BCG-unresponsive Patients Research Articles

Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for non-muscle invasive bladder cancer.

Intravesical gemcitabine and docetaxel (Gem/Doce) has been established as a safe and efficacious salvage treatment for recurrent NMIBC since 2015. Despite widespread adoption of this regimen, long-term outcomes have not been described. We report our experience with intravesical Gem/Doce following BCG failure in a large cohort of patients with extended follow-up. We retrospectively identified 97 patients at our institution treated with Gem/Doce for high-risk NMIBC after BCG failure between 2009 and 2017. Patients received six weekly intravesical Gem/Doce instillations. Monthly maintenance for 2 years was initiated if disease free at first follow-up. Outcomes included recurrence-free survival (RFS), high-grade recurrence-free survival (HG-RFS), progression-free survival (PFS), cystectomy-free survival (CFS), cancer-specific survival (CSS), and overall survival (OS). Survival probabilities were estimated using the Kaplan-Meier method. Median follow-up was 49 months. Median age was 73 years, and 71% of the cohort had CIS containing disease. Thirty five percent of the cohort had BCG-unresponsive disease. Complete response at 3-month surveillance was 74% and median duration of response was 25 months. At 1, 2, and 5 years, HG-RFS was 60%, 50%, and 30%, respectively. HG-RFS was similar among BCG-unresponsive patients and the overall cohort. During follow-up, 20 patients underwent cystectomy and 15 patients experienced disease progression. Five-year PFS, CFS, CSS, and OS were 82%, 75%, 91%, and 64%, respectively. In this long-term analysis, intravesical Gem/Doce for high-risk NMIBC after BCG failure yielded a 75% 5-year bladder preservation rate and a 91% 5-year cancer-specific survival rate. Further prospective trials are warranted.

Predictive clinico-pathological factors to identify BCG, unresponsive patients, after re-resection for T1 high grade non-muscle invasive bladder cancer.

Seventy-five percent of bladder cancers are non-muscle invasive. The treatment strategy includes the transurethral resection of bladder tumor (TURB) followed by intravesical immunotherapy with the bacillus of Calmette-Guerin (BCG) or chemotherapy, depending on the grade of bladder tumor. Despite a proper BCG intravesical instillations schedule, up to 40% of patients present a failure within 2 years. The aim of this retrospective study was to investigate the predictive factors in the response to BCG in patients with a high-grade non-muscle invasive bladder cancer diagnosis. Patients with non-muscle invasive bladder cancer from 13 hospitals and academic institutions were identified and treated, from January 1, 2002, until December 31, 2012, with TURB and a subsequent re-TURB for restaging before receiving BCG. Follow-up was performed with urine cytology and cystoscopy every 3 months for 1 year and, successively every 6 months. Univariate and multivariate Cox regression models addressed the response to BCG therapy. Kaplan-Meier overall survival (OS) and cancer-specific survival (CSS) estimates were determined for BCG responsive vs. BCG unresponsive patients. A total of 1,228 patients with non-muscle invasive bladder cancer were enrolled. Of 257 (20.9%) patients were BCG unresponsive. Independent predictive factors for response to BCG were: multifocality (HR: 1.4; 95% CI 1.05-1.86; P = 0.019), lymphovascular invasion (HR: 1.75; 95% CI 1.22-2.49; P = 0.002) and high-grade on re-TURB (HR: 1.39; 95% CI 1.02-1.91; P = 0.037). Overall survival was significantly reduced in BCG-unresponsive patients compared to BCG-responsive patients at 5 years (82.9% vs. 92.4%, P < 0.0001) and at 10 years (44.2% vs. 74.4%, P < 0.0001). Similarly, cancer-specific survival was reduced in BCG-unresponsive patients at 5 years (90.6% vs. 97.3%, P < 0.0001) and at 10 years (72.3% vs. 87.2%, P < 0.0001). Multifocality, lymphovascular invasion, and high-grade on re-TURB were independent predictors for response to BCG treatment. BCG-unresponsive patients reported worse oncological outcomes.

Treatment and disease management patterns for bacillus Calmette-Guérin unresponsive nonmuscle invasive bladder cancer in North America, Europe and Asia: A real-world data analysis.

