Intravesical Immunotherapy Research Articles

A prospective observational study on oral administration of Ellagic Acid and Annona Muricata in patients affected by non-muscle invasive bladder cancer not undergoing maintenance after 6-week intravesical prophylaxis.

BCG and MMC shortage and Covid-19 pandemic, more recently, limit accessibility to maintenance regimen in intravesical prophylaxis against recurrence of non-muscle invasive bladder cancer (NMIBC). Ellagic acid (EA) and Annona muricata (AM) exert antitumor activity against different human tumours. An observational prospective study on the prophylactic effect of oral administration of EA+AM in patients avoiding maintenance regimen is presented. Patients affected by NMIBC and not undergoing maintenance after a 6-week course of intravesical prophylaxis with MMC or BCG were entered. Tis and very high-risk tumours were excluded. After informed consent, the patients were subdivided in relation to the oral assumption or not of EA (100 mg) plus AM (100 mg), daily for 6 months. All patients were submitted to 3-month cytology and cystoscopy. 162 (90%) of 180 entered patients are evaluable, 90 and 72 receiving or not EA+AM. No difference emerged in patients' characteristics between the two groups. BCG was given in 86 (54%) and chemotherapy in 74 (46%) patients. The recurrence free rate at 3, 6 and 12 months in patients assuming or not EA was 96.5% versus 84.6% (p = 0.003), 85.4% versus 64.8% (p = 0.005) and 74.2% versus 60.6% (p = 0.246), respectively. The recurrence free survival at 12 months in patients assuming or not EA was 63.0% versus 34.5% (p < 0.0001). Our study suffers several limits: not randomized trial although prospective, limited number of patients and short follow-up, nevertheless it shows the prophylactic effect of oral EA+AM in absence of maintenance after intravesical chemotherapy or immunotherapy induction.

RECURRENCE RATE AFTER REPEAT TRANSURETHRAL RESECTION AMONG PATIENTS WITH NEWLY DIAGNOSED T1 BLADDER CANCER

Background: Transurethral resection of the bladder tumor (TURBT) is the cornerstone of diagnosis and TURBT followed by selective adjuvant intravesical chemotherapy or immunotherapy is the gold standard of treatment for the patients with non-muscle invasive bladder cancer (NMIBC). Even after complete resection of the tumor there is high risk of residual tumor and subsequent recurrence and progression of the disease. The recurrence of T1 tumor is found to be around 71 % within 5 years and High grade T1 lesions recur in more than 80% of the cases and progress in 50% of the patients within 3 years. Disease status at 3 months after initial resection is an important predictor of subsequent recurrence and progression. To assess the tumor recurrence rat Objective: e among patients with newly diagnosed T1 bladder cancer between repeat transurethral resection group and single TURBT group. Ra Type of study: ndomized controlled trial. Place of study: Department of urology, BSMMU, Dhaka, Bangladesh. This Randomi Materials And Methods: zed Controlled Trial was conducted in urology department of BSMMU, Dhaka, Bangladesh from February 2017 till September 2018. A total of 50 patients, diagnosed as a case of T1 bladder cancer and who fulll the selection criteria were randomly divided in two groups consisting of 25 patients in each group. After informed consent, repeat TUR was done after 4 weeks of the initial TURBT for only 22 patients in group I since 3 of the patients did not show up on the scheduled date of surgery. Whereas, repeat TUR was not done for other 25 patients in group II. All the patients in both the groups were further treated with intravesical therapy according to the histopathological report. The patients in both the groups were followed up at 3 months and 6 months of the initial intervention where detailed history was taken, relevant investigations were done and check cystoscopy was done. TURBT was done for recurrent tumors. Out of 22 patients in group I, 2 patients were excluded for follow up on the basis of repeat TUR ndings. Whereas in group II, 2 patients missed the follow up and one of them missed the normal scheduled dose of intravesical therapy. Hence, 22 patients completed the study in group II. The baseline variables like age and Results: sex were similar in both the groups with higher male predominance. There was no statistical signicant difference in tumor characteristics such as size, number and grade of the tumor between the two groups. Out of 22 patients in group I who underwent repeat TUR at 4 weeks of initial TUR, residual disease was found in 8 (36.36%) patients. One of the patient was found to have T2 disease and 1 patient had CIS during repeat TUR. These 2 patients were not followed up since the treatment strategy changed after the results of repeat TUR. After 6 months of follow up of all the patients, 2 (10%) out of 20 patients in group I were found to have tumor recurrence however, in group II, 9 (40.9%) patients had tumor recurrence. The tumor recurrence rate between the two groups was found to be statistically signicant (p=0.023). In the light of ndings of this Conclusion: study, it can be concluded that performing repeat transurethral resection in patients with newly diagnosed T1 bladder cancer at 4 weeks of initial TURBT, helps to detect signicant number of residual tumor and reduce early recurrence rate of the tumor.

Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer.

Intravesical immunotherapy using Bacille Calmette-Guérin (BCG) attenuated bacteria delivered transurethrally to the bladder has been the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) for several decades. BCG therapy continues to be limited by high rates of disease recurrence and progression, and patients with BCG-unresponsive disease have few effective salvage therapy options besides radical cystectomy, highlighting a need for new therapies. We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8+ T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8+ T cells are required for both bladder cancer immune surveillance and anti-CD40 agonist antibody responses. Using orthotopic murine models humanized for CD40 and Fcγ receptors, we demonstrate that intravesical treatment with a fully human, Fc-enhanced anti-CD40 agonist antibody (2141-V11) induces robust antitumor activity in both treatment-naïve and treatment-refractory settings, driving long-term systemic antitumor immunity with no evidence of systemic toxicity. These findings support targeting CD40-expressing DCs in the bladder cancer microenvironment through an intravesical agonistic antibody approach for the treatment of NMIBC.

Bacillus Calmette-Guerin (BCG)-induced balanitis following intravesical immunotherapy for urothelial cancer

A 64-year-old man presented with multiple whitish macules in penis of 1-week duration. Detailed history revealed that the patient was diagnosed with non-muscle invasive T1 high-grade urinary bladder cancer and...

Efficacy of three BCG strains (Connaught, TICE and RIVM) with or without secondary resection (re-TUR) for intermediate/high-risk non-muscle-invasive bladder cancers: results from a retrospective single-institution cohort analysis

Purpose(I) To evaluate the clinical efficacy of three different BCG strains in patients with intermediate-/high-risk non-muscle-invasive bladder cancer (NMIBC). (II) To determine the importance of performing routine secondary resection (re-TUR) in the setting of BCG maintenance protocol for the three strains.MethodsNMIBCs who received an adjuvant induction followed by a maintenance schedule of intravesical immunotherapy with BCG Connaught, TICE and RIVM. Only BCG-naïve and those treated with the same strain over the course of follow-up were included. Cox proportional hazards model was developed according to prognostic factors by the Spanish Urological Oncology Group (CUETO) as well as by adjusting for the implementation of re-TUR.Resultsn = 422 Ta-T1 patients (Connaught, n = 146; TICE, n = 112 and RIVM, n = 164) with a median (IQR) follow-up of 72 (60–85) were reviewed. Re-TUR was associated with improved recurrence and progression outcomes (HRRFS: 0.63; 95% CI 0.46–0.86; HRPFS: 0.55; 95% CI 0.31–0.86). Adjusting for CUETO risk factors and re-TUR, BGC TICE and RIVM provided longer RFS compared to Connaught (HRTICE: 0.58, 95% CI 0.39–0.86; HRRIVM: 0.61, 95% CI 0.42–0.87) while no differences were identified between strains for PFS and CSS. Sub-analysis of only re-TUR cases (n = 190, 45%) showed TICE the sole to achieve longer RFS compared to both Connaught and RIVM.ConclusionRe-TUR was confirmed to ensure longer RFS and PFS in intermediate-/high-risk NMIBCs but did not influence the relative single BCG strain efficacy. When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to the other strains for RFS outcomes.

Modulation of the RANK/RANKL/OPG system and FOXP3+ regulatory T cells in the tumor microenvironment of noninvasive bladder cancer after intravesical oncotherad immunotherapy associated with platelet-rich plasma.

