Therapeutic Benefits and Prognostic Value of a Model Based on 7 Immune-associated Genes in Bladder Cancer.

Objective: The emergence of immunotherapy has heralded a profound transformation in the therapeutic landscape of bladder cancer (BLAC). Immunotherapy, with its unique potential for "combination therapy", has brought about greater possibilities for treating BLCA. However, there is significant heterogeneity among bladder cancer patients, and a portion of those in advanced stages may not experience substantial benefits from chemotherapy. Immunotherapy offers a potential ray of hope for specific patient subsets. Thus, predicting the effectiveness of tumor immunotherapy and providing them with more precise treatment strategies hold paramount importance and clinical value in delivering personalized therapeutic interventions for advanced bladder cancer patients. This study is designed to establish a risk score model derived from immune-related genes that can effectively assess prognosis and immunotherapy outcomes in patients with bladder cancer. Methods: The IMvigor210 dataset served as our training set for developing the prognostic model based on immune-related genes. Robust 7-gene expression patterns were investigated from the training set. A time-dependent receiver operating characteristic (ROC) curve and Kaplan-Meier (KM)analysis were employed to determine the prognostic relevance of these gene patterns. Independent datasets collected from the Cancer Genome Atlas Program (TCGA) and Gene Expression Omnibus (GEO) databases were additionally utilized for re-determination. The association between the 7-gene signature-based risk score and immunological subtypes, tumor mutational burden (TMB), immune checkpoint expressions, and the proportion of immune cell infiltration was assessed within training and test sets. Furthermore, the training set's predictive potential for immunotherapy response was assessed using the 7-gene signature, and its validity was externally verified on three datasets (GSE176307, GSE140901, and GSE91016). By validating the 7-gene signature externally, we eneralized the findings beyond the original training set, and assessed the model's performance in diverse contexts. Consistent performance across these datasets reinforces the robustness and clinical utility of our 7-gene signature. Results: Employing the transcriptional and clinical information from the IMvigor210 for training, 348 patients were classified into two clusters with notable distinctions in prognostic stratification and immunotherapy efficacy. Seven immune-related genes Indoleamine 2,3-dioxygenase 1 (IDO1), TNF receptor superfamily member 17 (TNFRSF17), Killer Cell Lectin Like Receptor K1 (KLRK1), TNF receptor superfamily member 14 (TNFSF14), Lymphocyte-activation gene 3 (LAG3), Killer Cell Lectin Like Receptor C1 (KLRC1), and Ecto-5'-nucleotidase (NT5E) were screened based on different expression genes (DEGs) between the two clusters. The expression levels of these seven genes and the accompanying univariate component Cox regression coefficients, were computed to create a 7-gene signature-based risk score. The median value of the risk score was utilized to categorize the BLCA individuals into high-risk and low-risk groups. Researchers identified that in the low-risk group, individuals exhibited a noticeably improved chance of surviving. The external validation cohorts verified the risk score model's prognostic capacity. Furthermore, it was demonstrated that while low-risk individuals possessed higher TMB scores, higher expression of immune checkpoint genes, and lower levels of immunological infiltration, they responded more favorably to immunotherapy. The clinical relevance of the risk score model was validated in three immunotherapy groups. Conclusion: The risk score model might be utilized to forecast the prognosis and efficacy of immunotherapy in BLCA patients, offering a novel course of treatment for these individuals. For patients undergoing immunotherapy, this gene signature can help predict treatment response. Low-risk patients may benefit from more tailored monitoring and personalized immunotherapy regimens. However, more investigations are required to validate its accuracy and effectiveness in a prospective cohort with larger sample sizes.

Harnessing Natural Killer Cell Function for Genitourinary Cancers.

Natural killer (NK) cells are potently cytolytic innate lymphocytes involved in the immune surveillance of tumors and virally infected cells. Although much progress has been made in manipulating the ability of T cells to recognize and eliminate tumors, a comprehensive understanding of NK-cell infiltration into solid tumors, and their amenability to immunomodulation, remains incomplete. This article discusses recent studies showing that urologic tumors are infiltrated by NK cells and that these NK cells are often dysfunctional, but that strategies interfering with inhibitory axes have significant potential to alleviate this dysfunction.