BackgroundThis study examined real-world treatment and management of bacillus Calmette-Guérin (BCG)-unresponsive patients across 3 continents, including patients unable or unwilling to undergo cystectomy.Materials and methodsPhysicians actively involved in managing patients with nonmuscle invasive bladder cancer completed online case report forms for their 5 consecutive patients from the broad BCG-unresponsive population and a further 5 consecutive BCG-unresponsive patients who did not undergo cystectomy (in Japan, physicians provided a total of 5 patients across both cohorts).ResultsMost patients had received 1 (37%) or 2 (24%) maintenance courses of BCG. Five or more maintenance BCG courses were received by patients in Japan (59%) and China (31%), while in Germany 76% of patients received only 1 course. Most patients became BCG-unresponsive during their first (44%) or second (22%) treatment course; in Germany, 77% became BCG-unresponsive during their first treatment course. Most countries did not provide another course of BCG after a patient first became unresponsive, whereas unresponsive patients in Japan and China were most likely to be retreated with BCG. “Untreated - on watch and wait” was the main treatment/management approach received post-BCG treatment for 42% or more of patients in most countries except China (39%) and the United States (36%). “Following treatment guidelines” was consistently the top reason for post-BCG treatment selection across all treatment options.ConclusionsThis study confirmed the global unmet need for patients with nonmuscle invasive bladder cancer, and found that many patients experienced periods of no treatment after not responding to BCG therapy.

A Phase 1b Clinical Study of Intravesical Photodynamic Therapy in Patients with Bacillus Calmette-Guérin–unresponsive Non–muscle-invasive Bladder Cancer

BackgroundA phase 1b study of photosensitizer TLD-1433–mediated photodynamic therapy (PDT) was performed in bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients. ObjectiveThe primary objectives were safety and tolerability of PDT, with secondary objectives of (1) pharmacokinetic (PK) properties of TLD-1433 and (2) efficacy, as evaluated by recurrence-free survival and complete response (CR) at 90 and 180 d for patients treated at the maximum recommended starting dose (0.35 mg/cm2 bladder surface area) and the therapeutic dose (0.70 mg/cm2). Design, setting, and participantsSix BCG-unresponsive patients were enrolled in an open-label, single-arm, dose-escalating study of PDT. TLD-1433 was instilled intravesically for 60 min preoperatively. PDT was performed under general anesthesia using intravesically delivered irradiation of the bladder wall with green light (520 nm) to a dose of 90 J/cm2. Outcome measurements and statistical analysisPatients were followed by standard cystoscopy and cytology for up to 18 mo to assess time to recurrence. Results and limitationsPDT was well tolerated by all patients. All patients experienced at least one grade ≤2 adverse event (AE). There were no patient deaths or light sensitivity reactions. The most common AE was moderate bladder irritability, which resolved within the first weeks after treatment. AEs were independent of the TLD-1433 dose. TLD-1433 was cleared in the urine and from the plasma within 24 and 72 h, respectively. Of three patients treated at the therapeutic dose, two achieved a CR at 180 d, which was durable at 18 mo. The other patient was diagnosed with metastatic disease at 138 d. ConclusionsPDT with TLD-1433 appears safe for the treatment of BCG-unresponsive NMIBC. Early efficacy signals from full-dose photosensitizer are encouraging and warrant phase 2 trial investigation. The safety and PK results obtained support the potential for administration of consecutive PDT treatments as required. Patient summaryPhotodynamic therapy with TLD-1433 appears to be safe and effective for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer.

Mycobacterial surface characters remodeled by growth conditions drive different tumor-infiltrating cells and systemic IFN-γ/IL-17 release in bladder cancer treatment

ABSTRACT The mechanism of action of intravesical Mycobacterium bovis BCG immunotherapy treatment for bladder cancer is not completely known, leading to misinterpretation of BCG-unresponsive patients, who have scarce further therapeutic options. BCG is grown under diverse culture conditions worldwide, which can impact the antitumor effect of BCG strains and could be a key parameter of treatment success. Here, BCG and the nonpathogenic Mycobacterium brumae were grown in four culture media currently used by research laboratories and BCG manufacturers: Sauton-A60, -G15 and -G60 and Middlebrook 7H10, and used as therapies in the orthotopic murine BC model. Our data reveal that each mycobacterium requires specific culture conditions to induce an effective antitumor response. since higher survival rates of tumor-bearing mice were achieved using M. brumae-A60 and BCG-G15 than the rest of the treatments. M. brumae-A60 was the most efficacious among all tested treatments in terms of mouse survival, cytotoxic activity of splenocytes against tumor cells, higher systemic production of IL-17 and IFN-ɣ, and bladder infiltration of selected immune cells such as ILCs and CD4TEM. BCG-G15 triggered an antitumor activity based on a massive infiltration of immune cells, mainly CD3+ (CD4+ and CD8+) T cells, together with high systemic IFN-ɣ release. Finally, a reduced variety of lipids was strikingly observed in the outermost layer of M. brumae-A60 and BCG-G15 compared to the rest of the cultures, suggesting an influence on the antitumor immune response triggered. These findings contribute to understand how mycobacteria create an adequate niche to help the host subvert immunosuppressive tumor actions.

