Background: The utilization of neoadjuvant immune checkpoint inhibitor (ICI) therapy, including anti-PD1/L1 agents, prior to radical cystectomy (RC), is an emerging paradigm in muscle invasive bladder cancer (MIBC). Pathologic complete responses (pCR) have been observed in 25-40% of patients with neoadjuvant PD1/L1 inhibitor monotherapy for cisplatin-ineligible MIBC. In situ vaccination using stereotactic body radiation therapy (SBRT) may augment T-cell responses to tumor-specific antigens through immunogenic cell death. Sasanlimab (PF-06801591) is a humanized IgG monoclonal antibody that targets PD-1 selectively, for which there are both Phase 1 data and ongoing Phase 3 trials in early-stage urothelial carcinoma. There exists a strong rationale to evaluate a novel strategy of combination neoadjuvant ICI therapy with SBRT as an in situ vaccine to improve loco-regional control and decrease the risk of distant recurrence in cisplatin-ineligible patients with MIBC. Methods: This is a prospective, investigator-initiated, single-arm, single-institution, phase II trial that evaluates neoadjuvant sasanlimab in combination with SBRT as neoadjuvant therapy for patients with MIBC before RC. Eligibility requires patients to be cisplatin-ineligible (one of the following: ECOG-PS=2, creatinine clearance <60 ml/min, or comorbidities such as hearing loss or neuropathy) or those who refuse cisplatin-based chemotherapy. Sasanlimab (300 mg) will be administered subcutaneously on Day 1 of each 28-day cycle for a total of 2 cycles, in combination with SBRT to the primary tumor at a dose of 24Gy given in 3 fractions, starting on Day 1 of Cycle 2 with a 48-hour interval between fractions. The combination treatment will be assessed by using a Simon’s 2-Stage design, which the first 10 patients are enrolled as a safety lead-in to evaluate the safety and feasibility. Futility analysis will be performed after a total of 18 patients. The primary endpoint is pCR rate after neoadjuvant sasanlimab/SBRT, followed by RC. If pCR is observed in 4 or fewer patients, further enrollment of patients may be stopped with the conclusion that pT0 cannot be 40% or greater. Otherwise, an additional 15 patients will be accrued in stage II, resulting in a total of 33 patients. Secondary endpoints include adverse events, surgical complication rates, health related quality-of-life, overall survival, and recurrence free survival. Exploratory endpoints include analysis of and association with pCR of the tumor/germline genetic signatures, circulating tumor DNA, tumor PD-L1 expression, blood cytometry time-of-flight analysis to identify immune response. Enrollment opened on February 15, 2022. Clinical trial information: NCT05241340.