Bladder cancer: Predicting response to BCG.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 287-287
Author(s):  
Rafael Nunez-Nateras ◽  
Melissa L. Stanton ◽  
Erin N. Ferrigni ◽  
Cheryl A. Protheroe ◽  
Nancy A. Lee ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Immune Responses ◽  
Immune Therapy ◽  
Therapy Response ◽  
Immunohistochemical Analysis ◽  
Standard Of Care ◽  
Eosinophil Infiltration ◽  
Th2 Immune Response ◽  
Bcg Therapy

287 Background: Our preliminary immunohistochemical studies of bladder cancer patients have shown that the inflammatory/immune responses associated with bladder cancer appear to be Th2-polarized as judged by the preponderance of tumor infiltrating GATA-3+ (Th2) vs. T-bet+ (Th1) T cells, as well as by evidence of tumor-associated eosinophil infiltration and activation. The standard-of-care treatment for Tis bladder cancer is intravesical administration of BCG, a Th1-polarizing immunomodulator. The aim of the present study was to assess the Th2/Th1 ratio correlation with response to BCG therapy in patients with Tis bladder cancer. Methods: Two groups of patients were studied. Group A included 20 patients that responded to BCG, and Group B included 20 patients that did not respond to therapy. Response to BCG was determined as presence/absence of disease at 6 months post-BCG therapy. The initial diagnostic biopsies of these patients were subjected to immunohistochemical analysis using commercially available antibodies specific for Th2 (GATA-3+) and Th1 (T-bet+) lymphocytes, and our unique monoclonal antibody specific for eosinophil peroxidase (EPX-mAb). Ten random high powered (400X) fields at the maximum focus of mononuclear infiltration were examined and the number of GATA 3+ and T-bet+ tumor infiltrating T cells were counted to define the G/T ratio for each patient sample. Eosinophils and their degranulation activity were counted in the same fields. Results: Patients with response to BCG therapy had a G/T ratio of ≥ 3 and patients with non-response to BCG therapy had a G/T ratio of ≤ 1.5. Correlation of these scores with subsequent patient outcomes following BCG immune therapy demonstrated that patient responsiveness (i.e., tumor elimination at 6 months) trended with the higher G/T ratio patients. In addition, initial biopsies of BCG responsive patients display a higher number of eosinophils and degranulation relative to BCG non-responsive patients. Conclusions: Evaluations of initial biopsies revealed a strong correlation between Th1 and Th2 immune response with BCG therapy outcomes. The development of specific and novel tools to identify/measure Th2 immune responses in Tis bladder cancer provides a unique opportunity to predict outcomes at the time of diagnosis.

scholarly journals Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study

2021 ◽  
Vol 9 (3) ◽  
pp. e001941
Author(s):  
Niannian Ji ◽  
Neelam Mukherjee ◽  
Ryan M Reyes ◽  
Jonathan Gelfond ◽  
Martin Javors ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Γδ T Cells ◽  
Percentage Change ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Double Blind ◽  
Bcg Therapy ◽  
Intravesical Bcg ◽  
Muscle Invasive

BackgroundAlthough intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG’s antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC.MethodsA randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires.ResultsThirty-one patients were randomized (11 placebo, 8 rapamycin 2.0 mg, and 12 rapamycin 0.5 mg). AEs were similar across groups and most were grade 1–2. One (12.5%) patient randomized to 2.0 mg rapamycin was taken off treatment due to stomatitis. No significant differences in urinary symptoms, bowel function, or bother were observed between groups. The median (IQR) percentage change in BCG-specific γδ T cells from baseline per group was as follows: −26% (−51% to 24%) for placebo, 9.6% (−59% to 117%) for rapamycin 0.5 mg (versus placebo, p=0.18), and 78.8% (−31% to 115%) for rapamycin 2.0 mg (versus placebo, p=0.03). BCG-induced cytokines showed a progressive increase in IL-8 (p=0.02) and TNF-α (p=0.04) over time for patients on rapamycin 2.0 mg, whereas patients receiving placebo had no significant change in urinary cytokines. Compared with placebo, patients receiving 2.0 mg rapamycin had increased urinary γδ T cells at the first week of BCG (p=0.02).ConclusionsFour weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.

