Andrew T. Lenis

Immunotherapy for the Treatment of Urothelial Carcinoma

Purpose: We review the biological mechanisms of action, clinical safety and efficacy of immunotherapies for urothelial carcinoma. We also describe current areas of research in immunotherapy, and highlight ongoing trials and promising and novel investigational agents. Materials and Methods: Data were obtained by a search of PubMed®, ClinicalTrials.gov and Cochrane databases for English language articles published through February 2016. Applicable abstracts from recent Society of Urologic Oncology, European Association of Urology, American Urological Association and ASCO® meetings were used. Results: Bacillus Calmette‐Guérin is one of the most successful immunotherapies in cancer treatment and remains the gold standard of care for patients with high risk, nonmuscle invasive bladder cancer, with initial response rates of approximately 70%. However, with the exception of valrubicin and standard chemotherapeutics there is a paucity of available treatment options for patients with recurrence or progression to more advanced disease. Recently there has been significant interest in novel immunotherapeutic agents in the management of cases where bacillus Calmette‐Guérin fails, as well as cases of more advanced cancer. These investigational therapies can generally be classified into several broad categories, including recombinant bacillus Calmette‐Guérin and cell wall derived therapies, cytokines, gene therapy, cancer vaccines, immune checkpoint inhibitors, oncolytic viruses, adoptive immunotherapies and immune agonists, as well as several additional immunomodulatory agents. The majority of these agents are currently under investigation in phase I or II clinical trials. Recently investigators reported evidence that inhibition of the PD‐1/PD‐L1 pathway has clinical activity in patients with advanced bladder cancer. These findings, along with successful phase III trials and U.S. Food and Drug Administration approvals of other checkpoint inhibitors in melanoma, nonsmall cell lung cancer and renal cell carcinoma, ultimately led to Food and Drug Administration approval of atezolizumab for advanced disease, the first new treatment approved for advanced urothelial carcinoma in 20 years. Conclusions: While bacillus Calmette‐Guérin has demonstrated significant clinical efficacy in the treatment of patients with bladder cancer, additional therapies are needed for those in whom bacillus Calmette‐Guérin fails, as well as for those with advanced disease. Immunotherapy for urothelial carcinoma remains a promising and active area of research, and numerous agents, particularly the monoclonal antibodies targeting checkpoint inhibition pathways, are showing encouraging signs of clinical activity.

Cryoablation Versus Minimally Invasive Partial Nephrectomy for Small Renal Masses in the Solitary Kidney: Impact of Approach on Functional Outcomes

PURPOSE We evaluated the change in renal function after renal cryoablation and partial nephrectomy based on tumor complexity according to the R.E.N.A.L. nephrometry score. MATERIALS AND METHODS We retrospectively reviewed the data of patients who had a renal tumor in a solitary kidney, and underwent renal cryoablation and partial nephrectomy between December 2000 and January 2012. Renal tumor complexity was categorized into 3 groups by R.E.N.A.L. nephrometry score as low (4 to 6), intermediate (7 to 9) and high (10 to 12). All baseline demographic data, perioperative parameters and followup data including renal function were collected. Comparisons were made among similar tumor complexities. RESULTS In the renal cryoablation and partial nephrectomy groups 29 patients (43 tumors) and 33 patients were identified, respectively. In all renal tumor complexities, renal cryoablation provided a better perioperative outcome in terms of median operative time, estimated blood loss, transfusion, hospital stay and complications. The median change in serum creatinine and estimated glomerular filtration rate was slightly greater in the partial nephrectomy group. However, the differences were not statistically significant for any of the tumor complexities. Three patients (10%) in the renal cryoablation group and 2 (6%) in the partial nephrectomy group required long-term dialysis. CONCLUSIONS In patients with solitary kidneys, renal cryoablation is associated with superior perioperative outcomes compared to partial nephrectomy. Specifically, partial nephrectomy is not associated with greater loss of renal function than renal cryoablation regardless of the extent of tumor complexity.

Stem cell therapy for voiding and erectile dysfunction.

