BCG Immunotherapy For Bladder Cancer Research Articles

The Urothelial Transcriptomic Response to Interferon Gamma: Implications for Bladder Cancer Prognosis and Immunotherapy.

Interferon gamma (IFNγ) is central to the inflammatory immune response, such as that entrained by BCG immunotherapy for bladder cancer. However, immune-mediated tumour cell killing is subject to modulation by immunoinhibitory "checkpoint" receptors such as PD-L1. We investigated the effects of IFNγ on barrier-forming in vitro-differentiated normal human urothelium using mRNA-sequencing, and showed canonical upregulation of MHC class I/II and de novo expression of the T cell tropic CXCL9-11 chemokines. Normal urothelium constitutively expressed immunoinhibitory B7 family member VSIR (VISTA), while CD274 (PD-L1) expression was induced/upregulated by IFNγ. We generated a urothelial IFNγ response gene signature. When applied to the unsupervised clustering of non-muscle-invasive bladder cancers, the IFNγ-signature predicted longer recurrence-free survival. In muscle-invasive cancers, the IFNγ-signature split the basal/squamous consensus subtype, with significantly worse overall survival when weak or absent. This study offers novel insights into strategies to enhance immunotherapy via the IFNγ and VISTA/PD-L1 nexus.

A BCG success story: From prevention of tuberculosis to optimal bladder cancer treatment

BCG remains the most important vaccine for tuberculosis 100 years after its first use, and over the past 4 decades it has become the most widely accepted, effective drug used in the treatment of aggressive localized bladder cancer. This review chronicles the narrow path that led to approval and world-wide acceptance of BCG immunotherapy for bladder cancer while immunotherapy trials in other malignancies were abandoned. Six intravesical instillations of 5x10^8 CFU of BCG weekly after bladder tumor resection, first reported in 1976, is superior to resection alone and resection plus intravesical chemotherapy. Maintenance of effective immune stimulation is surprisingly difficult, but 3 weekly treatments 3, 6, and 12, 18, 24, 30 and 36 months after induction produces further significant reduction in tumor recurrence. This 3 week BCG maintenance schedule alone has reduced disease progression and mortality in multicenter randomized clinical trials. In the new age of immuno-oncology patients with many types of cancer now benefit from immunotherapy, but currently these modern agents are prohibitively expensive for most of the world. In contrast, the low cost and therefore low profitability of BCG has resulted in recurrent shortages that threaten both bladder cancer patients and children at risk for tuberculosis and other serious infections. Humanity has greatly benefited from early 20th century science that developed BCG and the benevolence of doctors Calmette and Guerin who put people over profit and widely shared cultures of the vaccine. The 21st century is bringing new immunotherapies and greatly expanding the types of malignancies that can be treated. Recombinant technology is expected to improve both the efficacy and production of BCG, hopefully expanding the availability of BCG and relieving the recurring supply shortage for both vaccination and cancer therapy.

Disseminated BCG Infection after intravesical BCG Immunotherapy of Bladder Cancer.

Disseminated BCG Infection after intravesical BCG Immunotherapy of Bladder Cancer.

PDE based geometry model for BCG immunotherapy of bladder cancer

BCG immunotherapy has shown significant success for bladder cancer treatment, but due to the complexity of the interaction between immunity and cancer, clinical outcomes vary significantly between patients. A possible approach to overcome this difficulty may be to develop new methodologies for personally predicting the results of therapy by integrating patient data with dynamic mathematical model.We present a model describing a BCG immunotherapy dynamic taking into consideration an approximation of the bladder's geometry using PDE.We show that the proposed model takes into account the initial distribution of the cancer cells in the geometry of the bladder and as such can provide more customized treatment by providing tumor polyp depth in the urothelium. In addition, time optimal treatment protocol for the average case and recover-rate optimal, personalized treatment protocol based on initial tumor distribution have been analyzed.

Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer.

