Immunotherapy for genitourinary malignancies is not new, as high-dose interleukin-2 (IL-2 [Proleukin]) for metastatic renal cell carcinoma (mRCC) and intravesical bacillus Calmette-Guérin for high-grade bladder cancer have been used since the 1990s. However, the modern era of immunotherapy for bladder, renal, and prostate cancer began in 2010 with the approval of sipuleucel-T (Provenge), the autologous, dendritic cell-based vaccine for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC), and it is a rapidly evolving landscape.
Since then, multiple checkpoint inhibitors (CPIs) have been approved for mRCC and metastatic urothelial carcinoma (UC), and numerous trials of immunotherapy for prostate cancer, UC, and RCC are ongoing.
This article discusses the current status and potential future developments in immunotherapy for genitourinary malignancies with insights from urologic oncology specialists Hyung L. Kim, MD, and Daniel P. Petrylak, MD.
Mechanism of action
Sipuleucel-T, which is the first therapeutic cancer vaccine approved by the FDA, stimulates an anti-tumor T-cell response using the patient’s own antigen-presenting cells that are removed, activated, and educated against tumor antigen ex vivo, and then reinfused.
Rather than inducing an immune response, CPIs release inhibitory mechanisms and restore the body’s natural T-cell-mediated antitumor response. The T-cell-mediated immune response is regulated by a system involving stimulatory and inhibitory molecules. The inhibitory molecules, which are known as immune checkpoints, regulate activation of cytotoxic lymphocytes and their effector function to maintain self-tolerance and minimize damage to normal collateral tissue during an immune response. The development of CPI immunotherapy for cancer was initiated by the finding that some tumors highly express immune checkpoint molecules.
The two CPIs currently approved for treatment of genitourinary cancers, nivolumab (Opdivo) and atezolizumab (Tecentriq), are monoclonal antibodies targeting the programmed death receptor-1 (PD-1) protein that is expressed on T cells or its ligand, programmed death-ligand 1 (PD-L1). Nivolumab, which targets PD-1, was approved in 2015 for patients with mRCC who progressed on prior anti-angiogenic therapy with an anti-VEGFR TKI agent. In February 2017, nivolumab received FDA approval for use as second-line therapy for patients with locally advanced or metastatic UC.
Atezolizumab is an anti-PD-L1 antibody that was approved in 2016 for use as second-line therapy in patients with locally advanced or metastatic UC. A February 2017 article published online in the New England Journal of Medicine reported positive results from the randomized, phase III KEYNOTE-045 clinical trial that investigated the anti-PD-1 antibody pembrolizumab (Keytruda) as second-line therapy in patients with platinum-refractory advanced UC. Compared with the control, which was standard of care treatment using the investigator’s choice of chemotherapy, pembrolizumab significantly improved median overall survival and was associated with a lower rate of treatment-related adverse events. The objective response rate was also significantly higher with pembrolizumab and the responses were more durable.