Voiding dysfunction comprises a variety of disorders, including stress urinary incontinence and overactive bladder, and affects millions of men and women worldwide. Erectile dysfunction (ED) also decreases quality of life for millions of men, as well as for their partners. Advanced age and diabetes are common comorbidities that can exacerbate and negatively impact upon the development of these disorders. Therapies that target the pathophysiology of these conditions to halt progression are not currently available. However, stem cell therapy could fill this therapeutic void. Stem cells can reduce inflammation, prevent fibrosis, promote angiogenesis, recruit endogenous progenitor cells, and differentiate to replace damaged cells. Adult multipotent stem cell therapy, in particular, has shown promise in case reports and preclinical animal studies. Stem cells also have a role in urological tissue engineering for ex vivo construction of bladder wall and urethral tissue (using a patients own cells) prior to transplantation. More recent studies have focused on bioactive factor secretion and homing of stem cells. In the future, clinicians are likely to utilize allogeneic stem cell sources, intravenous systemic delivery, and ex vivo cell enhancement to treat voiding dysfunction and ED.

Impact of Parturition on Chemokine Homing Factor Expression in the Vaginal Distention Model of Stress Urinary Incontinence

PURPOSE Human childbirth simulated by vaginal distention is known to increase the expression of chemokines and receptors involved in stem cell homing and tissue repair. We hypothesized that pregnancy and parturition in rats contributes to the expression of chemokines and receptors after vaginal distention. MATERIALS AND METHODS We used 72 age matched female Lewis rats, including virgin rats with and without vaginal distention, and delivered rats with and without vaginal distention. Each rat was sacrificed immediately, or 3 or 7 days after vaginal distention and/or parturition, and the urethra was harvested. Relative expression of chemokines and receptors was determined by real-time polymerase chain reaction. Mixed models were used with the Bonferroni correction for multiple comparisons. RESULTS Vaginal distention up-regulated urethral expression of CCL7 immediately after injury in virgin and postpartum rats. Hypoxia inducible factor-1α and vascular endothelial growth factor were up-regulated only in virgin rats immediately after vaginal distention. CD191 expression was immediately up-regulated in postpartum rats without vaginal distention compared to virgin rats without vaginal distention. CD195 was up-regulated in virgin rats 3 days after vaginal distention compared to virgin rats without vaginal distention. CD193 and CXCR4 showed delayed up-regulation in virgin rats 7 days after vaginal distention. CXCL12 was up-regulated in virgin rats 3 days after vaginal distention compared to immediately after vaginal distention. Interleukin-8 and CD192 showed no differential expression. CONCLUSIONS Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1α and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia.

A phase 2 study of TMX-101, intravesical imiquimod, for the treatment of carcinoma in situ bladder cancer

PURPOSE Imiquimod is a toll-like receptor agonist with proven antitumor activity as a topical treatment for skin cancer. TMX-101 (Vesimune) is a novel liquid formulation of imiquimod optimized for intravesical delivery. The agent demonstrated safety as an intravesical treatment for non-muscle-invasive bladder cancer in a phase 1 clinical trial. We report the results of a phase 2 prospective multicenter clinical trial assessing the safety and activity of TMX-101. MATERIALS AND METHODS Patients with non-muscle-invasive bladder cancer containing carcinoma in situ were eligible for inclusion. Enrolled patients received 6 weekly intravesical administrations of 200mg/50ml TMX-101 0.4%. End points included rate of adverse events, changes in urinary cytokine levels following treatment, and clinical response at 6 weeks following final instillation, defined as negative posttreatment bladder biopsy and urine cytology results. RESULTS A total of 12 patients were enrolled, with 10 available for efficacy analysis. Half of the patients (6/12) had received≥2 prior induction courses of bacillus Calmette-Guerin. All patients received all 6 doses of TMX-101 per protocol. Overall, 75% of patients experienced treatment-related adverse events, only 1 of which was>grade 2 (urinary tract infection). Furthermore, 2 patients demonstrated a negative cytology and biopsy result at 6 weeks following treatment. Significant increases in urinary cytokines, including IL-6 and IL-18, were seen following treatment. CONCLUSION In this phase 2 pilot study in patients with carcinoma in situ bladder cancer, intravesical TMX-101 was safe and well tolerated with common, mild genitourinary adverse effects. Clinical activity was suggested by the increase in posttreatment urinary cytokines. Complete responders were seen. Further investigation of the agent is warranted.

Testosterone replacement therapy in men with prostate cancer: a time-varying analysis.

