Oncolytic Newcastle disease virus can enhance anti-PD-1 checkpoint blockade for the treatment of muscle-invasive bladder cancer

Urothelial carcinoma (UC) is the most frequent malignancy of the urinary tract and the tenth most common cancer worldwide, resulting in almost 200,000 deaths every year. Muscle-invasive bladder cancer (MIBC) is an advanced stage of bladder cancer that affects 1 in 4 people diagnosed with UC. The standard treatment for MIBC is radical cystectomy, resulting in removal of the entire bladder and often the prostate in men and the ovaries in women. Only a small fraction of MIBC patients are eligible for bladder preservation therapy, consisting of a trimodal treatment with tumor resection, chemotherapy, and radiotherapy, but the efficacy remains low. There are several immunotherapy clinical trials for the treatment of MIBC, including checkpoint inhibitors as a monotherapy and in combination with chemotherapy, but durable response rates remain low. Despite preclinical data showing the efficacy of anti-programmed cell death protein-1 (anti-PD-1) and anti-programmed death-ligand 1 (anti-PD-L1) antibodies in inducing antitumor immune responses, 70-80% of patients remain unresponsive to immune checkpoint inhibition due to the immunosuppressive tumor microenvironment (TME). Currently, oncolytic virotherapy is being explored as a therapeutic for MIBC, specifically using Newcastle disease to mediate tumor cell lysis and activate tumor-specific immune responses. This article will explore the synergistic combination of oncolytic virotherapy with immune checkpoint blockade for the treatment of MIBC. Preclinical and clinical data have shown that increased immune cell infiltration and cytokine influx as a result of oncolytic virotherapy primes the TME for subsequent immune inhibitory checkpoint blockade. Other studies have shown that extensive tumor cell lysis and virus replication associated with oncolytic virotherapy is not necessary for immunotherapeutic efficacy when used in combination with checkpoint blockade. Therefore, understanding how the local TME changes after oncolytic virotherapy will allow us to exploit its immunomodulating effects and develop combination