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

2021 ◽  
Vol 13 (594) ◽  
pp. eabd1346
Author(s):  
Christopher S. Garris ◽  
Jeffrey L. Wong ◽  
Jeffrey V. Ravetch ◽  
David A. Knorr
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Mouse Models ◽  
Antitumor Immunity ◽  
Bladder Tumor ◽  
Immune Surveillance ◽  
Disease Recurrence ◽  
Bcg Therapy ◽  
Agonist Antibody

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.

Double-loaded mature dendritic cell (DC) therapy for non-HLA-restricted patients with advanced ovarian cancer: Final results of a clinical phase I study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3052-3052 ◽  
Author(s):  
Marianne Imhof ◽  
Markus Lipovac ◽  
Lukas Angleitner-Boubenizek ◽  
Johannes Barta ◽  
Ivan Gomez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Immune Responses ◽  
Immune Therapy ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Positive Trend ◽  
Clinical Phase ◽  
Dc Vaccine

3052 Background: Prognosis of ovarian cancer remains poor after initial responsiveness to surgery and chemotherapy followed by high recurrence and mortality rates and new experimental approaches are warranted. Our goal was to evaluate a novel DC-based vaccine, which exploits a unique dual loading strategy to amplify specific anti-tumor short- and long-term immune responses to delay or even prevent recurrent and metastatic disease. Methods: Monocytes were collected via apheresis, matured into DCs and pulsed with two universal tumor associated antigens (uTAA) in our GMP facility. DCs were loaded with TERT and Survivin via two different pathways (mRNA and peptide) to elicit CD8+ and CD4+T cells directly. Endpoints of the study were tolerability and safety, immunological and clinical responses. T cell responses against the IMP and loaded antigens were evaluated by cytokine bead array (CBA) and intracellular staining assays. Results: 15 non HLA-restricted patients with advanced ovarian cancer were enrolled 8 weeks after standard treatment (surgery and chemotherapy). Each patient was vaccinated intradermally on a weekly or fortnightly basis with a maximum of 8 doses of 13*106 double loaded DCs. The majority of treatment related side effects were grade 1 fever and erythema. Overall the therapy was well tolerated. Immune response data is available for 14/15 patients, 1 was withdrawn after the first administration. The IMP leads to strong immune responses with high frequency (>90%), which is proven for both uTAAs in CD8+ as well as CD4+ T cells. A clear positive trend in progression free survival is demonstrated compared to matched historical control. Conclusions: Therapy with our unique double loaded DC vaccine was feasible, safe and well-tolerated by patients. The vaccine was highly immune stimulatory and elicited both, long-term and short-term anti-tumor immune responses, establishing a promising platform for immune therapy for ovarian cancer and all solid tumors in general. The first two authors contributed equally. Clinical trial information: NCT01456065.

scholarly journals Recognition and Treatment of BCG Failure in Bladder Cancer

2011 ◽  
Vol 11 ◽  
pp. 602-613 ◽  
Author(s):  
Andrew J. Lightfoot ◽  
Henry M. Rosevear ◽  
Michael A. O'Donnell
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Treatment Options ◽  
Standard Of Care ◽  
Complete Response ◽  
Bcg Therapy ◽  
Risk Patients ◽  
Bcg Failure ◽  
Muscle Invasive ◽  
American Urological Association

Patients with high-grade Ta, T1, or carcinomain situnon–muscle-invasive bladder cancer (NMIBC) are at high risk for recurrence and, more importantly, progression. Thus, both the American Urological Association and European Association of Urology recommend initial intravesical treatment with bacillus Calmette-Guerin(BCG) followed by maintenance therapy for a minimum of 1 year. The complete response rate to BCG therapy in patients with high-risk NMIBC can be as high as ∼80%; however, most patients with high-risk disease suffer from recurrence. BCG failure can be further characterized into BCG refractory, BCG resistant, BCG relapsing, and BCG intolerant. Current recommendations include one further course of BCG or cystectomy. In patients who continue to fail conservative treatment and who refuse surgical therapy or are not surgical candidates, treatment options become even more complicated. In this setting, treatment options are limited and include repeat BCG treatment, an alternate immunotherapy regimen, chemotherapy, or device-assisted therapy. To date, however, further research is necessary for all secondary treatment options in order to determine which might be the most efficacious. All conservative treatments should be considered investigational. Currently, cystectomy remains the standard of care for high-risk patients who have failed BCG therapy.