462 Background: The activity of the receptor activator of nuclear factor-kβ RANK/RANKL in cancer cells has been correlated with tumor progression and poor prognosis in solid tumors including bladder cancer. Regulatory T cells (Tregs), often identified by FOXP3 biomarker, suppress the anti-tumor response and allow immune tolerance through suppression of T cells. Immunomodulator OncoTherad is an inorganic phosphate nanocomplex associated with glycosidic protein, developed by the University of Campinas/Brazil, with antitumor effects. Previous reports have demonstrated immune activation and antitumor effects of Platelet Rich Plasma (PRP). We evaluated the effects of OncoTherad associated with PRP in the RANK/RANKL system and Tregs in a mouse model of non-muscle invasive bladder cancer (NMIBC). Methods: C57BL/6J mice were assigned to groups (n = 42): Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50 mg/ml); PRP (0.1 ml); OncoTherad (20 mg/ml); OncoTherad+PRP 10 mg/ml and OncoTherad+PRP 20 mg/ml. The intravesical doses (0.1 ml) were instilled once a week for 6 consecutive weeks after induction. Results: After NMIBC induction, all animals in the Cancer group showed flat carcinoma in situ (pTis) and both percentages of RANK, RANKL, OPG, and FOXP3 positive cells and the intensity of immunoreaction for these antigens were significantly higher in comparison with healthy animals. In addition to ensuring this NMIBC model, these results indicated the involvement of RANK/RANKL in urothelial carcinogenesis and the presence of Tregs in a suppressed immune tumor microenvironment. Mice treated with PRP only showed a 28.6% rate of tumor progression inhibition (TPI) and exhibited papillary urothelial carcinoma (pTa) and pTis. In this group, the intensity of the RANKL and FOXP3 immunoreaction was weaker when compared to the Cancer group. Thus, PRP showed immunomodulatory effects, reducing Tregs that are sources of RANKL. Oncotherad immunotherapy led to an TPI of 85.7%, and benign flat hyperplasia was the most frequent diagnosis. Oncotherad reduced the total RANK and RANKL immunoreactivities and decreased the intensity of RANKL immunostaining in comparison to the Cancer. In the OncoTherad+PRP 10 mg/ml or 20 mg/ml group, TPI was 71.4%, with a predominance of non-malignant lesions such as flat hyperplasia, low-grade intraurothelial neoplasia, and reactive atypia. Treatments with Oncotherad and Oncotherad plus PRP decreased the percentage of FOXP3+ cells and reduced the intensity of FOXP3 immunoreaction compared to the Cancer and PRP groups. Conclusions: The tumor inhibition obtained with Oncotherad plus PRP was related to the alteration of the immune profile of the tumor microenvironment by decreasing RANK/RANKL expression and Tregs, resulting in an effective immune response against the tumor.

A potential new therapeutic option for the treatment of nonmuscle invasive bladder cancer: Combination of intravesical oncotherad immunotherapy and platelet rich plasma (PRP).

461 Background: Effective intravesical therapies remain lacking for non-muscle invasive bladder cancer (NMIBC) when Bacillus Calmette-Guerin fails. OncoTherad is a nanostructured inorganic phosphate complex associated with glycosidic protein, developed by the University of Campinas/Brazil, which triggers immunomodulatory and antitumor activities. Previous studies have shown that Platelet Rich Plasma (PRP) acts on immune activation and exerts antitumor effects. This study characterized the effects of the OncoTherad associated with PRP in the treatment of NMIBC chemically induced in mice and the modulation promoted in the Toll-like receptors (TLRs) signaling pathway. Methods: Forty-two C57BL/6J mice were divided into groups: Control; Cancer (N-ethyl-N-nitrosourea carcinogen, 50 mg/ml); PRP (0.1 ml); OncoTherad (20 mg/ml); OncoTherad+PRP 10 mg/ml and OncoTherad+PRP 20 mg/ml. The intravesical doses (0.1 ml) were instilled once a week for 6 weeks after induction. Results: The NMIBC induction decreases (p&lt;0.05) body weight, although after treatments the body weight was recovered similarly to the healthy mice. The treatments did not significantly alter the biochemical patterns of the urine and food and water consumption. There was no acute toxicity or kidney damage, and the presence of hydroureter was variable. The urinary bladders of mice treated with Oncotherad associated or not with PRP showed hyperemia associated with the inflammatory condition. The thickening of the urinary bladder wall in the Cancer group was more evident than in the treated groups, in which there were bladders without thickening or macroscopic lesions. Flat carcinoma in situ (pTis) was present in 100% of the mice in the Cancer group and the intensity of immunoreactivities for TLR2, IL-6, TLR4, and IRF-3 was significantly weaker in comparison with the Control, indicating suppression of the immune system in the tumor microenvironment. When treated intravesically with PRP only, mice showed 28.6% of tumor progression inhibition rate; with OncoTherad 85.7% and with OncoTherad+PRP 10 mg/ml or 20 mg/ml 71.4%. Intravesical treatments led to distinct activation of TLRs 2 and 4-mediated innate immune system in the interleukins (MyD88-dependent) and interferons (TRIF-dependent) signaling pathways. The combined treatment of OncoTherad+PRP increased (p&lt;0.05) the percentage of positive TLR4 urothelial cells and the intensity of immunoreaction for TLR4 compared to the isolated treatments and the immunoreactivities of NF-kB, IL-6, TLR4, IRF-3, and IFN-γ in comparison to the Cancer. Conclusions: Intravesical treatment with OncoTherad plus PRP promoted significant inhibition of tumor progression, possibly due to immunomodulatory activity involving the TLR pathway. This association can constitute a therapeutic strategy for refractory NMIBC patients.

