Enhancing immune response and survival in hepatocellular carcinoma with novel oncolytic Jurona virus and immune checkpoint blockade.

Members of the genus including Jurona virus (JURV) have emerged as promising immunotherapeutic agents, characterized by their tumor selectivity, fast kinetics, low seroprevalence, and minimal toxicity in humans. Here, we demonstrate that the administration of JURV leads to tumor regression in both hepatocellular carcinoma (HCC) xenograft and syngeneic models. Furthermore, our findings indicate that combining JURV and anti-PD-1 therapy reduced tumor burden and improved survival rates over JURV or anti-PD-1 alone in an orthotopic HCC model.

Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade.

Background: Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing.

Repurposing live attenuated trivalent MMR vaccine as cost-effective cancer immunotherapy.

It has long been known that oncolytic viruses wield their therapeutic capability by priming an inflammatory state within the tumor and activating the tumor immune microenvironment, resulting in a multifaceted antitumor immune response. Vaccine-derived viruses, such as measles and mumps, have demonstrated promising potential for treating human cancer in animal models and clinical trials. However, the extensive cost of manufacturing current oncolytic viral products makes them far out of reach for most patients.

Characterization of Morreton virus as an oncolytic virotherapy platform for liver cancers.

Background: Morreton virus (MORV) is an oncolytic Vesiculovirus , genetically distinct from vesicular stomatitis virus (VSV).

Aim: To report that MORV induced potent cytopathic effects (CPEs) in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) in vitro models.

Approach And Results: In preliminary safety analyses, high intranasal doses (up to 10 10 50% tissue culture infectious dose [TCID 50 ]) of MORV were not associated with significant adverse effects in immune competent, non-tumor-bearing mice.

Th17-inducing autologous dendritic cell vaccination promotes antigen-specific cellular and humoral immunity in ovarian cancer patients.

In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome).

Gastrointestinal Tract Dysbiosis Enhances Distal Tumor Progression through Suppression of Leukocyte Trafficking.

The overall use of antibiotics has increased significantly in recent years. Besides fighting infections, antibiotics also alter the gut microbiota. Commensal bacteria in the gastrointestinal tract are crucial to maintain immune homeostasis, and microbial imbalance or dysbiosis affects disease susceptibility and progression.

Regulatory T Cells in Gynecologic Cancer.

Increasing evidence supports that regulatory T cells (Tregs) within the tumor, tumor draining lymph nodes, ascites and peripheral blood of patients with cancer are associated with poor prognosis. Tregs are important mediators of active immune evasion in cancer. In this review, the potential mechanisms of Treg actions and the roles of Tregs specifically in the tumor microenvironment derived from three types of gynecological cancers, cervical, vulvar and ovarian, are described.

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian Cancer.

Ligation of programmed cell death-1 (PD-1) in the tumor microenvironment is known to inhibit effective adaptive antitumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients.

The glycosyltransferase GnT-III activates Notch signaling and drives stem cell expansion to promote the growth and invasion of ovarian cancer.

Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOCs) and leads to the production of abnormal truncated -linked glycan structures instead of the typical bisected forms. In this study, we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer.

Signaling Circuits and Regulation of Immune Suppression by Ovarian Tumor-Associated Macrophages.

The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages.

Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer.

Objective: Ovarian cancer is the most deadly gynecologic malignancy worldwide. Since the pathogenesis of ovarian cancer is incompletely understood, and there are no available screening techniques for early detection, most patients are diagnosed with advanced, incurable disease. In an effort to develop innovative and effective therapies for ovarian cancer, we tested the effectiveness of Galecti-3C in vitro.

Ovarian tumor ascites CD14+ cells suppress dendritic cell-activated CD4+ T-cell responses through IL-10 secretion and indoleamine 2,3-dioxygenase.

The observation that Th17 infiltration in ovarian cancer correlates with markedly improved survival has prompted the question of whether ovarian tumor antigen-specific Th17 responses could be stimulated by tumor vaccination. Dendritic cells (DCs) treated with IL-15 and an inhibitor of p38 MAPK signaling (DC(IL-15/p38inhib)) bias T-cell responses toward a Th1/Th17 phenotype, raising the prospect of therapeutic vaccination; however, significant barriers remain. Tumor vaccines, including DC vaccination, usually stimulate immune responses, but the lack of clinical responses in cancer patients has been disappointing.

