Faculty Bibliography

Background: Standard treatment (tx) for high-risk NMIBC is transurethral resection of bladder tumor (TURBT) followed by BCG induction and maintenance. However, <<50% of pts experience recurrence and/or progression after tx and may be ineligible for or refuse cystectomy. The PD-L1/PD-1 pathway may be involved with immune escape in NMIBC following BCG exposure. Here, we report results of atezo (anti- PD-L1) +/- BCG in BCG-unresponsive, high-risk NMIBC.
Method(s): This multicenter study (NCT02792192) enrolled pts with BCG-unresponsive NMIBC with carcinoma in situ who had repeat TURBT. Cohort 1A and 1B pts received atezo 1200 mg IV q3w for <96 wk. Cohort 1B pts also received standard BCG induction (qw x 6 doses) and maintenance (qw x 3 doses at 3 mo), with optional maintenance courses at 6, 12, 18, 24, and 30 mo. For cohort 1B only, de-escalation was allowed for <3 BCG dose levels (full dose 50 mg, 66% and 33% of full dose). Co-primary outcomes were safety and complete response (CR) rate at 6 mo (6-mo bladder biopsy required). Duration of CR and 3-mo CR rate (key secondary outcomes) and 12-mo CR rate (exploratory) were also shown.
Result(s): Cohorts 1A and 1B enrolled 12 pts each. Median age was 74 y; most pts had ECOG PS 0 (n = 7 [58%] in each cohort). At data cutoff (Sep 29, 2020), median atezo tx duration was 22.7 wk in cohort 1A and 31.6 wk in 1B. Following dose de-escalation in cohort 1B, the recommended BCG dose was 50 mg. BCG dose modification/interruption occurred in 4 pts (33%) due to an AE. The most common reason for tx discontinuation was disease recurrence or progression in both cohorts. Three pts (25%) in cohort 1A had atezo-related Gr 3 AEs (most common: maculopapular rash, n = 2); no atezo-or BCG-related Gr >=3 AEs were seen in cohort 1B. Three dose-limiting toxicities occurred (1 [8%] in cohort 1A and 2 [17%] in cohort 1B), all reported as AEs of special interest. No Gr 4/5 AEs were reported. CRs, which appeared durable, were seen in both cohorts (Table).
Conclusion(s): In this first report of atezo + BCG in NMIBC, atezo as mono- and combination therapy was well tolerated, with no new safety signals or tx-related deaths. Preliminary data suggested clinically meaningful activity, especially with atezo + BCG, requiring confirmation in a larger setting

INTRODUCTION/UNASSIGNED:The field of cancer therapy has undergone a major transformation in less than a decade due to the introduction of checkpoint inhibitors, the advent of next generation sequencing and the discovery of neoantigens. The key observation that the breadth of each patient's immune response to the unique mutations or neoantigens present in their tumor is directly related to their survival has led oncologists to focus on driving immune responses to neoantigens through vaccination. Oncology has entered the era of precision immunotherapy, and cancer vaccine development is undergoing a paradigm shift. AREAS COVERED/UNASSIGNED:Neoantigens are short peptide sequences found in tumors, but not noncancerous tissues, the vast majority of which are unique to each patient. In addition to providing a description of the distinguishing features of neoantigen discovery platforms, this review will address cross-cutting personalized cancer vaccine design themes and developmental stumbling blocks. EXPERT OPINION/UNASSIGNED:Immunoinformatic pipelines that can rapidly scan cancer genomes and identify 'the best' neoantigens are in high demand. Despite the need for such tools, immunoinformatic methods for identifying neoepitopes in cancer genomes are diverse and have not been well-validated. Validation of 'personalized vaccine design pipelines' will bring about a revolution in neoantigen-based vaccine design and delivery.