Disseminated BCG Infection after intravesical BCG Immunotherapy of Bladder Cancer.

Disseminated BCG Infection after intravesical BCG Immunotherapy of Bladder Cancer.

Bacillus Calmette Guerin (BCG) Balanitis: a Rare Organ Complication of Non-muscle Invasive Urinary Bladder Cancer Following Intravesical Immunotherapy

Bacillus Calmette Guerin (BCG) is widely used for prevention of recurrence and progression in non-muscle invasive urinary bladder cancers. However, it is associated with tolerable adverse events ranging from low-grade fever to lower urinary tract symptoms. While majority of complications are minor and local, systemic involvement warrants early treatment with antitubercular agents. Involvement of glans penis is rare with only few cases reported in the literature. We report one such case of BCG balanitis in a 64-year-old male treated with intravesical BCG for non-muscle invasive urinary bladder cancer.

Assessment of the oncological outcomes of three different bacillus Calmette–Guérin strains in patients with high-grade T1 non-muscle-invasive bladder cancer

ABSTRACT Objective : To determine whether there are significant differences in oncological outcomes between three different bacillus Calmette–Guérin (BCG) strains used for adjuvant intravesical immunotherapy in patients with high-grade T1 (T1HG) non-muscle-invasive bladder cancer (NMIBC). Patients and methods : Data of 590 patients with a diagnosis of primary T1HG NMIBC were retrospectively reviewed. The study included 138 (23.4%) patients who were treated with the Moreau, 272 (46.1%) with the TICE, and 180 (30.5%) with the RIVM strains. All patients included in the analysis received at least five instillations of an induction course and at least two installations of a maintenance course. Due to existing differences in baseline patient characteristics, the association between oncological outcomes and strain groups was investigated by complementary analysis with the implementation of inverse probability weighting (IPW). Results : The 5-year recurrence-free survival (RFS) rate was 70.5%, 66.7% and 55.2% for the Moreau, TICE and RIVM groups, respectively (P = 0.016). The 5-year progression-free survival (PFS) rates were 84.4%, 85% and 77.8% in the Moreau, TICE and RIVM groups, respectively (P = 0.215). The IPW-adjusted Cox proportional hazard regression analysis did not show any differences in RFS between the Moreau and TICE groups (P = 0.69), whereas the RIVM strain was significantly associated with worse RFS compared to the Moreau (hazard ratio [HR] 1.69 for RIVM; P = 0.034) and TICE (HR 1.87 for RIVM; P = 0.002) strains. The IPW-adjusted analysis did not show any significant differences between study groups in terms of PFS. Conclusions : The results of the present study suggest that the Moreau and TICE strains might be superior to the RIVM strain in terms of RFS in patients with T1HG NMIBC. Abbreviations: CIS: carcinoma in situ; IPW: inverse probability weighting; IQR: interquartile range; HR: hazard ratio; HG: high grade; LVI: lymphovascular invasion; MP: muscularis priopria; NMIBC: non-muscle-invasive bladder cancer; PFS: progression-free survival; RCT: randomised controlled trial; RFS: recurrence-free survival; T1HG, high-grade T1; (re-)TURB: (re-staging) transurethral resection of bladder; VH: variant histology

An uncommon cause of miliary disease: intravesical BCG immunotherapy.