Dendritic cell vaccination, immune regulation, and clinical outcomes in ovarian cancer.

Clinical optimism for dendritic cell vaccination against ovarian cancer has been tempered by the knowledge that tumors avail themselves of multiple mechanisms of immune evasion, thus blunting the efficacy of therapeutic vaccination. Mechanisms of immune suppression include infiltration by regulatory T cells (Treg) and myeloid suppressor cell populations, expression of co-inhibitory receptors, and expression of indoleamine 2,3-dioxygenase (IDO). Expression of both B7-H1 and IDO are associated with differentiation and recruitment of Treg, and clinical studies have shown that each of these mechanisms correlates independently with increased morbidity and mortality in ovarian cancer patients.

Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen.

The recent finding that Th17 infiltration of ovarian tumors positively predicts patient outcomes suggests that Th17 responses play a protective role in ovarian tumor immunity. This observation has led to the question of whether Th17 cells could be induced or expanded to therapeutic advantage by tumor vaccination. In this study, we show that treatment of ovarian tumor antigen-loaded, cytokine-matured human dendritic cells (DC) with a combination of IL-15 and a p38 MAP kinase inhibitor offers potent synergy in antagonism of CD4(+) Treg induction and redirection toward CD4(+) Th17 responses that correlate with strong CD8(+) cytotoxic T lymphocyte (CTL) activation.

The case for HER2/neu as a therapeutic target for gynecologic malignancies.

Evaluation of: Guzzo F, Bellone S, Buza N et al. HER2/neu as a potential target for immunotherapy in gynecological carcinosarcomas. Int.

CD4+ T-cell response against human papillomavirus type 16 E6 protein is associated with a favorable clinical trend.

The association between the CD8+ T-cell responses to human papillomavirus type 16 (HPV-16) E6 protein and a favorable clinical trend has been demonstrated previously. The roles of human papillomavirus (HPV)-specific CD4+ T-cell responses and of regulatory T-cells (Tregs) were examined. Subjects with a recent history of abnormal Papanicolaou smear were eligible, and colposcopy-guided biopsy was performed at enrollment.

Cancer testis antigen, ropporin, is a potential target for multiple myeloma immunotherapy.

Despite recent improvements in standard pharmacologic treatments of multiple myeloma (MM), immunotherapy may prove to be more effective due to its higher specificity and lower toxicity. A novel cancer/testis antigen, ropporin, is a testis-specific protein localized in the sperm flagella. Comparing ropporin expression in healthy and MM samples, we did not detect ropporin expression in the normal tissues, but positive signals were found in 44% of the MM primary samples.

Cancer testis antigens: novel biomarkers and targetable proteins for ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer death in women and the leading cause from gynecological malignancies. Despite the recently improved outcomes of new chemotherapeutical agents in the therapy of ovarian cancer and the increased 5-year survival rate, the mortality of this malignancy disease remains unchanged. Ovarian cancer therapy is often correlated to the stage of the tumor, but the first step is usually surgical treatment.

Understanding the cross-talk between ovarian tumors and immune cells: mechanisms for effective immunotherapies.

Despite decades of research, ovarian cancer remains a lethal disease. Recent studies have reported the critical role played by the immune system in controlling growth and spread of ovarian tumors. Accordingly, immunotherapy has been indicated as the most likely successful new approach in the treatment of the disease.

Prospects and challenges for immunotherapy of ovarian cancer--what can we learn from the tumor microenvironment?

Although there has been a marked resurgence of optimism that tumor vaccination or active immunotherapy may hold the prospect of clinical benefit for ovarian cancer patients, this optimism has been tempered by an appreciation that ovarian cancer represents a paradigm for the art of immunological defense. The pathogenesis of ovarian cancer is characterized by the evolution of multiple immunosuppressive mechanisms in the tumor microenvironment, several of which correlate with increased morbidity and mortality in ovarian cancer patients. This issue of International Reviews of Immunology focuses on the immunology of ovarian cancer, with a particular emphasis on the role of antigen-presenting cells in shaping immunological stasis within the tumor microenvironment.

Identification of AKAP-4 as a new cancer/testis antigen for detection and immunotherapy of prostate cancer.

Background: Prostate cancer (PC) is the second most common cancer in older men, after skin cancer. PC is difficult to diagnose because the prostate-specific antigen screening method is associated with many false positives. In addition there is a need to develop new and more effective treatments.