Putting the Brakes on Tumorigenesis with Natural Products of Plant Origin: Insights into the Molecular Mechanisms of Actions and Immune Targets for Bladder Cancer Treatment.

Bladder cancer is the 10th most commonly diagnosed cancer worldwide. Although the incidence in men is 4 times higher than that in women, the diagnoses are worse for women. Over the past 30 years, the treatment for bladder cancer has not achieved a significant positive effect, and the outlook for mortality rates due to muscle-invasive bladder cancer and metastatic disease is not optimistic. Phytochemicals found in plants and their derivatives present promising possibilities for cancer therapy with improved treatment effects and reduced toxicity. In this study, we summarize the promising natural products of plant origin with anti-bladder cancer potential, and their anticancer mechanisms-especially apoptotic induction-are discussed. With the developments in immunotherapy, small-molecule targeted immunotherapy has been promoted as a satisfactory approach, and the discovery of novel small molecules against immune targets for bladder cancer treatment from products of plant origin represents a promising avenue of research. It is our hope that this could pave the way for new ideas in the fields of oncology, immunology, phytochemistry, and cell biology, utilizing natural products of plant origin as promising drugs for bladder cancer treatment.

Mystery of neck lump: an uncommon presentation of urachal cancer.

We present the case of a 55-year-old male patient who presented with palpable cervical lymphadenopathy. Excisional biopsy showed metastatic adenocarcinoma of unknown origin. Imaging showed a bladder mass following which he underwent transurethral resection of bladder tumour. Histopathological evaluation of mass confirmed a poorly differentiated adenocarcinoma with signet-ring cell features. Immunohistochemistry was suggestive of metastatic urachal cancer. He agreed for enrollment in a clinical trial, however soon after 1st cycle, he developed immune pneumonitis requiring high dose steroids. On follow-up, MRI brain was done for evaluation of headache which showed metastatic intracranial disease. He completed radiotherapy following which he was started on FOLFOX chemo regimen (folinic acid, 5-fluorouracil and oxaliplatin).

Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) for the Treatment of Unresectable and Metastatic Cancers.

Metastatic spread is the mechanism in more than 90 percent of cancer deaths and current therapeutic options, such as systemic chemotherapy, are often ineffective. Here we provide a proof of principle for a novel two-pronged modality referred to as Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) having the potential to safely eradicate both primary tumors and distant metastatic foci. Using a combination of immune-checkpoint inhibition and plasmonic gold nanostar (GNS)-mediated photothermal therapy, we were able to achieve complete eradication of primary treated tumors and distant untreated tumors in some mice implanted with the MB49 bladder cancer cells. Delayed rechallenge with MB49 cancer cells injection in mice that appeared cured by SYMPHONY did not lead to new tumor formation after 60 days observation, indicating that SYMPHONY treatment induced effective long-lasting immunity against MB49 cancer cells.

Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.

Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγHigh/RXRαS427F/Y impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic "immuno-oncogenes" that modulate the immune microenvironment of cancer.Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease. Here the authors characterize diverse genetic alterations in MIBC that convergently lead to constitutive activation of PPARgamma/RXRalpha and result in immunosurveillance escape by inhibiting CD8+ T-cell recruitment.

Epidermal Growth Factor Receptor (EGFR)-targeted Photoimmunotherapy (PIT) for the Treatment of EGFR-expressing Bladder Cancer.