New Perspectives in the Medical Treatment of Non-Muscle-Invasive Bladder Cancer: Immune Checkpoint Inhibitors and Beyond.

Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette–Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation. The aim of this review is to analyse and describe the clinical activity of new emerging drugs in BCG-unresponsive NMIBC focusing on immunotherapy results.

Treatment Outcomes of High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) in Real-World Evidence (RWE) Studies: Systematic Literature Review (SLR).

BackgroundTo date, there has been limited synthesis of RWE studies in high-risk non-muscle invasive bladder cancer (HR-NMIBC). The objective of this research was to conduct a systematic review of published real-world evidence to better understand the real-world burden and treatment patterns in HR-NMIBC.MethodsAn SLR was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with the scope defined by the Population, Intervention Comparators, Outcomes, and Study design (PICOS) criteria. EMBASE, MEDLINE, and Cochrane databases (Jan 2015–Jul 2020) were searched, and relevant congress abstracts (Jan 2018–Jul 2020) identified. The final analysis only included studies that enrolled ≥100 patients with HR-NMIBC from the US, Europe, Canada, and Australia.ResultsThe SLR identified 634 RWE publications in NMIBC, of which 160 studies reported data in HR-NMIBC. The average age of patients in the studies was 71 years, and 79% were males. The rates of BCG intravesical instillations ranged from 3% to 86% (29–95% for induction and 8–83% for maintenance treatment). Five-year outcomes were 17–89% recurrence-free survival (longest survival in patients completing BCG maintenance), 58–89% progression-free survival, 71–96% cancer-specific survival (lowest survival in BCG-unresponsive patients), and 28–90% overall survival (lowest survival in patients who did not receive BCG or instillation therapy).ConclusionBCG treatment rates and survival outcomes in patients with HR-NMIBC vary in the real world, with better survival seen in patients completing maintenance BCG, responding to treatment, and not progressing to muscle-invasive disease. There is a need to better understand the factors associated with BCG use and discontinuation and for an effective treatment that improves outcomes in HR-NMIBC. Generalization of these results is limited by variations in data collection, reporting, and methodologies used across RWE studies.

Emerging treatments for bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer.

Intravesical bacillus Calmette–Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immunotherapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies ‘BCG-unresponsiveness’. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC.

Novel and emerging approaches in the management of non-muscle invasive urothelial carcinoma.

Non-muscle invasive bladder cancer (NMIBC) has traditionally been managed with transurethral resection followed by intravesical chemotherapy and/or bacillus Calmette–Guerin (BCG) in a risk-adapted manner. These tumors commonly recur and can progress potentially to lethal muscle invasive disease. A major unmet need in the field of NMIBC is bladder preserving therapy for recurrent high-grade NMIBC after adequate intravesical BCG therapy. The current gold standard treatment for these BCG-unresponsive patients is radical cystectomy, which is associated with considerable morbidity and mortality, particularly in older and frailer patients. It is therefore critical to provide alternative treatment options with acceptable oncological outcomes. In this review we explore novel bladder-sparing treatment options including combination intravesical therapy, enhanced instillation methods, immunotherapy, gene therapy, targeted therapy, photodynamic therapy and BCG variants across the spectrum of NMIBC disease states, ranging from low grade BCG-naïve patients through to high-grade BCG-unresponsive NMIBC.