scholarly journals The Recovery of an intravesical BCG-induced arthritis after RITUXIMAB treatment

2021 ◽  
Author(s):  
Nejla El amri ◽  
Héla Zeglaoui ◽  
Salma Hmila ◽  
dhouha khalifa ◽  
Sadok Lataoui ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Rare Case ◽  
Superficial Bladder Cancer ◽  
Standard Of Care ◽  
Severe Form ◽  
Bcg Therapy ◽  
Intravesical Bcg ◽  
Risk Of Relapse

BCG intra-vesical instillation is the standard of care for superficial bladder cancer at high risk of relapse and progression. Yet, this treatment can cause dysimmune complications. Osteoarticular manifestations related to BCG therapy are rare and frequently mild. We report a rare case of a severe form successfully treated with Rituximab.

Tumor and systemic immune responses to preoperative (pre-op) cryoablation (cryo) plus immune therapy with ipilimumab (ipi) in early-stage breast cancer (ESBC).

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 64-64 ◽  
Author(s):  
David B. Page ◽  
Jianda Yuan ◽  
Arielle Ginsberg ◽  
Zhiwan Dong ◽  
Phillip Wong ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Pilot Study ◽  
Early Stage ◽  
Immune Therapy ◽  
Cell Activity ◽  
Standard Of Care ◽  
Cell Receptor ◽  
Hormone Receptor Positive

64 Background: In mice, tumor cryo plus immunologic checkpoint blockade generates tumor antigen release, proliferation of tumor-specific T-cells, and enhanced survival. We previously demonstrated in a pilot study that pre-op cryo+ipi is well tolerated in women with ESBC and did not delay standard of care surgical resection. Here, we analyze pilot study tissue and blood to explore immune response. Methods: 18 ESBC patients (pts) were treated with preop cryo (n=6), single-dose ipi 10mg/kg (n=6), or cryo+ipi (n=6). As a potential surrogate for tumor immunogenicity, baseline T-cell tumor infiltrating lymphocyte (TIL) density was evaluated by T-cell receptor quantitative DNA sequencing. We explored the systemic immune response to cryo and/or ipi using previously described laboratory measures including inducible costimulator (ICOS, a marker of activated CD4+ T-cells) and plasma interferon gamma (IFNγ, a cytokine associated with T-cell activity). Results: Of the 18 study pts, 13 pts had hormone receptor-positive (HR+) disease, 2 pts had HER2+ disease (both treated with ipi alone) and 3 pts had triple-negative (TN) disease (1 ipi alone and 2 cryo/ipi). Baseline TIL density was highly variable overall (range 2-30%), but higher in HER2+ and TN pts (median 15%) compared with HR+ pts (median 5%). Sustained >2-fold elevations in ICOS and IFNγ were observed in the majority of cryo+ipi pts 30 days following treatment (ICOS: 5/6 pts; IFNγ: 4/6 pts), but in the minority of ipi pts (ICOS: 2/6 pts; IFNγ: 2/6 pts) or cryo pts (ICOS: 0/6 pts; IFNγ: 0/6 pts). Sustained ICOS and IFNγ elevations were observed regardless of baseline TIL density. Conclusions: Cryo+ipi was more likely to induce systemic immune activation compared to cryo or ipi alone. These potentially beneficial immune effects were observed in both HR+ and HR- subtypes, as well as in tumors with low or high baseline TIL density. These data support further studies of cryo+ipi in ESBC across HR+ and HR- subtypes, as well as in tumors that do not appear immunogenic at baseline.