INTRODUCTION The use of testosterone replacement therapy (TRT) in men with prostate cancer is controversial given concerns of androgen-related cancer progression. Although emerging evidence suggests that TRT may be safe in this setting, no study has investigated dose-related effects. AIM We used time-varying analysis to determine whether increasing TRT exposure is associated with worse outcomes. METHODS Using linked Surveillance, Epidemiology, and End Results-Medicare data, we identified 149,354 men diagnosed with prostate cancer from 1991 to 2007. Subjects treated with TRT were stratified by duration of treatment. Weighted propensity score methods were used to adjust for differences between groups. A Cox proportional hazards model was constructed to assess the effect of injectable TRT exposure on outcomes. MAIN OUTCOME MEASURE Overall mortality (OM), prostate cancer-specific mortality (PCSM), and use of salvage androgen deprivation therapy (ADT). RESULTS Men treated with TRT, regardless of duration, did not experience higher OM or PCSM (all hazard ratio [HR] <1.0, all P ≤ 0.002). We found no difference in use of salvage ADT in the ≤ 30-day and 31-60 day groups compared with no-TRT (HR 1.23 and 1.05, P=0.06 and 0.81, respectively), whereas it was lower for men on long-term TRT (HR 0.70, P=0.04). CONCLUSIONS TRT following prostate cancer diagnosis and treatment does not increase mortality or the use of salvage ADT. Using time-varying analysis, we demonstrate that longer duration of TRT is not associated with adverse mortality or greater need for ADT.

Sustained-release Formulation of Mitomycin C to the Upper Urinary Tract Using a Thermosensitive Polymer: A Preclinical Study

OBJECTIVE To evaluate the safety and feasibility of single and serial instillations of MitoGel into the upper urinary tract using a preclinical swine animal model. MitoGel is a novel sustained release formulation of mitomycin C (MMC) based on RTGel, a proprietary thermosensitive hydrogel technology. MitoGel is liquid at cold temperatures and solidifies to gel state at body temperature. It is intended as a treatment for upper tract urothelial carcinoma, given its ability to provide sustained release of MMC in the upper urinary tract. MATERIALS AND METHODS We utilized 23 pigs in a 3-phase design. All animals underwent bilateral nephrostomy tube placement. During phase 1, 3 animals underwent antegrade RTGel instillation, imaging, and euthanasia within 12 hours. In phase 2, 10 pigs underwent single antegrade instillation, unilateral nephrectomy 3 days following instillation, and contralateral nephrectomy and euthanasia 30 days following instillation. During phase 3, 10 animals underwent 6 instillations over 3 weeks, followed by bilateral nephrectomy and necropsy 30 days postinstillation. MitoGel (2 mg/mL and 4 mg/mL), aqueous MMC (2 mg/mL and 4 mg/mL), and RTGel alone were evaluated. RESULTS MitoGel remained visible within the pelvicalyceal system on fluoroscopic and computed tomography imaging for 4-6 hours. MMC plasma levels were well within acceptable safety thresholds. There was no evidence of urinary obstruction, acute kidney injury, sepsis, or myelosuppression. Histologic changes in the urinary system were mild and transient. CONCLUSION Antegrade MitoGel delivery to the pelvicalyceal system of Yorkshire swine is feasible and safe. Further evaluation of MitoGel in human clinical trials is warranted.

Patterns of Hardware Related Electrode Failures in Sacral Nerve Stimulation Devices

PURPOSE Abnormal electrical impedance in sacral nerve stimulation devices is a cause of device failure. Currently, there is scant literature evaluating the incidence and management of this problem. We evaluated the presentation, characteristics and management of sacral nerve stimulation devices with abnormal electrical impedance. MATERIALS AND METHODS A total of 565 patients were permanently implanted with sacral nerve stimulation devices using a tined lead between 2003 and 2011. Devices were interrogated postoperatively and at followup. Abnormal electrical impedance was classified as open circuit--impedance greater than 4,000 Ω or short circuit--impedance less than 50 Ω and/or equivalence of impedance. Details on presentation, characteristics and management were recorded. RESULTS Of the 565 patients 72 (12.7%) experienced a total of 86 abnormal electrical impedance events, of which 57 (66.2%) were open circuits and 28 (32.5%) were short circuits. One event (1.1%) was a simultaneous open and short circuit. Short circuits presented earlier than open circuits (median 3.5 months, IQR 2-7.5 vs 15, IQR 5.5-30.5, p <0.0001) and required surgical intervention more often (75.0% vs 54.3%, p = 0.09). Patient specific factors, such as trauma history and change in body mass index class, were not associated with abnormal electrical impedance. No electrode failure patterns could be identified. CONCLUSIONS Abnormal electrical impedance occurred in approximately 13% of cases permanently implanted in our series. Short circuits presented earlier and often required surgical intervention. Open circuits presented later and may have potentially been secondary to microfractures that accumulate with time at the sacral plate, resulting in later presentation. Almost a third of patients with abnormal electrical impedance associated with clinical inefficacy were treated conservatively, primarily with reprogramming.

Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials

Purpose We reviewed the literature on adjuvant therapies for patients with high risk localized kidney cancer following surgical resection. In this analysis we merge 2 recently published prospective trials with conflicting results within the context of their respective designs. In addition, we spotlight upcoming trials that use novel immunotherapy based checkpoint inhibitors and have the potential to establish a new standard of care. Materials and Methods We searched PubMed® for English language articles published through January 2017 using the keywords “renal cell carcinoma,” “kidney cancer,” “immunotherapy,” “targeted therapy” and “adjuvant therapy.” ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings are also included. Results Adjuvant therapies for high risk localized kidney cancer can be grouped into the categories of 1) traditional immunotherapy, 2) inhibitors of the vascular endothelial growth factor and mTOR (mammalian target of rapamycin) pathways, 3) vaccines and antibody dependent cytotoxic agents, and 4) immune checkpoint inhibitors. Several trials of traditional immunotherapy, such as interferon‐&agr; and high dose interleukin‐2, failed to demonstrate benefit as adjuvant treatment and were associated with significant adverse events. Vascular endothelial growth factor and mTOR inhibitors have less severe toxicity in metastatic disease and, therefore, are natural considerations for adjuvant trials. However, current data are conflicting. The ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients with Kidney Cancer that was Removed by Surgery, NCT00326898) trial found no recurrence‐free survival benefit of sorafenib or sunitinib over placebo, while S‐TRAC (Clinical Trial Comparing Efficacy and Safety of Sunitinib versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer, NCT00375674) revealed that 1 year of sunitinib improved recurrence‐free survival by 1.2 years. Vaccine based treatments and antibody dependent cytotoxic agents have had mixed results. New trials evaluating immune checkpoint inhibitors are planned, given the impressive efficacy and tolerability as second line agents in metastatic disease. Future adjuvant trials are likely to be guided by molecular signatures to treat patients most likely to benefit. Conclusions Based on the available data, there appears to be no role for traditional immunotherapy as adjuvant treatment in patients with high risk localized kidney cancer following surgical resection. S‐TRAC provides evidence that 1 year of adjuvant sunitinib in patients with higher risk locoregional disease increases the median time to recurrence. However, the data on overall survival are immature and adverse effects are common. Results from trials investigating immune checkpoint inhibitors are highly anticipated.

Serial retrograde instillations of sustained release formulation of mitomycin C to the upper urinary tract of the Yorkshire swine using a thermosensitive polymer: Safety and feasibility ☆ ☆☆

BACKGROUND MitoGel is a novel drug formulation intended for the treatment of upper tract urothelial cancer with proven feasibility and safety in an animal model. OBJECTIVE To evaluate the feasibility, safety, toxicokinetics, and histologic changes associated with serial retrograde MitoGel instillations to the upper urinary tract in a swine model. DESIGN, SETTING, AND PARTICIPANTS Overall, 27 Yorkshire swine underwent 6 once-weekly unilateral retrograde instillations of MitoGel. Doses of 14, 28, or 56-mg mitomycin C (respective concentrations of 2, 4, and 8mg/ml with 9 animals per group) were evaluated. Additionally, 6 animals received sterile water as a procedure control, and 9 received gel alone (without mitomycin C), as a vehicle control. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Blood and urine samples were collected for determination of MMC toxicokinetics and for hematology, biochemistry, coagulation, and urinalysis throughout the study. Two-thirds of the cohort were euthanized 24 hours after final instillation, and one-third was euthanized 1 month after final instillation. Necropsy was performed to evaluate the histologic effects of treatments. RESULTS AND LIMITATIONS All animals received all 6 doses of agents per protocol. No mortality, clinical adverse events, or meaningful changes in hematology, chemistry, coagulation, or urinalysis were attributable to MitoGel, RTGel alone, or water instillations. Peak plasma levels of MMC were 2 orders of magnitude less than known toxicity thresholds. MitoGel-related dose-dependent microscopic findings were seen in the treated kidneys and ureters, but were of limited severity, lacked associated clinical adverse findings, and decreased over time. CONCLUSIONS Serial retrograde instillations of MitoGel to the pyelocaliceal system were technically feasible, and produced no observable adverse clinical, laboratory, or histologic effects.