PCN349 Healthcare Resource Use (HCRU) of NON-Muscle Invasive Bladder Cancer (NMIBC) Patients Post Bacillus Calmette-Guérin (BCG)-Unresponsive Status in Multiple Countries

BCG is the standard-of-care treatment for NMIBC patients. However, many patients become BCG unresponsive with few options for subsequent treatment other than cystectomy. We evaluated HCRU in these patients, as little evidence is available. A retrospective chart review was conducted in five European countries, US, China, and Japan from January to May 2019. Urologists and medical/clinical oncologists abstracted data for BCG-unresponsive patients. BCG-unresponsive status was defined as having at least one of: persistent or recurrent carcinoma in situ (CIS) alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy; recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy; T1 high-grade disease at the first evaluation following an induction BCG course. HCRU data included physician visits, tests, procedures, and hospitalisations from the time patients were classified as BCG-unresponsive. 508 physicians abstracted data for 2,554 patients. Mean patient age was 72 years and 77% were male. 60% had a current ECOG of 0-1, and staging at diagnosis were CIS alone (34%), papillary disease only (34%), and papillary with CIS (32%). Since BCG-unresponsive status, patients visited their treating physician and PCP most frequently (mean 4.6 and 1.6 visits, respectively) and most patients (92%) underwent tests/procedures related to NMIBC. Most commonly, 75% of patients received CT scans, 50% underwent urine cytology tests and 41% TURBT. 43% were hospitalised, with 59% of these requiring ≥3 nights in hospital. The most common reasons for hospitalisation were standard procedure (49%), intractable gross haematuria (23%) and treating a complication (22%). 34% of patients were admitted through ER. Current management approaches resulted in considerable HCRU demand post BCG-unresponsive status. Most patients required multiple tests/procedures and a high proportion required overnight hospitalisations, which highlights the need for effective treatment and management strategies.

Sequential administration of Bacillus Calmette-Guerin (BCG) and Electromotive Drug Administration (EMDA) of mitomycin C (MMC) for the treatment of high-grade nonmuscle invasive bladder cancer after BCG failure

BackgroundThere is a need for effective nonsurgical treatment options in patients with nonmuscle invasive bladder cancer (NMIBC) in whom Bacillus Calmette-Guerin (BCG) therapy has failed. ObjectiveWe aimed to determine the efficacy of Electromotive Drug Administration (EMDA) of mitomycin C (MMC) with NMIBC after BCG failure. Design, Setting, and ParticipantsA retrospective review of 26 NMIBC patients in whom BCG therapy failed who received BCG/EMDA-MMC between 2013 and 2017 was performed. All but 4 patients fulfilled the FDA criteria for BCG unresponsive disease. Progression and recurrence-free survival (RFS)were calculated using Kaplan-Meier curves. Progression was defined as development of muscle invasive disease, presence of metastasis on imaging or treatment. We used FDA-defined criteria as complete response (CR) for single-arm trials of BCG-unresponsive patients. Results and LimitationsTwenty-six patients were included. Initial pathology was carcinoma in situ (CIS) in 53.8% (14/26), pT1 in 34.6% (9/26), and pTa HG disease in 11.6% (3/26). Twelve of 26 patients progressed (46.2%). Following BCG/EMDA-MMC treatment, progression-free survival rates were 58.3% (95% confidence interval [CI] 41.1–82.1) at 1 year and 48.9% (95% CI 48.9) at 2 years from the date of induction of BCG/EMDA-MMC, respectively. RFS was 41.9% (95% CI 25.9–67.8) at 1 year and 27.2% (95% CI 13.6–54.4) at 2 years. CR at 6, 12, and 18 months was observed in 16 (61.5%), 11 (44.0%), and 7 patients (30.4%), respectively. Side effects included dysuria (19.2%), hematuria (19.2%), and frequency (11.5%). Three patients were admitted for side effects but managed conservatively. Four patients (15.4%) died of bladder cancer over the course of the study. ConclusionsEMDA-MMC BCG represents a viable option in patients with BCG unresponsive NMIBC with close to 50% progression-free survival at 2 years. However, these patients have a high risk of death from bladder cancer (15% in our cohort at 2 years) thus warranting extremely close surveillance.

Correction to: PD-L1 expression in bladder primary in situ urothelial carcinoma: evaluation in BCG-unresponsive patients and BCG responders.

This correction is being done to update the right surname of first name of authors of this manuscript. This does not change the results or the views presented in this manuscript.

PD-L1 expression in bladder primary in situ urothelial carcinoma: evaluation in BCG-unresponsive patients and BCG responders.

