Novel Delivery Mechanisms for Existing Systemic Agents and Emerging Therapies in Bladder Cancer
Abstract:
Systemic agents including immune checkpoint inhibitors, antibody-drug conjugates, and targeted therapies play a critical role in the management of bladder cancer. Novel localized delivery mechanisms for existing systemic agents explore solutions to improve treatment response without compromising safety. Herein, we review the contemporary innovations in modern intravesical agents, hyperthermic drug delivery, reverse-thermal gels, nanocarriers, gene therapy, and subcutaneous therapies.
NK Cell-Targeted Immunotherapies in Bladder Cancer: Beyond Checkpoint Inhibitors
ABSTRACT:
BACKGROUND: For decades, immunotherapies have been integral for the treatment and management of bladder cancer, with immune checkpoint inhibitors (ICIs) transforming patient care in recent years. However, response rates are poor to T cell-targeted ICIs such as programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies, framing a critical need for complementary immunotherapies. Promising strategies involve harnessing the activation potential of natural killer (NK) cells. They quickly exert their antitumor activity via signaling through germline-encoded activating receptors and are rapidly sensitized to new tissue microenvironments via their regulation by polymorphic HLA class I, KIR and NKG2A receptors.
OBJECTIVE: In this review, we examined the roles of currently available NK-targeted antitumor treatment strategies such as engineered viral vectors, small-molecule IMiDs, NK agonist antibodies, interleukins, and chimeric antigen receptor (CAR) NK cells, and their potential for improving the efficacy of immunotherapy in the treatment of bladder cancer.
METHODS: Through review of current literature, we summarized our knowledge of NK cells in solid tumors and hematologic malignancies as their roles pertain to novel immunotherapies already being applied to the treatment of bladder cancer or that offer rationale for considering as potential novel immunotherapeutic strategies.
RESULTS: NK cells play a critical role in shaping the tumor microenvironment (TME) that can be exploited to improve T cell-targeted immunotherapies.
CONCLUSIONS: Emerging evidence suggests that NK cells are a prime target for improving antitumor functions in immunotherapies for the treatment of bladder cancer. Further research into profiling NK cells in settings of immunotherapies for bladder cancer could help identify patients who might maximally benefit from NK cell-targeted immunotherapies and the various approaches for exploiting their antitumor properties.
Hypofractionated Radiation Therapy (Hypo-RT) for the Treatment of Localized Bladder Cancer
Abstract:
BACKGROUND: Various radiotherapeutic regimens are used in the treatment of bladder cancer.
OBJECTIVE: We aimed to evaluate early toxicity and outcomes associated with hypofractionated radiation therapy (Hypo-RT), 55Gy in 20 fractions.
MATERIAL AND METHODS: We identified 40 patients who received definitive Hypo-RT for localized bladder cancer. Most patients were men (62.5%), elderly (median age 82), had high Charlson Comorbidity Index score (median 7, range 4–9) and were nonsurgical candidates (80%). Sixty-eight percent had a macroscopically complete transurethral resection of bladder tumor (TURBT) and 33 patients (82.5%) received concurrent chemotherapy. Acute (< =3mo) and late (>3mo) toxicities were assessed according to CTCAE v4.0. Survival outcomes were estimated using the Kaplan-Meier method. Median follow up after Hypo-RT was 32 months (95% CI: 28–49 months).
RESULTS: Overall rates of acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were 40% each, most commonly urinary frequency and diarrhea. Two cases of acute grade 3 GU/GI toxicity occurred. Late grade 2+ toxicity occurred in 3 patients (7.5%): 2 grade 2 GU and 1 grade 3 GI. Seventy-seven percent achieved a complete response (CR). Six patients (20%) developed disease recurrence at a median time of 9.1 months. The estimated 2-year DFS and 2-year DSS rate were 59% (95% CI, 45–78%) and 78% (95% CI, 65–93%), respectively. Receipt of concurrent chemotherapy (p = 0.003) and achieving a CR (p = 0.018) were univariably associated with improved DSS. Tis component was associated with worse DSS (p = 0.015).
CONCLUSION: Hypo-RT had a favorable toxicity profile and encouraging cancer control outcomes in this mostly elderly and frail patient cohort.
The Development of a Video-based Nutrition Education Curriculum for Patients Undergoing Radical Cystectomy
Abstract:
BACKGROUND: The treatment for patients with muscle-invasive bladder cancer includes neoadjuvant chemotherapy followed by radical cystectomy. The American Urological Association guidelines stress the optimization of patient performance status in the perioperative setting. Therefore, implementation of nutrition education is critical for the multi-disciplinary care of this vulnerable patient population and wide distribution of information is critical.
OBJECTIVE: The goal of our study was to create a nutrition-based video education series for patients undergoing chemotherapy and radical cystectomy for bladder cancer.
METHODS: Scripts for the videos were developed through an iterative process by experts in nutrition, urology, and communication. Providers and patient advocates were recruited to perform semi-structured interviews and surveys for additional feedback. Performer facial emotion recognition (Noldus™) was used to assess displayed emotion by the presenters. Mangold VisionPlayer software was used for participant eye movement tracking of the video content. A knowledge survey was created, and Item Content Validity Index (I-CVI) was calculated with a nutrition expert advisory board. Participants were recruited for cognitive interviewing to understand the mental processes and interpretations while answering questions.