An uncommon cause of miliary disease: intravesical BCG immunotherapy.

A man in his seventies with dyspnoea and ataxia after BCG instillation for bladder cancer.

BACKGROUND This case report introduces one of the first documented incidents of infectious complications of intravesical BCG immunotherapy in Norway. It took time to feel satisfied with the final diagnosis due to the diagnostic challenges related to obtaining positive results on microbiological analyses. CASE PRESENTATION A man in his seventies presented with malaise, fever and elevated liver enzymes after intravesical administration of BCG. He was given glucocorticoids against a potential hypersensitive reaction on the liver, but the patient soon returned with worsening general condition, persistent fever, cough and ataxia. CT thorax showed a miliary pattern in the lungs and brain MRI showed dural/meningeal enhancement. We were unable to detect viable bacilli in microbiological samples from the lungs, cerebral fluid or blood. Histologic finding of granulomas on lung biopsy, together with no other reasonable alternative diagnosis, was crucial for the decision to start antitubercular drugs. INTERPRETATION Although a rare complication, BCG infections should be considered early in patients developing illness after intravesical BCG instillation. The procedure is relatively common in Norwegian hospitals and adverse results do occur.

Radical cystectomy compared to intravesical BCG immunotherapy for high-risk non-muscle invasive bladder cancer – is there a long-term survival difference? A Swedish nationwide analysis

Objectives High-risk non-muscle invasive urinary bladder cancer (NMIBC) presents an increased risk of progression and cancer death. To reduce these risks, two different treatments are recommended – BCG or radical cystectomy (RC). The purpose of this study is to analyze cancer-specific survival of these two initial treatments. Materials and Methods BladderBaSe links information from the SNRUBC from 1997 to 2014, with a number of national healthcare and demographic registers. BCG was used for 3,862 patients (399 had delayed RC), while 687 had initial RC. Propensity scores were used to match the patients treated with RC and with relevant variables such as age, gender, and tumor stage with the same number treated with BCG (673 each arm). In a further comparison, an instrumental variable analysis using hospital strategy as the instrument was used. Results The 5-year cancer-specific survival chance was higher for the BCG group than it was for the initial RC group, 87 vs 71%, respectively. In the population with propensity score matching, 78 died from cancer in the BCG group during follow-up and 162 in the RC group. In the instrumental variable analysis, the multivariate adjusted risk difference of cancer-specific death 2 years after diagnosis was 32 per 100 treated patients, in favor of the BCG group. Conclusions BCG therapy had better cancer-specific survival than RC also when two different statistic methods were used to try to control for confounding. A prospective randomized trial will be necessary to rule out that selection is a major factor for the outcome.

Complications of intravesical BCG therapy in non-muscle invasive bladder cancer: our tertiary care centre experience

BackgroundUrothelial bladder carcinoma accounts for around 3.9% cases of all the male cancers in India. Non-muscle-invasive bladder carcinoma (NMIBC) is predominant group which constitute approximately three fourth of the urothelial bladder cancer. Intravesical BCG immunotherapy is the corner stone of today’s NMIBC management. However, as with any other therapy it has its own complications and its interruption due to these adverse effects is a major cause of suboptimal efficacy. The aim of this study was to assess the complications of intravesical BCG therapy and their management in NMIBC patients.MethodsThis was a retrospective descriptive study conducted between October 2016 and November 2019; a backward review of 149 patients with diagnosis of NMIBC that undergone intravesicle BCG therapy was performed. Patient’s demographical, clinical, diagnostic and procedural data regarding bladder tumour, BCG therapy, its complications and management were collected and analysed.ResultsTotal 149 patients were analysed, comprising 116 males and 33 females. The mean age was of 57.2 ± 6.7 years. Total 85.23% were primary and 14.76% were recurrent tumours. Total 96 patients (64.42%) completed the planned course, while 53 (35.57%) interrupted. The reasons for BCG interruption includes adverse effects (15.4%), progression of disease (6.7%), disease refractory to BCG (4.6%) and disease recurrence during BCG (3.3%). Most of the adverse events occurred in first 6 months and most interruptions occurred after the induction period. Cystitis was the most common observed adverse effect seen in 39.6% patients. Frequency, urgency, haematuria were common presentation. Radical cystectomy was the most common (16.10%) further treatment with patients whose treatment was interrupted.ConclusionBCG is an indispensable therapy available for NMIBC, but it is associated with array of adverse effects and complications, which are the main reasons for poor compliance to BCG therapy. Although BCG-related complications can affect any organ in the body, potentially life-threatening systemic BCG-related infections are encountered in only < 5% of patients. There are some difficulties in diagnosis of the BCG complications because acid-fast staining, culture and PCR test are not always positive; tissue biopsies should be indicated sometimes to evaluate histopathology and presence of M. bovis. A persistently monitored multidisciplinary approach with high index of suspicion and prompt anti-TB therapy can help to derive the maximum benefits while keeping the complications at check.

