dENdritic Cell Therapy Combined With SURgEry in Mesothelioma

Inclusion Criteria:

• Patients with a histologically confirmed diagnosis of epithelioid MPM who areeligible for 2 to 4 cycles of platinum-based chemotherapy. Patients who progressedafter chemotherapy will not be discontinued from the trial if they are stilleligible for eP/D and none of the exclusion criteria is present (e.g. localprogression with only focal chest invasion).

• Patients must be at least 18 years old and must be able to give written informedcon-sent.

• Resectable disease defined by stage cT1-3, N0-1, M0 (I to IIIA) according to UICCTNM classification (8th edition). A fluorodeoxyglucose (FDG)-positron emissiontomography (PET)-computerized tomography (CT) scan with fusion images showingabsence of M1, N2 involvement is required. Focal chest wall lesions are acceptable.

• Tumor tissue available after completing chemotherapy and before starting treatmentwith DCT. Tumor tissue can be obtained by either a CT-guided needle biopsy or aVideo-assisted thoracoscopic surgery (VATS) biopsy.

• Fit to receive platinum-based chemotherapy (as per standard of care of the treatingphysician/Institution) and undergo a P/D with optional removal of hemidiaphragm andpericardium. The responsible surgeon and chest physician should judge the requiredfitness prior to registration, taking into account the results of all the relevant (i.e. pulmonary, cardiac) examinations.

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix 2).

• Ability to return to the study center for adequate follow-up and vaccinations.

• Positive delayed-type hypersensitivity (DTH) skin test (induration > 2mm after 48hrs) against at least one positive control antigen tetanus toxoid.

• Written informed consent according to ICH-GCP.

• Subjects must have adequate organ function and adequate bone marrow reserve atscreening:

• creatinine ≤ 1.5 × upper limit of normal [ULN] or glomerular filtration rate ≥ 50 mL/min

• alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin ≤ 1.5 × ULN

• Absolute neutrophil count ≥1.5 x 109/L, platelet count ≥100 x 109/L, and Hb ≥9.0 g/dL. Criteria must be met without erythropoietin dependency and withoutpacked red blood cell (pRBC) transfusion within last 2 weeks.

• Women of childbearing potential must have a negative serum pregnancy test atscreening and a negative urine pregnancy test just prior to the first study drugadministration on Day 1, and must be willing to use an effective contraceptivemethod (intrauterine devices, hormonal contraceptives, contraceptive pill, implants,transdermal patches, hormonal vaginal devices, infusions with prolonged release) ortrue abstinence (when this is in line with the preferred and usual lifestyle)*during the study and for at least 12 months after the last study drugadministration.

*True abstinence is acceptable when this is in line with the preferred and usuallifestyle of the subject. Periodic abstinence (such as calendar, ovulation,symptothermal, post-ovulation methods) and withdrawal are not acceptable methods ofcontraception.

• Men must be willing to use an effective contraceptive method (e.g. condom,vasectomy) during the study and for at least 12 months after the last study drugadministration.

• Written informed consent according to the International Conference on Harmonisation (ICH)/Good Clinical Practice (GCP) guidelines.

Exclusion Criteria:

• Clinical or radiological invasion of mediastinal structures (heart, aorta, spine,esophagus, etc.) and widespread chest wall invasion (stage T4). Involvement of N2nodes. Stage IV (metastatic disease).

• Any different histology from the epithelioid MPM (as per assessed at time ofdiagnosis).

• Unavailability of tumor tissue after completing chemotherapy and before startingtreatment with DCT.

• Subject with any concurrent medical, psychological or psychiatric disease orcondition that is likely to compromise the ability to give informed consent or tointerfere with study procedures or results, or that in the opinion of theinvestigator would constitute a hazard for participating in this study.

• Use of >10 mg of prednisolone or equivalent/day (or other immunosuppressive agents)during the past 6 weeks before the first study drug administration and throughoutthe study. Prophylactic usage of dexamethasone (steroids) during chemotherapy isexcluded from this 6-week interval. Inhaled or topical steroids, and adrenalreplacement steroid ≤10 mg daily prednisone equivalent, are permit-ted in theabsence of active autoimmune disease.

• Major surgical procedure or significant traumatic injury within 28 days prior torandomization or anticipation of the need for major surgery (other than eP/D) duringthe course of study treatment.

• Subject with any previous malignancy except adequately treated basal cell orsquamous cell skin cancer, superficial or in-situ cancer of the bladder or othercancer for which the subject has been disease-free for at least 3 years.

• Prior treatment of any kind for mesothelioma, especially prophylactic trackirradiation after diagnostic procedures.

• Clinically significant pleural effusion that cannot be managed with thoracentesis orpleurodesis (according to institutional practice). If pleurodesis is considered, itshould be done before randomization.

• Subject with any known active serious infection, including human immunodeficiencyvirus (HIV), hepatitis B or C virus, or syphilis infection.

• Subject with a history of autoimmune disease, except for diabetes mellitus type I orother conditions, where patient can be eligible following discussion with medicalmonitor.

• Subject who has received an organ allograft.

• Serious intercurrent chronic or acute illness such as pulmonary (COPD or asthma) orcardiac (NYHA class III or IV) or hepatic disease or other illness considered by thestudy coordinator to constitute an unwarranted high risk for eP/D or investigationalDCT.

• Pregnant women, nursing mothers, lactating women, and women of child-bearingpotential who are unwilling to use effective contraceptive methods (intrauterinede-vices, hormonal contraceptives, contraceptive pill, implants, transdermalpatches, hormonal vaginal devices, infusions with prolonged release) during thestudy and for at least 12 months after the last study drug administration.

• Men unwilling to use effective contraception for the duration of the study and forat least 12 months after the last study drug administration.

• Inadequate peripheral vein access to perform leukapheresis

• History of receiving any investigational treatment within 28 days of randomization.

• Absence of assurance of compliance with the protocol. Lack of availability forfol-low-up assessment.

• Patients with a known allergy to shellfish (may contain KLH).