Propranolol With Tislelizumab Plus GC in Neoadjuvant Bladder UC

Inclusion criteria

• Voluntarily agrees to participate in the study, is able to provide written informed consent, and is willing to comply with study procedures and visit schedules.
• Age ≥ 18 years at the time of consent; sex unrestricted.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Histologically confirmed bladder urothelial carcinoma with clinical lymph node involvement (cT1-T4a, N1-N3, M0) based on the AJCC 8th edition. Mixed histology is permitted if the urothelial carcinoma component is ≥ 50%.
• No antihypertensive medication used during screening, with resting systolic blood pressure between 110-140 mmHg measured under natural conditions.
• Adequate organ function as demonstrated by laboratory results obtained within 14 days prior to enrollment:

a. No administration of hematopoietic growth factors within 14 days prior to sample collection.

i. Absolute neutrophil count ≥ 1.5 × 10⁹/L ii. Platelet count ≥ 90 × 10⁹/L iii. Hemoglobin ≥ 90 g/L b. INR or aPTT ≤ 1.5 × ULN c. Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN in patients with Gilbert syndrome or indirect hyperbilirubinemia) d. AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN e. Preoperative pulmonary function assessment indicating tolerance of major abdominal surgery.

• Cisplatin-eligible patients, or cisplatin-ineligible patients who meet at least one of the following:

• ECOG performance status > 1 or Karnofsky 60-70%
• Creatinine clearance < 60 mL/min
• Grade ≥ 2 hearing loss (NCI-CTCAE v5.0)
• Grade ≥ 2 peripheral neuropathy (NCI-CTCAE v5.0)
• New York Heart Association (NYHA) class III or above heart failure
• Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment and agree to use effective contraception during the study and for ≥ 120 days after the last dose. Male participants must agree to use effective contraception during the study and for ≥ 120 days after the last dose.

Exclusion criteria

• Prior treatment with PD-1, PD-L1, PD-L2, CTLA-4 inhibitors, or other T-cell co-stimulatory/checkpoint agents.
• Systemic antineoplastic therapy or immunomodulatory therapy within 28 days prior to enrollment, including interferon, interleukin-2, or TNF-based agents.
• Prior radiotherapy for bladder cancer.
• Prior systemic anticancer therapy except:

• Previous systemic chemotherapy completed ≥ 12 months before initiation of study treatment.
• Intravesical chemotherapy or immunotherapy completed ≥ 7 days prior to initiation of study treatment.
• Major surgery or significant trauma within 28 days prior to enrollment (vascular access placement and TURBT excluded).
• Receipt of live attenuated vaccines within 28 days prior to enrollment. Inactivated influenza vaccination is allowed; intranasal influenza vaccine is not permitted.
• Active autoimmune disease requiring systemic therapy, as judged by the investigator.
• Long-term systemic corticosteroid therapy or other immunosuppressive medications judged to interfere with study treatment.
• Uncontrolled systemic disease that may interfere with treatment, including:

• Clinically relevant electrolyte abnormalities
• Hypoalbuminemia
• Interstitial lung disease or non-infectious pneumonitis
• Uncontrolled diabetes, hypertension, or cardiovascular disease (including unstable angina, myocardial infarction, symptomatic heart failure, or medically managed ventricular arrhythmias within 6 months).
• Chronic hepatitis B infection with HBV DNA ≥ 500 IU/mL (2,500 copies/mL). Patients with inactive HBsAg carrier status or viral suppression (HBV DNA < 500 IU/mL) after antiviral therapy may be enrolled. HBV DNA testing is required if anti-HBc is positive.
• Active hepatitis C infection. Patients who are HCV antibody negative, or HCV antibody positive but HCV RNA negative, are eligible.
• History of immunodeficiency disorders (including HIV infection), congenital or acquired immune deficiency, or prior allogeneic stem cell transplantation or organ transplantation.
• Known hypersensitivity to monoclonal antibodies, or known allergy to propranolol or other β-adrenergic receptor blockers.
• Toxicities from previous therapies have not returned to baseline or stabilized, unless deemed not to pose a safety risk by the investigator (e.g., alopecia, neuropathy, specific laboratory abnormalities).
• Contraindications to propranolol, including but not limited to:

• Unstable angina
• Decompensated heart failure
• Symptomatic sinus bradycardia
• Atrioventricular block
• Severe asthma or bronchospasm
• Current use of oral or intravenous β-blockers (e.g., atenolol, bisoprolol, carvedilol, metoprolol) that cannot be safely discontinued or transitioned. If previously used, a washout period of at least 14 days with medical reassessment is required before enrollment.