Intravesical BCG instillation is the gold-standard adjuvant immunotherapy for patients with high-risk non-muscle-invasive bladder cancer. However, the precise mechanism of action by which BCG asserts its beneficial effects is still unclear. BCG has been shown to induce a non-specific enhancement of the biological function in cells of the innate immune system, creating a de facto heterologous immunological memory that has been termed trained immunity. Trained immunity or innate immune memory enables innate immune cells to mount a more robust response to secondary non-related stimuli after being initially primed (or trained) by a challenge such as BCG. BCG-induced trained immunity is characterized by the metabolic rewiring of monocyte intracellular metabolism and epigenetic modifications, which subsequently lead to functional reprogramming effects, such as an increased production of cytokines, on restimulation. Results from BCG vaccination studies in humans show that trained immunity might at leastpartly account for the heterologous beneficial effects of BCG vaccination. Additionally, immunity might have a role in the effect of BCG immunotherapy for bladder cancer. Based on these indications, we propose that trained immunity could be one of the important mechanisms mediating BCG immunotherapy andcould provide a basis for further improvements towards a personalized approach to BCG therapy in non-muscle-invasive bladder cancer.

Complications of Intravesical BCG Immunotherapy for Bladder Cancer.

An earlier incorrect version appeared online. This article was corrected on December 14, 2018.

An optimal control approach for the interaction of immune checkpoints, immune system, and BCG in the treatment of superficial bladder cancer

One of the major setbacks in BCG immunotherapy of bladder cancer is the action of immune checkpoints on the immune system. They suppress the activated immune cells from spreading, detecting and attacking cancer cells. Moreover, the excessive side effects and toxicity of the BCG to normal cells are quite alarming. We propose a mathematical model that studies this dynamics and uses an optimal control approach to suggest the optimal BCG dose required to minimize the cancer cells and action of the immune checkpoints, as well as maximizing the number of immune and normal cells in the bladder. Numerical simulations of the controlled system reveal that the optimal BCG dosage (control function) shows that the number of immune cells rises, the cancer cells are eliminated, the activities of the checkpoints are reduced, and normal cells stay high maintaining the threshold level.

964 - Immune responsiveness to tuberculin in vitro may predict clinical outcome of intravesical BCG immunotherapy in bladder cancer

964 - Immune responsiveness to tuberculin in vitro may predict clinical outcome of intravesical BCG immunotherapy in bladder cancer

Mycobacterium bovis Aneurysm

Abstract Bacillus Calmette-Guerin (BCG) is the attenuated strain of Mycobacterium bovis. Intravesicular live attenuated BCG is one of the well-known effective treatments for transitional cell carcinoma of the bladder. Severe disseminated mycobacterial infections in such patients are uncommon. Here, we present a case of M. bovis mycotic aneurysm of the left femoral artery, diagnosed 14 months after initiation of intravesical BCG immunotherapy for bladder cancer. Although rare, given the significant morbidity and mortality associated with mycotic aneurysms, physicians should be aware of this complication in appropriate clinical scenarios and should have high index of suspicion; appropriate treatment should be initiated promptly.

Abstract B41: Expression of programmed cell death ligand 1/2 and BCG immunotherapy in bladder cancer