Carcinoma in situ (CIS) is believed to be a precursor of muscle-invasive carcinomas that may arise from these flat high-grade, superficial urothelial lesions. CIS accounts for approximately 10% of all bladder tumors. Therapeutic options for urothelial CIS are limited, and in order to inhibit disease progression and recurrence, current guidelines recommend transurethral resection (TURBT) followed by intravesical administration of Bacillus of Calmette-Guerin (BCG). Approximately 30-40% of patients fail the BCG therapy with recurrence and progression of disease. In the present study, we examined the expression of PD-L1 both in neoplastic epithelial cells and in stromal inflammatory cells in patients with diagnosis of CIS primary responders and not responders to BCG therapy, in order to verify if the PD-L1 expression could identify patients resistant to BCG treatment. Moreover, we analyzed on the same cases the immunoreactivities of anti-PD-L1 MoAbs such as SP263, C23, and SP142. Our results have showed that PD-L1 expression in tumor cells and in immune cell compartment is higher in BCG-unresponsive group than in BCG responders, but only the PD-L1 22C3 expression in tumor cells seems to be associated with recurrence of disease (p = 0.035; OR 0.1204; CI 95% from 0.0147 to 1.023). Hence, our data suggest that the PD-L1 22C3 expression could help to identify CIS that fail the BCG therapy, supporting the hypothesis that enhanced levels of intratumoral PD-L1 22C3 expressed by the tumor cells may explain the failure of BCG immunotherapy.

BCG-Unresponsive Bladder Cancer: New Frontiers in the Treatment Landscape

This Ferring-organised Meet-The-Expert symposium at the European Society of Medical Oncology (ESMO) 2019 meeting aimed to discuss new treatment modalities in the management of high-risk, non-muscle invasive bladder cancer (NMIBC). The chairperson Prof Palou commenced the session by discussing the need for newer interventions to address the failure of bacillus Calmette–Guérin (BCG), the first-line treatment against NMIBC, in a substantial proportion of patients. Prof Palou emphasised the need to clearly define refractory disease to optimise second-line treatments, before introducing immune checkpoint inhibitors as a promising class of drug for the treatment of BCG-unresponsive NMIBC. Prof Shariat discussed a case study to define key clinical timepoints for evaluating therapeutic outcomes of BCG treatment. He further outlined factors to be considered before deciding on radical cystectomy in BCG-unresponsive NMIBC. Prof Babjuk listed some of the landmark trials conducted recently to investigate chemotherapeutic agents such as mitomycin C (MMC) and docetaxel in BCG-unresponsive patients before highlighting the role of advanced drug delivery technologies such as electromotive drug administration (EMDA), hyperthermic intravesical chemotherapy, and radiofrequency-induced thermo-chemotherapy effect (RITE) in improving the effectiveness of these agents. Prof Powles shared data from some of the trials investigating immune checkpoint inhibitors such as PURE-01, ABACUS, KEYNOTE, to underscore the importance of biomarkers in selecting appropriate treatment strategies for NMIBC.

Management of High-grade T1 Urothelial Carcinoma.

The optimal management of high-grade T1 (HGT1) urothelial carcinoma (UC) is complex given its high rate of recurrence, progression, and cancer-specific mortality as well as its clinical variability. Our current treatment paradigm has been supplemented by recent data describing the expanding options for salvage intravesical therapy, bladder preservation, and the promising role of molecular epidemiology. In the current review, we attempt to summarize and critically analyze these studies. Evidence describing new intravesical therapies has demonstrated an adequate safety profile and some efficacy in BCG-unresponsive patients who desire bladder preservation. However, response rates are still poor in this high-risk patient population, and it is important to keep these data in perspective when counseling patients. Concomitantly, the continued molecular characterization of non-muscle-invasive bladder cancer may suggest potential therapeutic targets as well as predictors of treatment response in the future. The integration of new intravesical therapies and molecular data into the current treatment paradigm for HGT1 urothelial carcinoma will be critical to improving oncologic outcomes in this particularly high-risk population.

Prognostic Implication of the United States Food and Drug Administration-defined BCG-unresponsive Disease