The use of light as a means of therapy for bladder cancer has a long history but has been hampered by a lack of tumor specificity and therefore, damage to the normal bladder mucosa. Here, we describe a targeted form of phototherapy called photoimmunotherapy (PIT), which targets EGFR-expressing bladder cancer. Anti-EGFR antibody panitumumab was labeled with the photoabsorber (PA), IRDye 700Dx (IR700), to create a panitumumab-IR700 antibody-PA conjugate that is activated by near-infrared radiation (NIR). Bladder cancer tissue microarray (TMA) and bladder cancer cell lines were analyzed for expression of EGFR. Mechanism of PIT-induced cell death was studied using proliferation assays, transmission electron microscopy (TEM), and production of reactive oxygen species. Finally, the in vivo effect was studied in xenografts. EGFR staining of TMAs showed that while most bladder cancers have expression of EGFR to a varying degree, squamous cell carcinomas (SCC) have the highest expression of EGFR. Panitumumab-IR700 activated by NIR light rapidly killed UMUC-5 cells, a bladder SCC line. Panitumumab alone, panitumumab-IR700 without NIR, or NIR alone had no effect on cells. TEM demonstrated that cell death is due to necrosis. Singlet oxygen species contributed toward cell death. NIR-PIT with panitumumab-IR700 reduced growth compared with only panitumumab-IR700-treated UMUC-5 xenograft tumors. PIT is a new targeted treatment for bladder cancer. Panitumumab-IR700-induced PIT selectively kills EGFR-expressing bladder cancer cells in vitro and in vivo and therefore warrants further therapeutic studies in orthotopic xenografts of bladder cancer and ultimately in patients. Mol Cancer Ther; 16(10); 2201-14. ©2017 AACR.

Development of anti-CD47 single-chain variable fragment targeted magnetic nanoparticles for treatment of human bladder cancer.

AIM: To develop a novel anti-CD47 single-chain variable fragment (scFv) functionalized magnetic nanoparticles (MNPs) for targeting bladder cell lines and its applicability in thermotherapy. MATERIAL & METHODS: An immunized murine antibody phage display library was constructed and screened to isolate anti-CD47 binders. A scFv was selected and conjugated to MNPs which was then utilized to discriminate CD47+ bladder cells along with assessing its efficacy in thermotherapy. RESULTS: An scFv with high affinity to bladder cells was efficiently conjugated to MNPs. Following a hyperthermia treatment, the function of scFv-MNP conjugates led to a considerable reduction in cell viability. CONCLUSION: The anti-CD47 scFv-MNP conjugate was an effective cancer cell thermotherapy tool that might pave the way for development of bionano-based targeting techniques in both early detection and treatment of cancer.

Intravesical Bacillus Calmette Guerin Combined with a Cancer Vaccine Increases Local T-Cell Responses in Non-muscle-Invasive Bladder Cancer Patients.

PURPOSE: Treatments with cancer vaccines may be delivered as combination therapies for better efficacy. Addition of intravesical immunostimulation with bacteria promotes vaccine-specific T cells in the bladder and tumor-regression in murine bladder cancer models. Here, we determined whether an adjuvanted cancer vaccine can be safely administered with concomitant standard intravesical Bacillus-Calmette-Guérin (BCG) therapy and how vaccine-specific immune responses may be modulated in patients with non-muscle-invasive bladder cancer (NMIBC). EXPERIMENTAL DESIGN: In a nonrandomized phase I open-label exploratory study, 24 NMIBC patients, apportioned in three groups, received 5 injections of a subunit cancer vaccine (recMAGE-A3 protein+AS15) alone or in two combinations of intravesical BCG-instillations. Safety profiles were compared between the three treatment groups, considering single vaccine injections or BCG instillations and concomitant interventions. Immune responses in blood and urine were compared between treatment groups and upon BCG instillations. RESULTS: The mild adverse events (AE) experienced by all the patients were similar to AE previously reported for this vaccine and standard BCG treatment. AEs were not increased by the double interventions, suggesting that BCG did not exacerbate the AE caused by the MAGE-A3 vaccine and vice-versa. All patients seroconverted after MAGE-A3 vaccination. In half of the patients, vaccine-specific T cells were induced in blood, irrespective of BCG treatment. Interestingly, such T cells were only detected in urine upon BCG-induced T-cell infiltration. CONCLUSIONS: Cancer vaccines, including strong adjuvants, can be safely combined with intravesical BCG therapy. The increase of vaccine-specific T cells in the bladder upon BCG provides proof-of-principle evidence that cancer vaccines with local immunostimulation may be beneficial. Clin Cancer Res; 23(3); 717-25. ©2016 AACR.