Recombinant BCG overexpressing STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

BCG remains first-line therapy for non-muscle invasive bladder cancer (NIMBC) but its mechanism of action is not fully understood nor is it completely efficacious. We engineered a recombinant BCG (rBCG) that releases increased levels of STING agonist, c-di-AMP and compared effects of rBCG to wild type BCG (WT-BCG) by assessing antitumor efficacy and its ability to elicit trained immunity in NMIBC models. Rat MNU-carcinogen model of NMIBC was used to compare antitumor efficacy of 6 weekly intravesical installations of WT-BCG versus rBCG by pathologic tumor grading of bladder tissue and qRT-PCR for Th1 cytokines. Primary human and murine macrophage and urothelial carcinoma cell lines were treated with WT-BCG and rBCG and cytokine response was compared using ELISAs while macrophage phenotypes were determined by flow cytometry. MB49 cells were injected into flanks of C57Bl/6J mice followed by intratumoral injection of WT-BCG and rBCG to compare infiltrating Tcells and Teffector responses by flow cytometry. An in vitro trained immunity model of primary human monocytes was used to evaluate epigenetic changes (H3K4Me3) on TNF-a and IL-6 gene promoters by ChIP-PCR. Compared to WT-BCG, intravesical installation of rBCG in MNU-rats resulted in significantly lower tumor involvement and a more potent induction of Th1 cytokines. rBCG treated primary macrophages showed increased IFN I, IL-6, TNF‑a MCP-1 and IL-12 levels concomitant with increased M1 polarization shift. More pronounced IL-6, TNF‑a and IL-1b levels were observed in several human and rodent urothelial carcinoma cells in response to rBCG. Intratumoral injection of rBCG caused increased tumor regression and stronger infiltration of IFN‑g producing CD4+ T cells in MB49 tumors. rBCG elicited more potent epigenetic changes (H3K4Me3) on the TNF-a and IL-6 gene promoters following monocyte training. Increased proinflammatory cytokines, potentiated IFN-g+CD4+ T cells, and increased macrophage reprogramming (increased M1 shift and increased epigenetic changes) contributes to enhanced antitumor efficacy of rBCG over WT-BCG in NMIBC tumor models. Recombinant rBCG may be a novel intravesical immunotherapy for patients with NMIBC.

Intra-arterial chemotherapy combined with intravesical chemotherapy compared with intravesical BCG immunotherapy retrospectively in high-risk non-muscle-invasive bladder cancer after transurethral resection of the bladder tumor.

To compare the efficacy and safety of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IVC) against intravesical BCG immunotherapy in high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of the bladder tumor (TURBT). 130 patients with high-risk NMIBC who had underwent TURBT were divided into two groups, of which IAC + IVC group received four courses of IAC (cisplatin and epirubicin) combined with IVC (epirubicin or pirarubicin) after surgery and BCG group received intravesical BCG immunotherapy. Recurrence rate and progression rate were assessed by Chi-square test, while recurrence-free survival and progression-free survival were calculated using the Kaplan-Meier method. In this study, the recurrence rate was 27.9% (12/43) in IAC + IVC group and 26.4% (14/53) in BCG group, while progression rate was 9.3% (4/43) in IAC + IVC group and 9.4% (5/53) in BCG group. Both of the recurrence and progression rate did not show a significant difference. In the Kaplan-Meier plot, no difference was found with respect to recurrence-free survival and progression-free survival. Moreover, 46.5% (20/43) patients suffered from adverse events of IAC and 83.1% (49/59) patients suffered from adverse events associated with BCG, of which 6 patients discontinued treatment due to serious adverse events of BCG. Univariate analysis suggested that only recurrent tumor could be an independent risk factor related to recurrence. IAC combined with IVC used in high-risk NMIBC could reduce the recurrence and progression as effective as BCG instillation with lower adverse events.

