Stage II-IIIa Urothelial Cancer Randomizing Pre-operative Nivolumab With or Without Relatlimab

Inclusion Criteria:

* Willing and able to provide informed consent
* Age ≥ 18 years
* Resectable muscle-invasive UC of the bladder, defined as cT2-4aN0M0 OR cT1-4aN1M0. In cT1N1 patients, lymph node positivity would need to be cytologically or histologically confirmed.
* Surgical resection (cystectomy) is the advised locoregional treatment and is accepted by the subject after consultation with the urologist.
* Patients are either cisplatin ineligible or elect to not undergo cisplatin based neoadjuvant chemotherapy after a balanced discussion of risks and benefits with the treating physician. Cisplatin eligibility is determined based on the Galsky criteria
* World Health Organization (WHO) performance Status 0 or 1.
* Urothelial cancer is the dominant histology (\>50%). Any component of small cell or adenocarcinoma is not allowed.
* Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available.
* Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, GFR\>30 ml/min, AST ≤ 1.5 x ULN, ALT ≤1.5 x ULN, Bilirubin ≤1.5 X ULN
* Negative pregnancy test (βHCG in blood or urine) within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
* Highly effective contraception for female subjects if the risk of conception exists. Female patients of childbearing potential must comply with contraception methods as requested by the study protocol (→ 8.2.1 Pregnancy, contraception and breastfeeding)

Exclusion Criteria:

* Subjects with active autoimmune disease in the past 2 years. Patients with diabetes mellitus, properly controlled hypothyroidism or hyperthyroidism, vitiligo, psoriasis or other mild skin disease can still be included.
* Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).
* Previous intravenous systemic therapy or radiotherapy for UC.
* Upper urinary tract disease, unless all disease is planned to be resected in the same surgery as for UBC. This includes non-muscle-invasive disease.
* Prior CTLA-4, LAG3 or PD-1/PD-L1-targeting immunotherapy.
* Known active Human Immunodeficiency Virus infection, or tuberculosis, or other active infection:
* HIV-positive patients are eligible if the following applies:
* No AIDS defining opportunistic infection within the last year and a current CD4 count \>350 cells/uL.
* Received antiretroviral therapy (ART) for at least 4 weeks prior to treatment and continued while enrolled on study
* CD4 counts and viral load are monitored per standard of care by a local health care provider
* In patients with a known history of hepatitis B or hepatitis C infection, Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA) should be negative
* Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events. Examples may include severe pulmonary disease with extensive radiological abnormalities or intestinal disease causing severe diarrhea, not covered by other eligibility criteria, that may obscure colitis.
* Medical condition requiring the use of immunosuppressive medications, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) will be allowed.
* Use of other investigational drugs before study drug administration.
* Malignancy, other than urothelial cancer, in the previous 2 years, with a high chance of recurrence (estimated \>10%). Patients with low-risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.
* Pregnant and lactating female patients.
* 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.
* Severe infections within 2 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
* 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 and unstable angina.