Rationale of hyperthermia for radio(chemo)therapy and immune responses in patients with bladder cancer: Biological concepts, clinical data, interdisciplinary treatment decisions and biological tumour imaging.

Bladder cancer, the most common tumour of the urinary tract, ranks fifth among all tumour entities. While local treatment or intravesical instillation of bacillus Calmette-Guerin (BCG) provides a treatment option for non-muscle invasive bladder cancer of low grade, surgery or radio(chemo)therapy (RT) are frequently applied in high grade tumours. It remains a matter of debate whether surgery or RT is superior with respect to clinical outcome and quality of life. Surgical resection of bladder cancer can be limited by acute side effects, whereas, RT, which offers a non-invasive treatment option with organ- and functional conservation, can cause long-term side effects. Bladder toxicity by RT mainly depends on the total irradiation dose, fraction size and tumour volume. Therefore, novel approaches are needed to improve clinical outcome. Local tumour hyperthermia is currently used either as an ablation therapy or in combination with RT to enhance anti-tumour effects. In combination with RT an increase of the temperature in the bladder stimulates the local blood flow and as a result can improve the oxygenation state of the tumour, which in turn enhances radiation-induced DNA damage and drug toxicity. Hyperthermia at high temperatures can also directly kill cells, particularly in tumour areas which are poorly perfused, hypoxic or have a low tissue pH. This review summarises current knowledge relating to the role of hyperthermia in RT to treat bladder cancer, the induction and manifestation of immunological responses induced by hyperthermia, and the utilisation of the stress proteins as tumour-specific targets for tumour detection and monitoring of therapeutic outcome.

Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.

Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452-62. ©2016 AACR.

Capsaicin-mediated apoptosis of human bladder cancer cells activates dendritic cells via CD91.

OBJECTIVES: Immunostimulation by anticancer cytotoxic drugs is needed for long-term therapeutic success. Activation of dendritic cells (DCs) is crucial to obtain effective and long-lasting anticancer T-cell mediated immunity. The aim of this study was to explore the effect of capsaicin-mediated cell death of bladder cancer cells on the activation of human monocyte-derived CD1a+ immature DCs. METHODS: Immature DCs (generated from human peripheral blood-derived CD14+ monocytes cultured with granulocyte-macrophage colony stimulating factor and interleukin-4) were cocultured with capsaicin (CPS)-induced apoptotic bladder cancer cells. DC activation was investigated using immunofluorescence and flow cytometric analysis for key surface molecules. In some experiments, CD91 was silenced in immature DCs. RESULTS: We found that capsaicin-mediated cancer cell apoptosis upregulates CD86 and CD83 expression on DCs, indicating the induction of DC activation. Moreover, silencing of CD91 (a common receptor for damage-associated molecular patterns, such as calreticulin and heat-shock protein-90/70) in immature DCs led to the inhibition of DC activation. CONCLUSIONS: Our data show that CPS-mediated cancer cell apoptosis activates DCs via CD91, suggesting CPS as an attractive candidate for cancer therapy.

Effects of Kuan-Sin-Yin decoction on immunomodulation and tumorigenesis in mouse tumor models.

