The expanding role of immunotherapy in urologic cancers

Urologic malignancies including prostate, kidney, and bladder cancer are common diseases. Despite advances in traditional treatment modalities for these malignancies, sequential cellular mutations often lead to resistance against therapeutic measures and eventual disease progression. An important factor in this process is the ability of cancer cells to evade the host immune system.

Under normal circumstances, the immune response provides a desirable profile for combating malignancy. T cells have excellent specificity due to their ability to recognize major histocompatibility complexes on the surface of cells. This allows for recognition of both intracellular and extracellular peptides. Additionally, T cells are able to produce memory, which allows for rapid and targeted response in the event of future recurrence.

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Finally, T cells have the ability to adapt to the changing antigen profile of recurrent cancer cells. This is held in check by a series of stimulatory and co-inhibitory signals to prevent excessive immune activation, autoimmunity, and non-selective tissue destruction.

Cancer cells, as we have learned, often adopt a number of strategies to evade the host immune response. Upregulation of co-inhibitory signaling molecules such as programmed cell death ligand-1 (PD-L1) inhibits cell killing when interacting with programmed death 1 (PD-1) receptors on effector T-cells (figure 1).

Similarly, upregulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) leads to T-cell tolerance and evasion of the immune system (figure 2). The ability to restore immune recognition through antibody mediated checkpoint blockade has provided an appealing therapeutic target in the treatment of cancer and ushered FDA approval of several novel agents.

This article explores the current and potential future use of immunotherapy in prostate, kidney, and bladder cancer.

Next: Prostate cancer

Immunotherapy has enjoyed success in the treatment of prostate cancer over the last decade. Sipuleucel-T (Provenge), which received FDA approval in 2010, remains a first-line treatment for metastatic hormone-refractory prostate cancer. Sipuleucel-T is a patient-specific treatment in which a patient’s peripheral blood mononuclear cells are removed and then activated in the presence of a recombinant fusion protein and prostatic acid phosphatase (figure 3).

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The IMPACT trial, which is the basis for the use of sipuleucel-T, demonstrated a 4.1-month improvement in overall survival in men with metastatic castrate-resistant prostate cancer despite no obvious change in overall disease burden (N Engl J Med 2010; 363: 411-22).

Following the IMPACT trial, several randomized trials have been conducted regarding the use of sipuleucel-T in biochemically recurrent patients. The PROTECT trial randomized biochemically recurrent patients to receive either sipuleucel-T or placebo following 4 months of androgen deprivation therapy (ADT). Patients who received sipuleucel-T were found to have a nearly 50% prolongation in PSA doubling time when compared to controls (Clin Cancer Res 2011; 17:4558-67).

The STAND trial also assessed the use of ADT followed by sipuleucel-T or in the opposite order. While findings of the study suggested improved anti-tumor activity when sipuleucel-T preceded ADT, the clinical impact of these findings is unclear (Clin Cancer Res 2017; 23:2451-9). Multiple ongoing trials are exploring the use of sipuleucel-T in combination with androgen receptor antagonists (NCT02456571) and with checkpoint inhibitors (NCT01804465, NCT03024216).

CTLA-4 inhibitors have demonstrated efficacy in the treatment of hormone-refractory and metastatic prostate cancer. A recent phase III trial demonstrated antitumor activity in patients who received ipilimumab (Yervoy) versus placebo for metastatic prostate cancer without visceral metastasis. Progression-free survival was found to be 1.8 months longer in the treatment arm, but interestingly there was no improvement in overall survival (J Clin Oncol 2017; 35:40–47).

There are currently two ongoing clinical trials exploring the expanded use of CTLA-4 inhibitors in metastatic prostate cancer. First is a phase II trial investigating the role of ipilimumab in conjunction with abiraterone acetate (ZYTIGA) in chemotherapy- and immunotherapy-naive patients (NCT01688492). Second is a phase II study is currently investigating the role of ipilimumab in combination with hormonal therapy in those with incomplete response to hormonal therapy (NCT01498978).

Humanized monoclonal antibodies against PD-1 and its ligand PD-L1 are also being explored for their use in the treatment of metastatic prostate cancer. Most notably, the KEYNOTE-028 trial comparing response rate in patients receiving the PD-1 inhibitor pembrolizumab (KEYTRUDA) alone versus those receiving prior docetaxel treatment and targeted hormonal therapy has demonstrated partial response in some patients receiving anti-PD1 therapy (Ann Oncol 2016; 27[suppl_6], 725PD). In addition, the ongoing KEYNOTE-199 study, a nonrandomized open-label phase II trial, will also explore response rates to pembrolizumab in patients with metastatic prostate cancer whose tumors demonstrate PD-L1 expression (NCT02787005).

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Additional studies exploring the use of anti-PD-L1 will shed light on its use in metastatic prostate cancer. An open-label, phase II trial evaluating the use of atezolizumab (TECENTRIQ) in solid tumors, including prostate cancer, is ongoing (NCT02458638).