scholarly journals Immunohistochemical Analysis of Lyme Disease in the Skin of Naive and Infection-Immune Rabbits following Challenge

2001 ◽  
Vol 69 (6) ◽  
pp. 4094-4102 ◽  
Author(s):  
Celeste Chong-Cerrillo ◽  
Ellen S. Shang ◽  
David R. Blanco ◽  
Michael A. Lovett ◽  
James N. Miller
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Erythema Migrans ◽  
Immunohistochemical Analysis ◽  
Lymphocytic Infiltrate ◽  
Polymorphonuclear Cells ◽  
Cellular Immune Responses ◽  
Skin Biopsies ◽  
Immunohistochemical Techniques ◽  
Cellular Immune

ABSTRACT In this study, skin histopathology from naive and infection-derived immune rabbits was compared following intradermal challenge usingBorrelia burgdorferi B31 strain. The presence or absence of spirochetes in relationship to host cellular immune responses was determined from the time of intradermal inoculation to the time of erythema migrans (EM) development (∼7 days in naive rabbits) and through development of challenge immunity (∼5 months in naive rabbits). Skin biopsies were obtained and analyzed for the presence of spirochetes, B cells, T cells, polymorphonuclear cells (PMNs), and macrophages by immunohistochemical techniques. In infected naive animals, morphologically identifiable spirochetes were detected at 2 h and up to 3 weeks postinfection. At 12 and 24 h postinfection there was a marked PMN response that decreased by 36 to 48 h; by 72 h the PMNs were replaced by a few infiltrating macrophages. At the time of EM development and 14 days postinfection, the PMNs and macrophages were replaced by a lymphocytic infiltrate. There was a greater number of spirochetes at 14 days, a time when EM had resolved, than at 7 days postinfection. By 3 weeks postinfection there were few organisms and lymphocytes detectable. In contrast to infected naive rabbits, intact spirochetes were never visualized in skin biopsies from infection-immune rabbits; only spirochetal antigen was detected at 2, 12, and 24 h in the presence of a numerous PMN infiltrate. By 36 h postchallenge, spirochetal antigen could not be detected and the PMN response was replaced by a few infiltrating macrophages. By 72 h postchallenge, PMNs and macrophages were absent from the skin; B and T cells were never detected at any time point in skin from infection-immune rabbits. The destruction of spirochetes in immune animals in the presence of PMNs and in the absence of a lymphocytic infiltrate suggests that infection-derived immunity is antibody mediated.

A Dendritic Cells-Targeting Nano-Vaccine by Coupling Polylactic-Co-Glycolic Acid-Encapsulated Allergen with Mannan Induces Regulatory T Cells

2021 ◽  
pp. 1-11
Author(s):  
He Wen ◽  
Litian Qu ◽  
Yu Zhang ◽  
Beilei Xu ◽  
Shiqi Ling ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Glycolic Acid ◽  
Tolerance Induction ◽  
Treg Cells ◽  
Intercellular Adhesion Molecule ◽  
Allergen Specific Immunotherapy ◽  
Th2 Immune Response