Abstract Background: Immunotherapy based on BCG has been a standard therapy to prevent tumor recurrence and progression in bladder cancer. Activation of immune checkpoint pathways by binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. Tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanism. We investigated expression of immune checkpoints and their effects on T cells in bladder cancer. Methods: A panel of transitional cell carcinoma cell lines (UC-3, T24, K1919 and 253J) and normal human bladder urothelial cells (SVHUC1) were used to evaluate expression of immune checkpoints including PD-1, PDL1, PD-L2 and CTLA-4. Western blot analysis was used for protein expressions from cell lines and qPCR for RNA expression from human bladder tissues. Human bladder cancer/normal paired tissues were obtained at two time points; surgical resection and then after BCG immunotherapy. Immunohistochemical staining was performed to assess infiltration and distribution of CD4+ and CD8+ T cells in bladder tumor tissues and normal bladder tissues. Immune cells were isolated and T cells were isolated by FACS sorting after immune cell isolation from tumor/normal tissues. Results: PD-L1 and PD-L2 proteins were highly expressed in bladder cancer cell lines compared to normal bladder epithelial cell line (SVHUC-1). In paired human samples (cancer and normal tissues), PD-L1 and 2 were also highly expressed in bladder cancer tissues compared with paired normal tissues. Real time RT-PCR comfirmed the high expression of PD-L1/2 in bladder cancer tissues. Interestingly, normal epithelial tissues regenerated after surgical resection of the tumor and BCG immunotherapy had low PD-L1/2 expression while recurred tissues after surgical resection of the tumor and BCG had high expression of PD-L1/2, which suggest that PD-L1/2 might be involved in tumor relapse after surgical resection and BCG immunotherapy. Immunohistochemical staining with CD4 and CD8 showed that the number of T cells was in bladder cancer tissues compared with paired normal tissues regardless of PD-L1/2 expression. T lymphocytes isolated from human bladder cancer tissues and paired normal tissues showed that infiltrating T cell function is significantly deteriorated in bladder cancer tissue compared with cells from paired normal tissues. Conclusions: PD-L1 and PD-L2 are highly expressed in bladder cancer and though to be involved in relapse after BCG intravesical immunotherapy through suppressing infiltrating T cell function. Our data suggest that immunecheckpoint might be a novel targets in bladder cancer. Citation Format: Jun Hyeok Heo, Hye Young Kim, Ki Chung Park, Sung Joon Hong, Kang Su Cho, Kyung Seok Han. Expression of programmed cell death ligand 1/2 and BCG immunotherapy in bladder cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B41.

Abstract 1322: Expression of programmed cell death ligand 1/2 and BCG immunotherapy in bladder cancer

Abstract Background: Immunotherapy based on BCG has been a standard therapy to prevent tumor recurrence and progression in bladder cancer. Activation of immune checkpoint pathways by binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. Tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanism. We investigated expression of immune checkpoints and their effects on T cells in bladder cancer. Methods: A panel of transitional cell carcinoma cell lines (UC-3, T24, K1919 and 253J) and normal human bladder urothelial cells (SVHUC1) were used to evaluate expression of immune checkpoints including PD-1, PDL1, PD-L2 and CTLA-4. Western blot analysis was used for protein expressions from cell lines and qPCR for RNA expression from human bladder tissues. Human bladder cancer/normal paired tissues were obtained at two time points; surgical resection and then after BCG immunotherapy. Immunohistochemical staining was performed to assess infiltration and distribution of CD4+ and CD8+ T cells in bladder tumor tissues and normal bladder tissues. Immune cells were isolated and T cells were isolated by FACS sorting after immune cell isolation from tumor/normal tissues. Results: PD-L1 and PD-L2 proteins were highly expressed in bladder cancer cell lines compared to normal bladder epithelial cell line (SVHUC-1). In paired human samples (cancer and normal tissues), PD-L1 and 2 were also highly expressed in bladder cancer tissues compared with paired normal tissues. Real time RT-PCR comfirmed the high expression of PD-L1/2 in bladder cancer tissues. Interestingly, normal epithelial tissues regenerated after surgical resection of the tumor and BCG immunotherapy had low PD-L1/2 expression while recurred tissues after surgical resection of the tumor and BCG had high expression of PD-L1/2, which suggest that PD-L1/2 might be involved in tumor relapse after surgical resection and BCG immunotherapy. Immunohistochemical staining with CD4 and CD8 showed that the number of T cells was in bladder cancer tissues compared with paired normal tissues regardless of PD-L1/2 expression. T lymphocytes isolated from human bladder cancer tissues and paired normal tissues showed that infiltrating T cell function is significantly deteriorated in bladder cancer tissue compared with cells from paired normal tissues. Conclusions: PD-L1 and PD-L2 are highly expressed in bladder cancer and though to be involved in relapse after BCG intravesical immunotherapy through suppressing infiltrating T cell function. Our data suggest that immunecheckpoint might be a novel targets in bladder cancer. Citation Format: Jun Hyeok Heo, Ki Chung Park, Kang Su Cho, Sung Joon Hong, Kyung Seok Han. Expression of programmed cell death ligand 1/2 and BCG immunotherapy in bladder cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1322. doi:10.1158/1538-7445.AM2015-1322