Next: Kidney cancer

Immunotherapy has been long established in the treatment of metastatic kidney cancer. For years, interleukin-2 (IL-2) and interferon alpha (IFN-alpha) remained the standard of care for metastatic renal cell carcinoma. While the explosion of tyrosine kinase, VEGF, mTOR, and MET inhibitors has supplanted the use of IFN-alpha and IL-2 in more recent years, this early experience highlighted the importance of the tumor immune environment. This has provided a fertile space for the recent arrival of checkpoint blockade.

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The recently published CheckMate 025 trial was the first phase III clinical trial to demonstrate benefits in overall survival and objective response rate in patients receiving nivolumab (Opdivo) when compared to everolimus in patients who had failed prior anti-VEGF therapy (Eur Urol 2017; 72: 962-71). Not surprisingly, the promising results of CheckMate 025 paved the way for increased exploration of checkpoint blockade in first-line therapy for metastatic renal cancer. The recently reported CheckMate 214 phase III trial demonstrated a significant benefit in overall survival (median survival not reached vs. 26 months) in intermediate- and poor-risk patients who received combination therapy with ipilimumab and nivolumab when compared with sunitinib (Sutent) in previously untreated metastatic renal cancer (N Engl J Med 2018; 378:1277-90). The ongoing IMmotion150 phase III trial of atezolizumab (anti-PD-L1) alone or in combination with the anti-VEGF agent bevacizumab (Avastin) compared with sunitinib in patients with untreated metastatic renal cell carcinoma will further explore the use of upfront checkpoint blockade in patients with renal cancer (NCT02420821).

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The success of checkpoint blockade has also generated interest in adjuvant checkpoint therapy. This is currently being investigated as part of the ongoing PROSPER RCC trial, which aims to explore the use of adjuvant nivolumab following nephrectomy (NCT03055013).

Next: Bladder Cancer

Nonmuscle-invasive bladder cancer (NMIBC) has long benefited from localized immunotherapy in the form of intravesical bacillus Calmette-Guerin therapy (BCG [TICE BCG]). BCG is an attenuated form of the tuberculosis bacteria that promotes immune infiltration and cellular cytotoxicity. While an effective treatment for NMIBC, a portion of patients will go on to develop muscle-invasive disease and eventual metastatic cancer. Despite the early successes with BCG, few new treatment options have emerged over the past 4 decades and platinum-based chemotherapy remains the standard for metastatic urothelial cell carcinoma. Fortunately, checkpoint blockade has proven to be a fertile ground for treatment of patients with metastatic urothelial cell carcinoma.

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The need for new therapeutic options afforded a unique opportunity for metastatic urothelial cell carcinoma. In 2017, PD-1 blockade (pembrolizumab and nivolumab) and PD-L1 blockade (atezolizumab, avelumab [BAVENCIO], and durvalumab [Imfinzi]) received orphan designation from the FDA for treatment of metastatic urothelial cell carcinoma. This has since led to clinical trials investigating the use of single-agent and combination therapy in the metastatic setting as well as advancement into the treatment of localized disease.

Based on the results of KEYNOTE-052 and IMvigor 210, pembrolizumab (anti-PD1) and atezolizumab (anti-PD-L1) are currently FDA-approved for the treatment of cisplatin-ineligible metastatic urothelial cell carcinoma (Lancet Oncol 2017; 18:1483–92; Lancet 2017; 389:67–76). Additionally, pembrolizumab is now recommended as second-line therapy following failure of standard cisplatin-based chemotherapy (N Engl J Med 2017; 376:1015-26).

While these trials have shown promise in the treatment of metastatic disease, it should be noted that the majority of patients enrolled did not respond to checkpoint blockade. This highlights the lack of understanding regarding appropriate patient selection and ideal agents in the metastatic setting. While the vast majority of trials did include some assessment of PD1 and PD-L1 expression, the clinical utility of this information as it relates to objective response or overall survival remains unclear at best.

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Despite these areas of uncertainty, the use of checkpoint blockade has continued to advance. Ongoing phase II clinical trials utilizing pembrolizumab in the BCG-refractory NMIBC population will explore the role of checkpoint blockade in the non-metastatic population (NCT02625961). Additionally, a number of clinical trials are currently investigating the role of anti-PD-1, anti-PD-L1, and anti-CTLA-4 in the neoadjuvant setting for patients with muscle-invasive bladder cancer (NCT02365766, NCT02736266, NCT02989584, NCT03234153, NCT03294304, and NCT03498196).

Summary

The rapidly expanding role of checkpoint blockade (PD-1, PD-L1, and CTLA-4) alone and in combination with other agents has demonstrated a new source of therapeutic avenues across the breadth of urologic cancers. While the early experience demonstrates benefits in the metastatic setting, it is possible that we may soon see the emergence of immunotherapy in local, neoadjuvant, and adjuvant therapy as well. The ideal candidate for checkpoint blockade remains unclear. Further investigation into patient selection, checkpoint expression, and potential biomarkers is still needed to best implement these new therapeutic options into clinical practice.

Dr. Hart is a urology resident, and Dr. Gupta is associate professor of urology, radiology, and surgery, Loyola University Medical Center, Maywood, IL.

Section Editor Christopher M. Gonzalez, MD, MBA, is professor and chair of the department of urology at Loyola University Chicago Stritch School of Medicine, Maywood, IL.