BACKGROUND: Complementary therapies are widely used among cancer patients. Kuan-Sin-Yin (KSY) decoction, a popular qi-promoting herbal medicine, was constituted with several herbs known to exhibit immunomodulating or anticancer activity. After combining these herbs as a compound formula, it is necessary to reassess the immunomodulation effects, the effects on tumor growth, and possible toxicity of KSY. METHODS: The anti-cancer effects of KSY in vivo were determined by measuring the tumor volumes, anticancer-associated cytokines (IFN-gamma, TNF-alpha, IL-2, and IL-12), accumulation of tumor infiltrating leukocytes (TILs), proliferation and apoptosis-related molecular markers (Ki-67, p53, p21, activated caspase 3, and cleaved PARP), and an in situ TUNEL assay. The body weight and serum chemistry of treated mice were also assessed. In vitro, the effects of KSY were evaluated using MTT assay, BrdU incorporation assay and cell growth curve. RESULTS: In vivo, KSY suppressed bladder or lung cancer growth but did not promote the production of cytokines nor increase the accumulation of TILs. The expression of p53 and p21 in KSY-treated mice were increased. The numbers of apoptotic tumor cells and the expression of apoptosis marker proteins (Caspase 3 and cleaved PARP) were not significantly elevated after KSY treatment. In vitro, the viability and proliferation of tumor cells, but not normal cells, were suppressed by KSY treatment. No significant toxicity was found in KSY-treated mice. CONCLUSIONS: KSY suppressed the tumor growth in vivo and in vitro, which resulted from its cytostatic effects on cancer cells, rather than the induction of anti-cancer immunity. Under these experimental conditions, no apparent toxicity was observed.

The mechanism of action of BCG therapy for bladder cancer--a current perspective.

Bacillus Calmette-Guérin (BCG) has been used to treat non-muscle-invasive bladder cancer for more than 30 years. It is one of the most successful biotherapies for cancer in use. Despite long clinical experience with BCG, the mechanism of its therapeutic effect is still under investigation. Available evidence suggests that urothelial cells (including bladder cancer cells themselves) and cells of the immune system both have crucial roles in the therapeutic antitumour effect of BCG. The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. Immune system cell subsets that have potential roles in BCG therapy include CD4(+) and CD8(+) lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. Bladder cancer cells are killed through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), and, to some degree, by the direct action of BCG. Several gaps still exist in our knowledge that should be addressed in future efforts to understand this biotherapy of cancer.

Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer.

OBJECTIVES: In this article, we review the various options for and the potential role of interferon alfa (IFN-α) in the treatment of non-muscle-invasive bladder cancer (NMIBC). METHODS: PubMed was searched for journal articles on IFN-α use in treating bladder cancer. The references listed in the National Comprehensive Cancer Network guidelines were used as a guide to identify relevant publications on treatments for NMIBC. RESULTS: Transurethral resection with adjuvant intravesical chemotherapy or immunotherapy is the standard treatment option for NMIBC. Adjuvant IFN-α therapy has limited efficacy in preventing recurrences in intermediate-risk and high-risk patients; bacillus Calmette-Guérin (BCG) monotherapy is the recommended first-line treatment in these patients. Unfortunately, cancer progression or recurrence is a common outcome; radical cystectomy, which is often the lifesaving approach in such a scenario, is associated with significant morbidity, mortality, and decreased quality of life. Current alternatives to cystectomy include repeat intravesical immunotherapy, conventional instillation chemotherapy, and device-assisted intravesical chemotherapy. The efficacy of any chemotherapy after BCG failure, either conventional or device assisted, has not been established. BCG and IFN-α combination intravesical therapy has not been investigated thoroughly; based on available data, combination therapy appears to be most effective in patients with carcinoma in situ and may be preferentially considered as an alternative to radical cystectomy for patients with intermediate-risk or high-risk NMIBC who do not tolerate the standard BCG dose or experience BCG failure after 1 year of therapy. However, this approach requires close follow-up and should only be chosen after careful consideration of all risk factors. CONCLUSIONS: There is a lack of efficacious treatment options for patients with NMIBC recurrence or progression after initial BCG treatment. There is a need for well-designed clinical trials investigating the safety and efficacy of available therapies, including BCG and IFN-α2b combination therapy.

1 alpha, 25-dihydroxylvitamin D3 promotes Bacillus Calmette-Guérin immunotherapy of bladder cancer.