Combination of novel intravesical xenogeneic urothelial cell immunotherapy and chemotherapy enhances anti-tumor efficacy in preclinical murine bladder tumor models

BackgroundImmune checkpoint inhibitors induce robust and durable responses in advanced bladder cancer (BC), but only for a subset of patients. Xenovaccination has been proposed as an effective immunotherapeutic approach to induce anti-tumor immunity. Thus, we proposed a novel intravesical xenogeneic urothelial cell immunotherapy strategy to treat advanced BC based on the hypothesis that implanted xenogeneic urothelial cells not only provoke xeno-rejection immune responses but also elicit bystander anti-tumor immunity.MethodsMouse advanced bladder cancer models were treated with vehicle control, intravesical xenogeneic urothelial cells, cisplatin + gemcitabine, or the combination and assessed for tumor responses to treatments. Tumors and spleens samples were collected for immunohistological staining, cellular and molecular analysis assessed by antibody staining, ELISA, cytotoxicity, and flow cytometry, respectively.ResultsThe combination treatment of xenogeneic urothelial cell immunotherapy with chemotherapy was more efficacious than either single therapy to extend survival time in MBT-2 graft bladder tumor model and to suppress tumor progression in murine carcinogen BBN-induced bladder tumor model. The single-cell immunotherapy and combined therapy increased more tumor-infiltrating immune cells in MBT-2 graft tumors compared to vehicle control and chemotherapy treatment groups. The activated T-cell proliferation, cytokine production, and cytotoxicity capacities were also higher in mice with xenogeneic urothelial cell immunotherapy and combination treatments.ConclusionsOur results suggest the potential for a novel xenogeneic urothelial cell-based immunotherapy alone and synergy with chemotherapy in the combination therapy. Therefore, our study supports developing xenogeneic urothelial cells as an immunotherapeutic agent in combination with chemotherapy for BC treatment.

Focus on Biochemical and Clinical Predictors of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma: Where Do We Stand?

Urothelial bladder cancer is one of the most lethal cancers worldwide with barely 5% five-year survival in patients with metastatic disease. Intravesical immunotherapy with Bacillus Calmette-Guérin and platinum-based chemotherapy are currently the standard of care for non-muscle invasive and advanced or metastatic urothelial cancer (mUC), respectively. Recently, a subset of patients with locally advanced or mUC has shown to be responsive to immune checkpoint inhibitors (ICIs), e.g., the anti-cytotoxic T-lymphocyte-associated protein 4 and programmed cell death -1/programmed death-ligand1 (PD-1/PD-L1) antibodies. Due to the relevant clinical benefit of immunotherapy for mUC, in 2016, the United States Food and Drug Administration (FDA) approved five immunotherapeutic agents as second-line or first-line treatments for patients with advanced bladder cancer who did not profit from or were ineligible for standard therapy. In this review, we discuss the role of immunotherapy in bladder cancer and recent clinical applications of PD-1/PD-L1 blockade in mUC. Furthermore, we evaluate a variable response rate to ICIs treatment and outline potential biomarkers predictive of immunotherapy response.

Recurrence and progression of non-muscle invasive bladder cancer following trans-urethral resection of bladder tumour with adjuvant intravesical chemo-immunotherapy

Background: Trans-urethral resection of bladder tumor is an essential diagnostic tool as well as effective treatment modality for non-muscle invasive bladder cancer. We aimed to evaluate the recurrence and progression of the non-muscle invasive bladder cancer in Nepalese patients.&#x0D; Methods: This was a retrospective study of 43 patients with non-muscle invasive bladder cancer, who underwent trans-urethral resection of bladder tumour followed by adjuvant intravesical instilla­tion of chemo or immunotherapy between January, 2013 to December, 2018. Patients were divided into low, intermediate and high-risk groups according to the clinical and pathological factors used by the European Organization for Research and Treatment of Cancer scoring system. Outcomes were calculated in terms of recurrence and progression in each group.&#x0D; Results: Out of 43 patients, 11 (25.58%) patients had low risk, 18 (41.86%) patients had intermediate risk and 14 (32.56%) patients had high risk of recurrence categories. No recurrence and progression of the disease noted in low risk group. In the intermediate risk group, out of 18 patients, 4 (22.2%) patients developed recurrence and 2 (11.1%) patients had progression of disease. In high risk group, out of 14 patients, 4 (26.8%) patients developed recurrence and 2 (14%) patients developed progres­sion of the disease.&#x0D; Conclusions: Even in a low volume centre of bladder cancer, effective treatment for non-muscle inva­sive bladder cancer with trans-urethral resection of bladder tumour followed by adjuvant intravesical chemo or immunotherapy can be given safely to reduce recurrence and progression of the disease.