The category “BCG-unresponsive disease”, formulated by experts at the request of the United States Food and Drug Administration, denotes a group of patients with recurrent non-muscle-invasive bladder cancer for whom continued BCG treatment is unlikely to provide benefit. Although quickly adopted for trial design, many of the nuances within the definition lack validation. In this study, we evaluated the prognostic value of BCG unresponsive designation (i.e. recurrence after induction plus at least 1 maintenance course of BCG) by comparing the oncologic outcomes of these patients with those recurring after induction BCG alone. We confirm that appropriately defined, BCG-unresponsive patients are more likely to require salvage radical cystectomy (54.5% vs 17.9%, p=0.002). Moreover, those opting for second-line bladder-sparing therapies are less likely to remain free of tumor recurrence (23% vs 69.2%, p=0.003). On multivariate analysis, BCG-unresponsive disease independently predicts inferior high-grade recurrence-free survival (hazard ratio [HR]: 6.25, 95% confidence interval [CI]: 2.27–16.67; p<0.001) and cystectomy-free survival (HR: 3.85, 95% CI: 1.49–10.0; p=0.006). Our data confirm the prognostic implication of the BCG unresponsive definition i.e. recurrence of high grade disease after induction and one course of maintenance BCG, and support its use in counseling and risk stratification of patients with tumor recurrence after BCG.Patient summary: Patients who have BCG-unresponsive disease, that is, high-grade non-muscle-invasive bladder cancer recurring after BCG induction and maintenance, have a low likelihood to respond to further BCG treatment and should consider radical cystectomy or clinical trial enrollment.

Immune modulation by combination type I interferon and checkpoint blockade therapy in murine urothelial carcinoma

Abstract Type I interferon (IFN) has potent antitumor effects in bladder cancer and provides an essential alternative treatment option for patients who do not respond to Bacillus Calmette-Guerin (BCG). However, the mechanism of the IFN-stimulated immune response in bladder cancer is not well understood. We hypothesized that type I IFN enhances recruitment and activation of immune cells in murine bladder cancer tumors, and makes them more responsive to anti-PD-1 mAb therapy. To incite an IFN-driven inflammatory response, poly(I:C) was given to murine MB49 bladder cancer tumors peritumorally alone and in combination with anti-PD-1 mAb to determine effects on tumor growth and animal survival. IFN induction in MB49 tumors significantly inhibited tumor growth. This response was reliant on both innate and adaptive immune subsets, shown in the increased influx of intratumoral Ly6G+ neutrophils and the increase in IFNy+CD8 T cells. In addition, depleting specific immune cell subsets indicated that no one type of immune cell was critical for the IFN-mediated anti-tumor response. When used in combination with anti-PD-1 mAb, poly(I:C) prolonged mouse survival and enriched gene pathways involved in metabolism, extracellular matrix formation and organization, and PI3K and AKT signaling. To examine effects of IFN-I in BCG-unresponsive patients, tumor samples were analyzed for RNA expression and immunohistochemical (IHC) staining both before and after treatment with adenoviral interferon-α. Among these samples, 25% showed increased expression of T cell and checkpoint markers, similarly reflected in IHC analysis. Our findings suggest type I IFN grooms the tumor-immune landscape in bladder cancer by activating both innate and adaptive immune cells.

A multicenter clinical trial of intravesical BCG in combination with ALT-803 in patients with BCG-unresponsive non-muscle invasive bladder cancer.

TPS544 Background: BCG unresponsive NMIBC includes patients with persistent high-grade disease or recurrence within 6 months of receiving at least two courses of BCG; or T1 high-grade disease at the first evaluation following BCG induction alone. The recommendation after failing BCG in patients suitable for surgery is cystectomy or for unwilling/unfit patients, salvage chemotherapy or immunotherapy (administered with limited success). This highlights a critical need for novel preservation therapies to facilitate a better quality of life and reduce health-care costs for patients who are unresponsive to BCG (Correa 2015, Dalbagni 2006, Dinney 2013, Kamat 2017). Altor BioScience has initiated a phase II clinical study in BCG unresponsive patients to expand on promising data collected from a compassionate use patient who remains disease free more than 2.5 years after ALT-803 plus BCG treatment for refractory NMIBC (Huang 2017). Methods: This is a Phase II, open-label, single-arm, multicenter study of intravesical BCG plus ALT-803 in patients with BCG unresponsive high grade NMIBC. Group A will enroll patients who have histologically confirmed presence of CIS [with or without Ta or T1 disease]. Group B will enroll patients who have histologically confirmed high-grade Ta or T1 disease (in the absence of CIS). All patients will receive BCG plus ALT-803 weekly for 6 consecutive weeks. A cystoscopy will be performed at Week 12. Patients with no disease or low-grade Ta will receive a maintenance course of therapy (3 weekly instillations of BCG plus ALT-803). Patients with residual CIS and/or high-grade Ta will receive a re-induction course of therapy. Presence of Ta will require a TURBT. Patients with greater than or equal to T1 disease or new CIS will be deemed treatment failures. Patients with a Complete Response (CR) or low-risk disease at Months 6, 9 and 12 are eligible for continued BCG plus ALT-803 maintenance. Patients will be followed for recurrence, progression, and survival. The primary endpoint is to assess complete response (CR; absence of lesions on cystoscopy or negative, for cause, biopsies along with negative urine cytology) of CIS at six months. Enrollment is underway. Clinical trial information: NCT03022825.