Bacillus Calmette-Guérin (BCG), a vaccine against tuberculosis(TB), has been used and proven to be one of the most effective treatments for non-muscle invasive bladder cancer (BCa). However, the mechanisms of BCG action have not been completely understood, thereby limiting the improvement of BCG therapy. Vitamin D deficiency has been associated with a high risk of TB infection, and the beneficial effect of UV exposure in TB patients was proven to be mediated via activation of vitamin D signals of innate immune cells. Thus, vitamin D signals might be involved in mediating BCG immunotherapy. To test this hypothesis, we examined the impact of 1 alpha, 25-dihydroxyvitamin D3 (1,25-VD) on BCG-induced response in BCa cells and macrophage cells. Our data revealed that 1,25-VD promotes BCG-induced interleukin 8 (IL-8) secretion by BCa cells, consequently inducing the migration of macrophage, THP-1. This THP-1 cell migration promoted by 1,25-VD can be blocked by IL-8 neutralized antibody. Furthermore, 1,25-VD increased BCG-induced expression of macrophage markers in THP-1 cell, and enhanced the BCG-induced THP-1 cytotoxicity against low-grade BCa cells. Importantly, a pre-clinical trial using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCa mouse model revealed that intravesical co-treatment of 1,25-VD with BCG can prolong mice survival. These data demonstrate a novel mechanism by which 1,25-VD promotes BCG-mediated anti-BCa pathways and provides a platform for improving BCG efficacy with combination of 1,25-VD.

Toll-like receptors in urothelial cells--targets for cancer immunotherapy.

Toll-like receptors (TLRs) have an important role in the activation of both innate and adaptive immunity in response to pathogens and danger signals. These receptors are expressed in immune cells and in some epithelia. They are expressed in the epithelium of the urinary bladder, where they actively participate in the fight against infection by uropathogens. TLR expression is decreased (although still evident) in bladder tumours, especially in non-muscle-invasive tumours. Intravesical immunotherapy with BCG to prevent recurrence of these tumours has been shown to involve the participation of three different TLRs (TLR2, TLR4, and TLR9). However, alternative therapies are needed as BCG fails in some patients and can sometimes cause severe adverse effects that are difficult to tolerate. In recent years, TLR2, TLR4, TLR7, and TLR9 agonists have been tested in vitro and in vivo for their ability to activate an antitumour immune response against bladder cancer. Promising results from these studies have led to the testing of TLR7 and TLR9 agonists in clinical trials.

A novel adjuvant Ling Zhi-8 enhances the efficacy of DNA cancer vaccine by activating dendritic cells.

DNA vaccine has been suggested to use in cancer therapy, but the efficacy remains to be improved. The immunostimulatory effect of a fungal immunomodulatory protein Ling Zhi-8 (LZ-8) isolated from Ganoderma lucidum has been reported. In this study, we tested the adjuvanticity of LZ-8 for HER-2/neu DNA vaccine against p185(neu) expressing tumor MBT-2 in mice. We found that recombinant LZ-8 stimulated mouse bone marrow-derived dendritic cells (DCs) via TLR4 and its stimulatory effect was not due to any microbe contaminant. In addition, LZ-8 enhanced the ability of DCs to induce antigen-specific T cell activation in vitro and in a subunit vaccine model in vivo. Surprisingly, LZ-8 cotreatment strongly improved the therapeutic effect of DNA vaccine against MBT-2 tumor in mice. This increase in antitumor activity was attributed to the enhancement of vaccine-induced Th1 and CTL responses. Consistent with the results from DCs, the promoting effect of LZ-8 on DNA vaccine was diminished when the MBT-2 tumor cells were grown in TLR4 mutant mice. Thus, we concluded that LZ-8 may be a promising adjuvant to enhance the efficacy of DNA vaccine by activating DCs via TLR4.

Hyperthermia as a treatment for bladder cancer.

Modern cancer care is characterized by a focus on organ-sparing multi-modal treatments. In the case of non-muscle-invasive bladder cancer this is particularly true; treatment is focused on reducing the frequency of low-risk recurrences and preventing high-risk progression. Deep regional hyperthermia is an oncologic therapeutic modality that can help achieve these two goals. The combination of hyperthermia with chemotherapy and radiotherapy has improved patient outcomes in several tumor types. In this review, we highlight the biology of therapeutic fever-range hyperthermia, discuss how hyperthermia is administered and dosed, demonstrate how heat can be added to other treatment regimens, and summarize the data supporting the role of hyperthermia in the management of bladder cancer.