Immunotherapy has emerged as an important treatment modality for cancer. In contrast to most other cancer treatments, immunotherapy can induce durable clinical response in metastatic disease. Antibodies targeting PD-1 and anti-PD-L1 have shown significant clinical activity in multiple diseases. Importantly, dramatic clinical responses have been seen in patients with the metastatic bladder, a disease in which no new drugs have been approved for over 20 years. The mechanism by which these immunotherapies work in cancer patients is unknown, nor are there robust biomarkers that predict of response to these treatments. We will perform a clinical study administering anti-PD-L1 antibody in patients with localized bladder cancer prior to these patients undergoing planned surgery for their cancer. We propose to study the effects of anti-PD-L1 antibody treatment not just in the blood but within the actual tumor. We will determine whether this immunotherapy increases the number of T cells into the tumor by examining tissues from biopsies obtained before treatment and from the bladder tumor resected following treatment. We will use next generation sequencing to track individual T cell clones in the blood and tumors to also determine whether T cells present in the tumor are being recruited to the tumor site or were already at the tumor. We will study how this treatment activates a systemic immune response. Understanding how these treatments work within patients, including at the level of the tumor tissue, will provide avenues t improve the efficacy of this approach and/or develop biomarkers to identify those patients that can benefit from treatment. Moreover, if significant tumor regression is seen, this treatment approach could transform our approach to localized bladder cancer. Finally, the clinical and laboratory findings derived from this trial may also help transform in how metastatic bladder cancer could be treated and contribute significantly to the design of future clinical trials with P-L1 and/or PD-1 targeted drugs.
Bladder cancer represents a relative common malignancy with limited treatment options that have changed over the last 30 years. Immunotherapy with anti-PD-L1 antibodies has recently been shown to have significant clinical activity with minimal toxicity in this disease. This application proposes correlative studies for a phase II clinical tril of neoadjuvant anti-PD-L1 antibody treatment in patients with localized bladder cancer to dissect the immunomodulatory effects of this treatment in both the blood and tumor microenvironment.
| Mariathasan, Sanjeev; Turley, Shannon J; Nickles, Dorothee et al. (2018) TGF? attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554:544-548 |
