressed on platinum/pemetrexed-based first-line chemotherapy (NCT02610140).
Methods:
Patients (≥18 years) with unresectable locally advanced or metastatic MPM are eligible. Patients should have recurrent or relapsing disease after having previously receiving first-line treatment with pemetrexed-based chemotherapy, with or without bevacizumab. Obligatory biomarker sampling will be performed on all patients at pre-screening and mesothelin-positivity as determined by Ventana MSLN (SP74) companion diagnostic assay as a requirement for entry. The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS) per modified RECIST criteria for MPM per central review. The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Approximately 210 patients will be randomized in a 2:1 ratio to receive anetumab ravtansine 6.5 mg/kg Q3W or vinorelbine 30 mg/m[2] QW. Novel study methods include a grading system for AEs of special interest and the PRO instruments.
Results:
This trial is open and currently accruing patients globally.
Conclusion:
Section not applicable.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-049 - Optimisation of Malignant Mesothelioma Registration at the Belgian Cancer Registry (ID 3907)
14:30 - 14:30 | Author(s): J.P. Van Meerbeeck
- Abstract
Background:
Malignant mesothelioma (MM) is a rare but aggressive cancer mostly caused by asbestos exposure, and for which diagnosis is difficult to make. Completeness and correctness of MM registration at the Belgian Cancer Registry (BCR) is assessed using information from three independent national databases, i.e. the standard cancer registration, the population-based mortality statistics (death certificates, COD) and the Belgian Mesothelioma Registry (BMR).
Methods:
The study cohort includes all MM diagnoses reported to BCR (incidence years 2004-2012; n=2,344), all patients reviewed by the pathology commission of BMR (2004-2012; n=2,019), and COD data for all Belgian citizens (2004-2013). All available data are compared for diagnosis and immunohistochemical (IHC) tests as derived from the available pathology reports (APD) at BCR or registered by BMR.
Results:
Preliminary analyses (n=1,927; 81% of the study cohort) showed that 94% of diagnoses were concordant between BCR and BMR. The proportion of MM without specified histological diagnosis (28% before project start) could be reduced to less than 1%. IHC results derived from APD and/or BMR were available for 86% of the cases. The most commonly performed markers were calretinin, CEA, CK5/6 and TTF1, as expected. Different IHC patterns could be distinguished in concordance with MM histology. MM was mentioned in 165 COD between 2004-2011 that remained uncoupled to BCR. For 139 patients registered at BCR with a different diagnosis, COD indicated MM as cause of death.
Conclusion:
This projects aims to achieve a complete and correct registration of MM diagnoses in Belgium by comparing information from three independent national databases. Discordant cases will be explored in detail and if necessary, a pathology revision will be performed. Once a definitive database is obtained, further analyses will be conducted including in-depth profiling of long-term survivors and description of treatment patterns for MM.
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P3.05 - Poster Session with Presenters Present (ID 475)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Palliative Care/Ethics
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.05-019 - Patients with Advanced Lung Cancer: What Do They Know, What Would They Like to Know, What Should They Know about Their Disease (ID 3872)
14:30 - 14:30 | Author(s): J.P. Van Meerbeeck
- Abstract
Background:
The treating oncologist has to take up the responsibilty fot at least a part of the EPC process. Communication about the palliative setting is often a barrier for many physicians. We want to break this taboo by asking patients what they know and what they want to know about their cancer (treatment).
Methods:
In this multicentre study a questionnaire surveyed three domains of interest : perception of prognosis, presumed treatment goal and preferences about information regarding prognosis and end-of-life (EoL) care.
Results:
64% of participants (N= 106) know they can’t be cured, only 45% know their treatment can’t cure them. Comparing treatment goals between patients who know their treatment cannot cure and patients who are likely to think that their treatment can cure them the former choose more QoL (39% versus 9%) and the latter cure (36% versus 13%)(Chi square = 17,7, p = .001). . Figure 1 Figure 2
Conclusion:
Only 45% of patients know their treatment is not curative, although this study shows they should know the palliative intent. Patients with advanced lung cancer who know they cannot be cured, are more aware of the primary goal of a palliative treatment. 57% and 51% wants to have a conversation about EoL care and their prognosis.
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SC06 - Novel Therapies in Malignant Pleural Mesothelioma and Thymic Malignancies (ID 330)
- Event: WCLC 2016
- Type: Science Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
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SC06.04 - Immunotherapy of Malignant Pleural Mesothelioma and Thymic Malignancies: The End of the Beginning? (ID 6624)
15:30 - 15:45 | Author(s): J.P. Van Meerbeeck
- Abstract
- Presentation
Abstract:
The significant improvement in outcome observed with immune checkpoint 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 tumor-derived 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
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 immune-mediated 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/NCT02364076Trial Drug Phase Line N Subtype ORR/DCR (%) PFS DETERMINE (2) Tremelimumab 3 2/3 382 Ep: 83% 4.5/31.7 2.8 m KEYNOTE 28 (4) Pembrolizumab 2 2 25 all PDL1+ 28/76 49.4% @ 6m NIVOMES (5) Nivolumab 2 NR 18 NR 27/49 NR JAVELIN (6) Avelumab 1b 2-5 53 Ep: 83% 9.4/56.6 17.1 w
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