BCG immunotherapy for bladder cancer—the effects of substrain differences

Genetic mutations have been progressively introduced to BCG by repeated serial passage over many decades of its culture and global dissemination. Thus, marked differences exist in the phenotype, antigenicity, reactogenicity, and clinical characteristics of the numerous substrains of BCG currently in use for bladder cancer immunotherapy. These differences influence proposed mycobacterial antitumour mechanisms and toxicity, potentially resulting in variations in clinical efficacy and adverse effects. However, although there is evidence of substrain-related differences in the clinical efficacy of BCG as a tuberculosis vaccine, evidence of an effect on bladder cancer immunotherapy remains elusive, owing to the lack of appropriately powered head-to-head comparative clinical trials, the nonstandardization of BCG manufacture, and variation in treatment protocols--possibly itself a response to underlying substrain differences. Advances in our understanding of mycobacterial genetics, structure and function, and host-pathogen interactions might explain differences in clinical practice and outcomes. These advances are guiding the identification of biomarkers for reactogenicity and efficacy, and the rational design of immunotherapeutic strategies to eliminate the use of live bacilli for bladder cancer therapy.

Abstract 5390: Anti-IL10-R1 monoclonal antibody with concomitant bacillus calmette-Guérin (BCG) prevents metastatic bladder cancer in an in vivo mouse model

Abstract Introduction: Induction of Th1 immunity is required for effective intravesical BCG immunotherapy of bladder cancer. IL-10 down-regulates the Th1 response and is associated with BCG failure. We previously demonstrated that blocking IL-10 receptor (IL-10R) by systemic administration of anti-IL-10R1 mAb enhanced intravesical BCG (living Pasteur strain) treatment of bladder cancer in an orthotopic mouse model. Here we investigated the effect of anti-IL-10R1 mAb on clinically used BCG (lyophilized TICE strain) for induction of anti-bladder cancer immunity. Methods: Splenocytes were incubated with BCG alone or plus control IgG or ant-IL-10R1 mAb for 24 hours, followed by ELISA analysis of IFN-γ production. Bladder RNA was extracted after 6 treatments (twice weekly) with intravesical (i.b.) BCG plus intraperitoneal (i.p.) control IgG or anti-IL-10R1 mAb, followed by qPCR analysis of IFN-γ mRNA expression. Three groups of 20 mice were inoculated with luciferase-expressing MB49 bladder cancer cells and treated with i.b. PBS plus i.p. PBS (Group 1), i.b. BCG plus i.p. control IgG (Group 2), or i.b. BCG plus i.p. anti-IL-10R1 mAb (Group 3) 2x/wk for 6 total treatments. Mice were monitored weekly using IVIS luminescence and followed for 76 days. A bioluminesence cutoff of 5X104 p/s was used to establish the presence of bladder cancer. At animal death bladders were collected, weighed and processed for histological analysis. In suspected cases of metastatic disease the affected organs were also collected for histological analysis. Results: BCG plus anti-IL-10R1 mAb induced increased IFN-γ production by splenocytes in a dose-dependent manner. BCG plus anti-IL-10R1 mAb substantially increased IFN-γ mRNA. Eleven, 17 and 9 mice from Groups 1, 2 and 3, respectively, developed bladder cancer. One mouse in Group 2 and 2 mice in Group 3 showed cancer regression. 36%, 53% and 0% of Groups 1, 2 and 3 developed metastatic bladder cancer, respectively (p=0.020). While bladder weights for the groups were different, the differences did not reach statistical significance. Conclusions: Anti-IL-10R1 mAb enhances BCG-induced Th1 immune responses both in vitro and in vivo. Intravesical BCG plus anti-IL-10R1 mAb shows statistical significance in preventing metastasis of bladder cancer in an orthotopic bladder tumor mouse model. Anti-IL-10R1 mAb may prove useful in clinical practice for the prevention of metastatic bladder cancer in high-risk patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5390. doi:1538-7445.AM2012-5390

CASE REPORT Reactive arthritis after application of intravesical BCG immunotherapy in bladder cancer

CASE REPORT Reactive arthritis after application of intravesical BCG immunotherapy in bladder cancer

CASE REPORT Reactive arthritis after application of intravesical BCG immunotherapy in bladder cancer

CASE REPORT Reactive arthritis after application of intravesical BCG immunotherapy in bladder cancer