RESULTS: The video series is available to the public on the Bladder Cancer Advocate Network (BCAN) website at the following URL: https://bcan.org/facing-bladder-cancer/nutrition-bladder-cancer/eating-healthy-bladder-cancer/. Cinematic filming methods, (smaller depth of field, lighting, and camera movement) enhanced message delivery along with music and text on screen to anchor important concepts.
CONCLUSIONS: This study can be a framework for the development of a patient education video library accessible through electronic medical records, health care applications, and patient advocacy websites.
Electromotive Drug Administration Chemotherapy with Mitomycin C Versus Bacillus Calmette-Guerin for the Treatment of Non-Muscle Invasive Bladder Cancer
Abstract:
BACKGROUND:
Devices that increase the penetrance of intravesical chemotherapeutics are emerging as alternatives to classical Bacillus Calmette Guérin (BCG) treatment.
OBJECTIVE:
To compare the efficacy of mitomycin C applied with the electromotive drug delivery device (MMC-EMDA) versus BCG in patients with intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) without carcinoma in situ (CIS).
METHODS:
Prospective non-randomized study in which 47 patients received MMC-EMDA (40 mg of MMC diluted in 50 mg of distilled water at 20 mA for 30 min. Regimen of 6 weekly and then 6 monthly instillations) and 48 patients received BCG (50 mg of OncoCITE® diluted in 50 ml of normal saline for 60 min. Regimen of 6 weekly instillations and then 3 weekly instillations at months 3, 6 and 12). The primary endpoint was the recurrence-free rate (RFR) at 24 months. Secondary endpoints were time to recurrence and progression-free rate (PFR) at 24 months follow-up.
RESULTS:
Baseline patient assessment and mean follow-up time were similar in both groups (MMC-EMDA group: 26.4 months; BCG group: 28.4 months (p = 0.44)). The RFR at 24 months was 80.9% for the MMC-EMDA group and 77.1% for the BCG group (p = 0.969). The mean time to recurrence was 12.5 months in the MMC-EMDA group and 14 months in the BCG group (p = 0.681). At 24 months, PFR was 97.9% in the MMC-EMDA group and 93.8% in the BCG group (p = 0.419).
CONCLUSIONS:
No differences were found between MMC-EMDA and BCG treatments in patients with high-risk and intermediate-risk NMIBC without CIS.
Predictive Value of Computed Tomography Following Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer
Abstract:
BACKGROUND: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) remains standard treatment for select patients with muscle-invasive bladder cancer (MIBC). Although computed tomography (CT) is often obtained prior to RC, its ability to predict pathologic response is poorly characterized.
OBJECTIVE: The purpose of this study is to evaluate the predictive value of CT in assessing disease burden after NAC.
METHODS: Patients with MIBC having received NAC prior to RC were identified. Pre- and post-NAC CT scans were reviewed by an abdominal radiologist. The correlation between pathologic complete response (PCR) and radiologic complete response (RCR) was determined as the primary aim. As a secondary aim, the correlation between pathologic partial response (PPR) and radiologic partial response (RPR) was determined. Logistic regression analysis was utilized to determine the predictive value of CT in determining disease burden at RC.
RESULTS: A total of 141 patients were identified for analysis. PCR and PPR was achieved in 34% and 16% of patients, respectively. The positive predictive value of post-NAC CT was 53.5% for PCR and 28.8% for PPR. The negative predictive value of post-NAC CT was 73.5% for PCR and 46.2% for PPR. There was no significant association between RCR and PCR (OR 1.13, p = 0.67). Similarly, there was no meaningful association between RPR and PPR, lymph node involvement, or presence of extravesical disease.
CONCLUSIONS: CT findings correlate poorly with final pathology at RC and should not be used to evaluate local disease burden.
Association of Histone H3 Trimethylation in Circulating Monocytes with Lack of Early Recurrence in Patients with Bladder Cancer following BCG Induction Therapy
Abstract:
BACKGROUND: The mode of action of Bacillus Calmette-Guérin (BCG) in the treatment of patients with non-muscle invasive bladder cancer (NMIBC) is incompletely understood, but recent studies support an association between BCG-induced trained immunity in circulating monocytes and disease-free survival.
OBJECTIVE: We compared epigenetic profiles in monocytes from NMIBC patients with early disease recurrence with those from recurrence-free patients.
METHODS: We conducted chromatin immunoprecipitation and DNA sequencing (ChIP-seq) on monocytes from seven patients treated with BCG (four with early recurrences and three recurrence-free after one year) to determine genome-wide distribution and abundance of histone 3 lysine 4 trimethylation (H3K4me3) prior to and after five weeks of induction therapy.
RESULTS: Genome-wide H3K4me3 profiles before or after BCG induction distinguished patients with early recurrences from those remaining recurrence-free. Furthermore, H3K4me3 levels at genes involved in specific pathways were increased in the recurrence-free group. Independent quantification showed increased H3K4me3 levels in elements of the Wnt and AMPK signaling pathways in the recurrence-free group before BCG initiation, while elements of the MAPK showed increased levels after five weeks of induction in the same group. Validation of these genes on an independent cohort of four additional patients that remained recurrence-free after one year and three with early recurrences revealed consistent increases in H3K4me3 levels associated with MAPK pathway genes after five weeks of BCG treatment in the recurrence-free group.
CONCLUSIONS: Recurrence-free survival following BCG immunotherapy for NMIBC is associated with the accumulation of H3K4me3 at specific gene loci, and could lead to identification of prognostic biomarkers.