Efficacy of mycobacterium phlei cell wall-nucleic acid complex (MCNA) in BCG-unresponsive patients.

342 Background: Previously, we reported the results of a single-armed, multi-institutional study on the efficacy of MCNA in patients who failed intravesical BCG treatment. Since that publication, a new standardized definition for BCG-unresponsiveness has been established. We re-analyzed the oncologic outcomes following intravesical MCNA in patients classified as BCG-unresponsive according to the new definition. Methods: Patients with recurring high grade NMIBC after intravesical BCG were enrolled. For this analysis, we focused on the patients satisfying the minimum criterion for adequate BCG treatment (5/6 induction and 2/3 maintenance). Treatment course included 6 weekly intravesical instillations of 8mg MCNA followed by 3 weekly instillations at months 3, 6, 12, 18, and 24. Followup assessments included cystoscopy, urine cytology and biopsy. Patients absent of high grade disease confirmed by central review of biopsy were deemed disease-free. Results: Of the 129 patients enrolled, 94 (68 CIS with/without papillary tumors, 26 papillary only tumors) fit the criteria for the new BCG-unresponsive definition. In the group with papillary tumors, DFS measured at months 6, 12, and 24 were 61.2%(38.2-77.8%), 61.2(38.2-77.8%), and 50.1%(27.5-69%). In the CIS-containing group, the corresponding DFS were 44.8%(32.3-56.4%), 26.5%(16.3-37.9%), and 16.6%(8.6-26.9%), respectively. Conclusions: Intravesical MCNA therapy has the potential to offer 26.5% of patients with CIS and 61.2% of patients with papillary tumors a chance to safely preserve their bladder for at least 1 year. The efficacy in BCG-unresponsive patients was higher than that reported with all-comers, suggesting that adequate priming with BCG might be required for further immune-based response.

Efficacy of Mycobacterium Phlei Cell Wall-Nucleic Acid Complex (MCNA) inBCG-Unresponsive Patients.

Background: We have previously reported the results of a prospective multi-institutional study on the efficacy of MCNA in patients who recurred after intravesical BCG treatment [1]. Since that publication, a new standardized definition for BCG-unresponsiveness has been established [2].Objective: We re-analyzed the oncologic outcomes following intravesical MCNA in patients classified as BCG-unresponsive according to the new definition.Methods: For this analysis, we focused on the enrolled patients who satisfied the requirements for BCG Unresponsiveness: i.e. adequate BCG treatment (at least 5/6 induction and 2/3 maintenance instillations) and high grade tumor within 6 months of prior BCG. Treatment course included 6 weekly intravesical instillations of 8 mg MCNA followed by 3 weekly instillations at months 3, 6, 12, 18, and 24. Followup assessments included cystoscopy, urine cytology and biopsy. Patients absent of high grade disease confirmed by central review of biopsy were deemed disease-free.Results: Of the 129 patients enrolled, 94 (68 CIS with/without papillary tumors, 26 papillary only tumors) fit the criteria for the new BCG Unresponsive definition. Overall, disease free survival (DFS) for all BCG unresponsive patients was 48.9% (95% CI 38.0–59.0%) at 6 months, 34.8% (95% CI 24.7–45%) at 1 year and 28.3% (15.7–34.3%) at 2 years post induction. In the group with papillary tumors, DFS measured at months 6, 12, and 24 were: 61.2% (38.2–77.8%), 61.2(38.2–77.8%), and 50.1% (27.5–69%). In the CIS-containing group, the corresponding DFS were: 44.8% (32.3–56.4%), 26.5% (16.3–37.9%), and 16.6% (8.6–26.9%), respectively.Conclusions: For patients who are BCG Unresponsive, MCNA has the potential to render 26.5% of patients with CIS and 61.2% of patients with papillary tumors disease-free for at least 1 year with an intact bladder. The higher efficacy noted in the true BCG-unresponsive cohort than was previously reported with all-comers emphasizes the importance of having clearly defined criteria for clinical trials investigating new intravesical therapies after BCG failure.