Prevention of Adverse Effects of BCG Immunotherapy in Bladder Cancer

Prevention of Adverse Effects of BCG Immunotherapy in Bladder Cancer

Mycobacterium Bovis Endophthalmitis from BCG Immunotherapy for Bladder Cancer

Background: We report a patient who developed BCG endophthalmitis after BCG immunotherapy for bladder cancer. Comparison of this case with 2 other reported cases reveals a similar pattern of elderly, debilitated and immunocompromised patients with poor response to systemic antituberculous therapy in whom systemic steroids are used concurrently. Age and glucocorticoids are known to lead to thymic involution, reduce cell mediated immunity, and a lowering in the number of naïve T cells capable of mounting an effective defense to new infectious agents. Conclusions: Physicians should be aware of the potential for ocular complications of BCG immunotherapy in the elderly, immunocompromised, on oral steroids.

The Bcg host-resistance gene.

In the mouse, resistance and susceptibility to intracellular growth of mycobacteria in macrophages is controlled by the Bcg (Nramp1) gene, which has been cloned and shown to encode a macrophage phagosomal membrane protein with a putative transporter function. In the homologous human NRAMP1 gene, a total of 11 polymorphisms have been identified, which are being used to test for the linkage of NRAMP1 alleles with human responses to mycobacteria, including susceptibility to tuberculosis and leprosy, as well as BCG immunotherapy in bladder cancer.

EFFECTS OF ACETYLIC SALICYLIC ACID AND PENTOXIFYLLINE ON THE EFFICACY OF INTRAVESICAL BCG THERAPY IN ORTHOTOPIC MURINE BLADDER CANCER (MB49)

Intravesical immunotherapy with bacillus Calmette-Guerin (BCG), which has become the gold standard in the adjuvant treatment of superficial bladder cancer, is hampered by local side effects. Anti-inflammatory drugs may be helpful, but as an undesired side effect, therapeutic efficacy of BCG might be impaired. Therefore, we investigated the effects of anti-inflammatory drugs on the efficacy of intravesical BCG in an animal model. Syngenic tumor cells were implanted into the bladders of 75 mice according to our modification of the method. Mice were randomized to 5 groups with 15 animals each and treated with phosphate buffered saline (PBS), group 1; BCG, group 2; BCG + acetylic salicylic acid (ASA), group 3; BCG + pentoxifylline (POF), group 4; autoclaved BCG (aBCG), group 5. Intravesical instillation of 1.35 mg. BCG was initiated one day after tumor inoculation and repeated in weekly intervals for 4 instillations altogether. ASA and POF in doses of 200 mg./kg. and 150 mg./kg., respectively, were given continuously with the drinking water starting at the first instillation. Autoclaved BCG served as control for the importance of viability and was given at the same dose as viable BCG. Mice were monitored for survival, gross hematuria and body weight and after 28 days evaluated for bladder weight and tumor occurrence. Autoclaved BCG and PBS had no effect on tumor growth, whereas animals treated with viable BCG alone and in combination with POF and ASA, respectively, showed a significant reduction in bladder weight: PBS, 248 mg.; BCG, 140 mg. (p = 0.0009); BCG + ASA, 123 mg. (p = 0.0001); BCG + POF, 145 mg. (p = 0.0004); autoclaved BCG, 283 mg. (p = 0.21). Mice treated with BCG, BCG + ASA and BCG + POF showed a significantly higher proportion of survival until day 28 as compared to PBS alone. Autoclaved BCG had no therapeutic efficacy (Kaplan-Meier method/log rank test: BCG, p = 0.0053; BCG + ASA, p = 0.0044; BCG + POF, p = 0.0027; aBCG, p = 0.33). No significant differences among the 3 groups treated with viable BCG, with or without anti-inflammatory drugs, regarding bladder weight and survival were detectable. The efficacy of BCG therapy in murine orthotopic bladder cancer is dependent on BCG viability and is not compromised by ASA or POF. Clinical trials to evaluate the efficacy of routine ASA or POF to reduce BCG side effects in patients, using self-assessment criteria, should be initiated.

BCG Immunotherapy in Bladder Cancer: A Reassessment

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