Advances on immunotherapy in genitourinary and renal cell carcinoma

Abstract

Genitourinary (GU) cancers are a group of epithelial malignancies associated with the organs involved in the excretion of urine. Renal cell, urothelial, and prostatic carcinoma are the overwhelming subtypes diagnosed by oncologists. Each of these was traditionally treated surgically when local and non-invasive. When these carcinomas spread, invade, or metastasize, surgical control lacks in efficacy. Chemotherapeutic regimens have been implemented for decades and have increased overall survival but many patients progress. Molecular targeting through tyrosine kinase inhibition of the vascular endothelial growth factor (VEGF) has emerged as a frontline therapy in kidney cancer with more durable responses. More recently, immunotherapy has begun to find efficacy in many other solid tumors including melanoma and non-small cell lung cancer. The inherent genetic instability of this group of cancers makes them ideal solid tumors for immune modulation. Vaccines manufactured to initiate T-Cell regulation through neoplastic-antigen presentation are available for prostate cancer and are currently on trial in renal cell carcinoma (RCC). Programmed death-1 (PD-1) and its ligand (PD-L1) are intricate members of cellular immunity against neoplastic cells. In an activated, unbound state, these molecules permit T-cell activation and cytotoxic killing of cancer cells. However, when they are linked, cellular immunity is attenuated and local cancer cells are permitted the opportunity to proliferate and invade. A novel class of monoclonal antibodies have been developed which stop PD-1 linkage and thus uncouple the 'stop' signal of these neoplastic regulatory cells. The increased overall and progression free survival have made them attractive options alone as well as in combination with anti-VEGF inhibitors for patients. Although more tolerable than chemotherapy, immunotherapeutics have adverse potential toxicities. Overall, the use of immunomodulatory medications have opened a new paradigm in the anti-neoplastic regimen of GU cancers and further developments will determine the appropriate patient to treat for optimum tumor burden eradication.

Keywords: Genitourinary cancers; checkpoint inhibitors; immun-otherapy; programmed death-1 (PD-1); programmed death-ligand 1 (PD-L1).

Figure 1

Prostate cancer therapies. Patients without evidence of metastatic disease are first divided into low, intermediate, or high risk, with active surveillance being appropriate for low risk patients, and surgery and/or radiation with ADT used for higher risk patients. The treatment of disseminated disease focuses on the use of ADT, but patients who develop castration resistant disease are candidates for newer agents targeting the androgen signaling pathway, or the Sipuleucel-T vaccine. Clinical trials are currently underway to investigate the use of combination immunotherapy and other vaccines in this clinical situation as well. (Blue: standard of care, Orange: clinical trials).

Figure 2

Urothelial carcinoma therapies. Therapies are first divided between those that are invasive versus those that are not. If noninvasive, the first treatment is BCG with a current trial underway for pembrolizumab in the second line. For invasive urothelial carcinoma, if platinum based chemotherapy is contraindicated, pembrolizumab can be used in the first line setting. Otherwise, a platinum based regimen should be implemented with nivolumab (PD-1) or atezolizumab (PD-L1) in the second line setting. Avelumab is currently in trial in the first and second line settings. (Blue: Standard of Care, Orange: Clinical Trials).

Figure 3

Renal cell carcinoma (RCC) therapies. Therapies are first divided between those that are local versus metastatic at diagnosis. If local, nephrectomy can cure and induce an inflammatory response that kills residual disease. If metastatic, nephrectomy can also be considered by a multidisciplinary team to induce a similar reaction prior to initiation of systemic treatment. First-line FDA approved agents include IL-2 (in very selective patients and centers) and anti-VEGF tyrosine kinase inhibitors. Those with a poor prognosis can be initiated on Temsirolimus in the first-line setting. Trials are ongoing with immunotherapy as frontline therapy. After progression on anti-VEGF TKI, nivolumab is FDA approved in the second line setting. Other PD-1 and PD-L1 inhibitors are currently in clinical trials for additional therapeutic options. (Blue: Standard of Care, Orange: Clinical Trials).