PURPOSE/OBJECTIVE:Smoking has a strong causal association with bladder cancer but the relationship with recurrence is not well established. We sought to assess the association of smoking status on recurrence of non-muscle invasive bladder cancer (NMIBC) in a contemporary cohort of patients with predominantly high-risk, recurrent NMIBC managed with photodynamic enhanced cystoscopy. MATERIALS AND METHODS/METHODS:We performed a retrospective study of patients with NMIBC included in a multi-institutional registry. Our primary exposure of interest was smoking status. Our primary outcome was first recurrence of NMIBC. Kaplan-Meier analysis was used to calculate recurrence free probabilities and Cox proportional hazards regression was used to evaluate the impact of smoking status on recurrence free survival. RESULTS:Our analytic cohort included 723 adults with bladder cancer, 11.5% with primary NMIBC and 88.5% with recurrent NMIBC. The majority of patients were white, male, and had high-risk NMIBC (72.6%). 52.6% of included patients were former smokers and 12.7% were current smokers. During the three-year study period, there was a NMIBC recurrence in 259 of the 723 patients (35.8%). The 1- and 3-year probability of recurrence was 19% and 44%, respectively. The grade and stage of recurrences were 28.9% LG Ta, 34.4% HG Ta, 15.8% pure CIS, 0.3% LG T1, 15.4% HG T1, and 5.4% unknown. After adjustment for a priori clinical and demographic factors, smoking status had no significant association with recurrence. CONCLUSION/CONCLUSIONS:Smoking status was not significantly association with recurrence in a study of patients with predominantly high-risk recurrent NMIBC managed with photodynamic enhanced cystoscopy.

Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic.

AIM/OBJECTIVE:This review article summarizes the current clinical practice guidelines around disease definitions and risk stratifications, and the treatment of non-muscle-invasive bladder cancer (NMIBC). Recently completed and ongoing clinical trials of novel and investigational therapies in Bacillus Calmette-Guérin (BCG)-naïve, BCG-recurrent, and BCG-unresponsive patient populations are also described, e.g., those involving immune checkpoint inhibitors, targeted therapies, other chemotherapy regimens, vaccines, and viral- or bacterial-based treatments. Finally, a brief overview of enhanced cystoscopy and drug delivery systems for the diagnosis and treatment of NMIBC is provided. BACKGROUND:A global shortage of access to BCG is affecting the management of BCG-naïve and BCG-recurrent/unresponsive NMIBC; hence, there is an urgent need to assist patients and urologists to enhance the treatment of this disease. METHODS:Searches of ClinicalTrials.gov, PubMed, and Google Scholar were conducted. Published guidance and conference proceedings from major congresses were reviewed. CONCLUSION/CONCLUSIONS:Treatment strategies for NMIBC are generally consistent across guidelines. Several novel therapies have demonstrated promising antitumor activity in clinical trials, including in high-risk or BCG-unresponsive disease. The detection, diagnosis, surveillance, and treatment of NMIBC have also been improved through enhanced disease detection.

Muscle-invasive bladder cancer (MIBC) is associated with high rates of recurrence and poor prognosis despite aggressive treatment. Neoadjuvant chemotherapy before radical cystectomy (RC) improves outcomes in cisplatin-eligible patients; however, the improvement in overall survival is modest. Standard of care for cisplatin-ineligible patients remains RC; more effective systemic therapies are needed. Recent Phase Ib/II studies suggest pembrolizumab monotherapy and combination therapy are effective neoadjuvant therapies for MIBC. The randomized Phase III KEYNOTE-866 and KEYNOTE-905/EV-303 studies are being conducted to evaluate efficacy and safety of perioperative pembrolizumab or placebo with chemotherapy in cisplatin-eligible patients with MIBC (KEYNOTE-866) and of pembrolizumab monotherapy versus pembrolizumab plus enfortumab vedotin versus RC plus pelvic lymph node dissection alone in cisplatin-ineligible patients with MIBC (KEYNOTE-905/EV-303). Clinical trial registration: NCT03924856 & NCT03924895 (ClinicalTrials.gov).

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer.

Improvement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.