<b><i>Background:</i></b> The efficacy of allergen-specific immunotherapy (AIT) is mainly depended on the tolerogenic immune responses elicited. Properly conjugated nano-vaccine has the advantages of both specific targeting and continuous and on-demand release of allergen. <b><i>Objectives:</i></b> The aim of this study is to investigate the effects of a dendritic cells (DCs)-targeting nano-vaccine for AIT. <b><i>Methods:</i></b> The nano-vaccine was produced by coupling polylactic-co-glycolic acid (PLGA)-encapsulated ovalbumin (OVA) with mannan. Allergen capture, human monocytes-derived DCs (hMoDCs) activation, and T cells responses were assessed by flow cytometry, confocal microscopy, quantitative real-time PCR, ELISA, and Cytometric Bead Array. Balb/c mice were immunized with the nano-vaccines, and the immune responses were analyzed. <b><i>Results:</i></b> OVA-PLGA nanoparticle (NP) displayed favorable safety profile. OVA-mannan-PLGA NP was captured more efficiently by hMoDCs than OVA-PLGA NP, which was mediated mainly through DC-specific intercellular adhesion molecule 3-grabbing nonintegrin. A tolerogenic phenotype of hMoDCs was induced by OVA-mannan-PLGA NP, but not OVA-PLGA NP, and increased number of regulatory T (Treg) cells was generated subsequently in in vitro coculture. Immunization of Balb/c mice with OVA-mannan-PLGA NP resulted in lower serum level of OVA-specific immunoglobulins and less production of pro-inflammatory cytokines in splenocytes culture than the mice immunized with OVA-PLAG NP, PLGA NP, or OVA, while the number of splenic Treg cells was higher in OVA-mannan-PLGA group than in other groups. Moreover, preimmunization with OVA-mannan-PLGA NP significantly inhibited the Th2 immune response induced by OVA sensitization. <b><i>Conclusions:</i></b> The biocompatible PLGA-encapsulated OVA coupling with mannan has augmented ability for tolerance induction and could be developed as a novel vaccine for AIT.

597 In situ vaccination with oncolytic vesicular stomatitis virus improves anti-tumor immune response and outcome in bladder cancer

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A632-A632
Author(s):  
Coby Rangsitratkul ◽  
Christine Lawson ◽  
Lee-Hwa Tai
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Cell Lines ◽  
Vesicular Stomatitis Virus ◽  
Cd8 T Cells ◽  
Solid Cancer ◽  
Bcg Therapy ◽  
Vesicular Stomatitis ◽  
Human Immune ◽  
Bladder Sparing

BackgroundThe majority of nonmuscle invasive bladder cancer (NMIBC) cases progress towards muscle invasive disease. Transurethral resection followed by chemotherapy and/or BCG immunotherapy can stall progression in the minority of NMIBC cases. Cystectomy prior to muscle invasion provides the best option for survival. However, bladder removal significantly affects morbidity and quality of life. There are no effective treatment options for patients with chemo/BCG-resistant and late stage disease. Compared to other solid cancer types, the urinary bladder is an ideal organ to evaluate oncolytic virotherapies due to the urgent medical need for alternative bladder-sparing therapies and its established immunosensitivity to BCG therapy. The current study will determine whether a novel oncolytic Vesicular Stomatitis Virus (VSVd51) containing human immune transgenes can treat NMIBC.MethodsA novel recombinant OV containing a human immune transgene was rescued on the VSVd51 backbone. Features of immunogenic cell death (ICD) on mouse and human bladder cancer cell lines were measured by microscopy, flow cytometry, immunoblot, luminometry, qRT-PCR and ELISA following infection by recombinant VSVd51. The mediating role of immune effector cells was evaluated through pharmacologic in vivo depletion, while combination injection of recombinant VSVd51 following BCG failure was performed in the C57Bl/6-MB49 model. Measurements of ICD was additionally carried out in human BC spheroids and bladder cancer patient tissue following recombinant VSVd51 infection ex vivo.ResultsRecombinant VSVd51 liberated danger signals (calreticulin, HMGB1, ATP) and immunogenic cytokines/chemokines were detected from infected mouse and human BC cell lines. Intravesical instillation of recombinant VSVd51 promoted enhanced activation of systemic and bladder infiltrating natural killer (NK) and cytotoxic CD8+ T cells. The increased functionality of NK and CD8+ T cells was associated with improved survival as determined through depletion studies. Moreover, improved survival and reduced bladder tumor volume was observed in recombinant VSVd51 treated mice who failed BCG therapy. In parallel, VSVd51-induced inflammation of the tumor microenvironment was recapitulated in human BC cell lines, spheroids and patient tissue exposed to recombinant VSVd51 infection.ConclusionsThese translational results suggest that a recombinant VSVd51 is a promising immunotherapy that could provide a bladder-sparing therapeutic benefit in individuals diagnosed with NMIBC each year.Ethics ApprovalThe study was approved by the CIUSSS de l’Estrie CHUS Ethics Board, approval number 2018-2465.

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