A CASE OF RUPTURED MYCOTIC ANEURYSM AFTER DISSEMINATED MYCOBACTERIUM BOVIS INFECTION

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Dissemination is a rare complication of intravesical bacille Calmette-Guerin (BCG) therapy for bladder malignancy. CASE PRESENTATION: An 86 year-old male with medical history of atrial fibrillation, cerebrovascular accident, and bladder carcinoma treated with intravesical BCG who initially presented with worsening lower back pain. A contrast CT showed left psoas abscess abutting posterior and left lateral wall of the infrarenal abdominal aorta without evidence of aneurysm formation or contrast extravasation. Culture from the left psoas abscess aspirate returned positive for mycobacterium tuberculosis complex with a monoresistance pattern for Pyrazinamide consistent with the diagnosis of Mycobacterium Bovis(M.Bovis). He was started on a multidrug antitubercular regimen with a plan for close-follow up with serial imaging. After 3 months, he developed worsening back pain and was brought to the emergency room with increasing somnolence. Vitals were remarkable for hypotension and tachycardia. On physical examination, the patient was disoriented and had mild abdominal tenderness. Rest of the exam was unremarkable. His blood work revealed hemoglobin 6.2mg/dl and creatinine 2.2mg/dl. Abdominal CT angiography showed large left retroperitoneal hematoma and contained rupture of the infrarenal aortic aneurysm. He was resuscitated with blood products and anticoagulation was held. He underwent emergent endovascular aneurysm repair. His postoperative period was complicated by the deterioration of renal functions resulting in anuric renal failure. He was transitioned to hospice as hemodialysis was not consistent with his goals of care. DISCUSSION: BCG contains a weak strain of M. Bovis which is used as a vaccination against mycobacterium tuberculosis infection in some parts of the world and also as intravesical immunotherapy for the treatment of bladder cancer. Common side effects of intravesical BCG treatment include transient fever, fatigue, dysuria, or hematuria. Rarely, it can lead to disseminated infection leading to pneumonitis, prostatitis, hepatitis, or endovascular involvement. The pathogenesis of endovascular invasion by BCG is unclear but it is postulated to be associated with instrumentation of the bladder. Presentation of endovascular involvement may be subtle and is usually discovered after the development of complications like a ruptured aneurysm. Mycotic aneurysm related to disseminated BCG infection should be suspected based on relevant history. Diagnosis requires imaging as well as a specimen collection for microscopic analysis and culture. Mycobacterium Bovis isolates are inherently resistant to pyrazinamide. On biopsy, there is usually evidence of granulomatous inflammation. Management involves multidrug antitubercular regimen and surgical repair of the aneurysm. CONCLUSIONS: Physicians should be aware of late complications of intravesicular BCG administration. Reference #1: A. Steg, S. Adjiman, B. Debre BCG therapy in superficial bladder tumors—complications and precautions Eur Urol, 21 (suppl 2) (1992), pp. 35-40 Reference #2: J.M. LaBerge, R.K. Kerlan Jr, L.M. Reilly, T.A. Chuter Diagnosis please: Case 9: mycotic pseudoaneurysm of the abdominal aorta in association with mycobacterial psoas abscess—a complication of BCG therapy Radiology, 211 (1999), pp. 81-85 Reference #3: D.L. Lamm, P.M. van der Meijden, A. Morales, S.A. Brosman, W.J. Catalona, H.W. Herr, et al. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer J Urol, 147 (1992), pp. 596-600 DISCLOSURES: No relevant relationships by Shahrukh Arif, source=Web Response No relevant relationships by Firas Jafri, source=Web Response