Neoadjuvant Immune Checkpoint Inhibitor Treatment in Urothelial Cancer

Inclusion Criteria: Cohort-Specific Inclusion Criteria • Bladder cohort: Histopathologically confirmed carcinoma of the urothelium (T1 high grade -T4a) in the bladder with mixed or rare histological subtypes such as squamous cell or adenocarcinoma. Patients with mixed histologies are required to have a dominant non- transitional cell pattern. • UTUC cohort: Histopathologically confirmed,high grade or high risk upper urinary tract urothelial carcinoma (renal pelvis and ureter). This cohort includes all patients with upper tract malignancy who in the opinion of the investigators qualify for radical surgery (nephroureterectomy or distal ureter resection). Urothelial carcinoma of the upper urinary tract qualifies as high-risk disease if any of the below factors are present: * Hydronephrosis * Tumour size \>2cm on cross sectional imaging * High grade cytology * High grade biopsy * Multifocal disease * Variant histology * Previous radical cystectomy for urothelial cancer of the bladder All patients undergoing radical surgery with curative intent in the opinion of the investigator are eligible. Radical surgical interventions include nephroureterectomy or distal ureteral resection. General inclusion criteria: 1. Willing and able to provide written informed consent 2. Ability to comply with the protocol 3. Age ≥ 18 years 4. Residual disease after TURBT or URS (surgical opinion, endoscopy or radiological presence). 5. Fit and planned for radical surgery with curative intent in the opinion of the investigator (according to local guidelines). 6. N0 or M0 disease CT or MRI (within 4 weeks of registration) 7. Representative formalin-fixed paraffin embedded (FFPE) tumour samples with an associated pathology report that are determined to be available and sufficient for central testing. 8. Patients who refuse neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 10. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential. 11. For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate \[\<1% per year\] when used consistently and correctly) and to continue its use for 90 days after the last dose of atezolizumab. 12. Adequate hematologic and end-organ function within 4 weeks prior to the first study treatment defined by the following: 1. ANC ≥ 1500 cells/μL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1) 2. WBC counts \> 2500/μL 3. Lymphocyte count ≥ 500/μL 4. Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to Cycle 1, Day 1) 5. Haemoglobin ≥ 9.0 g/dL (patients may be transfused or receive erythropoietic treatment to meet this criterion). 6. AST or ALT,and alkaline phosphatase ≤ 2.5 times the institutional upper limit of normal (ULN) (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled). 7. INR and aPTT ≤ 1.5 × the institutional ULN. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose. 8. Calculated creatinine clearance ≥ 20 mL/min (Cockcroft-Gault formula) Exclusion Criteria: 1. Pregnant and lactating female patients. 2. Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis. 3. Previously intravenous chemotherapy for urothelial cancer. 4. Patients with prior allogeneic stem cell or solid organ transplantation. 5. Prior treatment with CD137 agonists,anti-CTLA-4,anti-programmed death-1 (PD-1),or anti-PD-L1 therapeutic antibody or pathway-targeting agents. 6. Patients must not have had oral or IV steroids for 14 days prior to study entry. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e.,for adrenal insufficiency), and mineralocorticoids (e.g. fludrocortisone) is allowed. 7. Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (Patients receiving prophylactic antibiotics (e.g.,for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible). 8. Administration of a live,attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live,attenuated vaccine will be required during the study. 9. Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin \[IL\]-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment. 10. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrolment. 11. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome). 12. Malignancies other than UC within 5 years prior to Cycle 1,Day 1,with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) or localized prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse or incidental prostate cancer (Gleason score ≤ 3 + 4 and PSA \< 10 ng/mL undergoing active surveillance and treatment naive). 13. Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteraemia,or severe pneumonia. 14. Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina. 15. History of idiopathic pulmonary fibrosis (including pneumonitis),drug-induced pneumonitis, organizing pneumonia (i.e.,bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan (History of radiation pneumonitis in the radiation field (fibrosis) is permitted). 16. Patients with uncontrolled Type 1 diabetes mellitus. Patients with Type 1 diabetes controlled on a stable insulin regimen are eligible. 17. Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen \[anti-HBc\] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Positive test for HIV 19. Patients with active tuberculosis 20. History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug. 21. Uncontrolled hypercalcemia (\> 1.5 mmol/L ionized calcium or Ca \> 12 mg/dL or corrected serum calcium \> the institutional ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead while on study. 22. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. 23. Patients with a history of autoimmune-related hypothyroidism, unless on a stable dose of thyroid-replacement hormone. 24. History of severe allergic, anaphylactic,or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins 25. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation