Integration of the PD-L1 Inhibitor Atezolizumab and WT1/DC Vaccination Into Platinum/Pemetrexed-based First-line Treatment for Epithelioid Malignant Pleural Mesothelioma

Inclusion Criteria:

Subjects must meet all the following criteria to be eligible to participate in the study:

* Signed informed consent
* Diagnosis with histologically proven epithelioid unresectable MPM (stage I-IV)
* Age ≥ 18 years at the time of signing informed consent
* World Health Organization (WHO) performance status 0-1
* Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained at the time of screening:

  * Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L (1500/μL) without granulocyte colony- stimulating factor support
  * Lymphocyte count ≥ 0.5 x 10\^9/L (500/μL)
  * Platelet count ≥ 100 x 10\^9/L (100,000/μL) without transfusion
  * Hemoglobin ≥ 90 g/L (9 g/dL) Patients may be transfused to meet this criterion
  * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), with the following exceptions:
  * Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
  * Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
  * Total bilirubin ≤ 1.5 x ULN with the following exception:
  * Patients with known Gilbert disease: total bilirubin ≤ 3 x ULN
  * Creatinine ≤ 1.5 x ULN
  * Albumin ≥ 25 g/L (2.5 g/dL)
  * For patients not receiving therapeutic anticoagulation: prothrombin international normalized ration (PT-INR) and activated partial thromboplastin time (APTT) ≤ 1.5 x ULN
* Negative Human Immunodeficiency Virus (HIV) test at screening
* Negative hepatitis B surface antigen (HBsAg) test at screening
* Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening

  * The HBV DNA test will be performed only for patients who have a negative HBsAg test and a positive total HBcAb test.
* Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening. The HCV RNA test must be performed for patients who have a positive HCV antibody test.
* Willing and able to comply with the study protocol, as judged by the treating physician
* Women of childbearing potential must have a negative serum or urine pregnancy test at the time of screening and agree to use effective contraception (\<1% failure rate per year) before, during and for at least five months after the last atezolizumab administration or at least hundred days after the last WT1/DC vaccine administration (whichever takes longer). Men must agree to use effective contraception before, during and for at least hundred days after the last study treatment administration.

Exclusion Criteria:

Subjects who fulfill any of the following criteria will not be eligible for admission into the study:

* History of malignancy within 3 years prior to initiation of study treatment, with the exception of the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \> 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
* Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:

  * Measurable disease, per RECIST v1.1, must be present outside the CNS.
  * The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
  * The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.
  * The patient has no ongoing requirement for corticosteroids as therapy for CNS disease.
  * If the patient is receiving anti-convulsant therapy, the dose is considered stable.
  * Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
  * There is no evidence of interim progression between completion of CNS directed therapy and initiation of study treatment.
  * Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy and/or surgery, with no need to repeat the screening brain scan.
* History of leptomeningeal disease
* Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

  * Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
  * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
  * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

    * Rash must cover \< 10% of body surface area
    * Disease is well controlled at baseline and requires only low-potency topical corticosteroids
    * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.
* History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
* Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
* Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
* Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety
* Prior treatment for MPM
* Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease (COPD) exacerbation) are eligible for the study.
* Prior allogeneic stem cell or solid organ transplantation
* Use of any investigational agent within 28 days before study enrollment
* Pregnant or breastfeeding. Female subjects who are breastfeeding should discontinue nursing prior to the first dose of study treatment and until at least hundred days after the last study treatment administration.
* Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab.
* Current treatment with anti-viral therapy for HBV
* Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
* Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α \[TNF-α\] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

  * Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study after Medical Monitor confirmation has been obtained.
  * Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low dose corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
* Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or 5 drug-elimination half-lives of the drug, whichever is longer, prior to initiation of study treatment
* History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
* Any other condition, either physical or psychological, or reasonable suspicion thereof on clinical or special investigation, which contraindicates the use of atezolizumab, pemetrexed, cisplatin/carboplatin and/or WT1/DC vaccination, or may negatively affect patient compliance, or may place the patient at higher risk of potential treatment complications.