Stephanie Downs-Canner

A comparison of clinical trial enrollment between adolescent and young adult (AYA) oncology patients treated at affiliated adult and pediatric oncology centers.

Purpose Over the past 30 years, there has been a dramatic increase in the survival rates of younger pediatric cancer patients in contrast to adolescent and young adult (AYA) oncology patients. The reasons for this discrepancy are multifactorial, but it is clear that clinical trial enrollment correlates with better outcomes. Patients and Methods We examined the rate of clinical trial accrual of AYA oncology patients (aged 15 to 22 y) treated at affiliated pediatric and adult cancer centers, the Childrens Hospital of Pittsburgh and the University of Pittsburgh Cancer Institute. We retrospectively analyzed all new cancer diagnoses and clinical trial enrollment status between 2003 and 2006 for AYA patients at both institutions. Results There were 91 new AYA cancer diagnoses at Childrens Hospital of Pittsburgh, of which 24 (26%) were enrolled on a clinical trial. During the same time period, only 5 of 121 new AYA cancer patients (4%) at University of Pittsburgh Cancer Institute were enrolled on a clinical trial, which was significantly lower (P<0.001). Conclusions Our data demonstrate that clinical trial enrollment was superior when AYA patients were treated at a pediatric cancer center. As most AYA patients are not treated at pediatric centers, this may partly explain why their cure rates have not improved as significantly as younger pediatric oncology patients.

First-in-man Study of Western Reserve Strain Oncolytic Vaccinia Virus: Safety, Systemic Spread, and Antitumor Activity

Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.

Suppressive IL-17A+ Foxp3+ and ex-Th17 IL-17Aneg Foxp3+ Treg cells are a source of tumour-associated Treg cells

Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17–Treg imbalance is associated with inflammatory immunosuppression in cancer. Here we show that Th17 cells are a source of tumour-induced Foxp3+ cells. In addition to natural (n)Treg and induced (i)Treg cells that develop from naive precursors, suppressive IL-17A+Foxp3+ and ex-Th17 Foxp3+ cells are converted from IL-17A+Foxp3neg cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A+, ex-Th17 and iTreg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Treg cell subsets. Although all Foxp3-expressing subsets are immunosuppressive, glycolysis is a prominent metabolic pathway exerted only by IL-17A+Foxp3+ cells. Transcriptome analysis and flow cytometry of IL-17A+Foxp3+ cells indicate that Folr4, GARP, Itgb8, Pglyrp1, Il1rl1, Itgae, TIGIT and ICOS are Th17-to-Treg cell transdifferentiation-associated markers. Tumour-associated Th17-to-Treg cell conversion identified here provides insights for targeting the dynamism of Th17–Treg cells in cancer immunotherapy.

The indolent nature of pulmonary metastases from ductal adenocarcinoma of the pancreas.

The natural history of pulmonary metastases from pancreatic ductal adenocarcinoma (PDAC) is not well studied. Limited evidence suggests patients with isolated pulmonary metastases from PDAC follow a more benign clinical course than those with other sites of metastases.

Complement Inhibition: A Novel Form of Immunotherapy for Colon Cancer

BackgroundComplement is a central part of both the innate and adaptive immune response and its activation has traditionally been considered part of the immunosurveillance response against cancer. Its pro-inflammatory role and its contribution to the development of many illnesses associated with inflammatory states implicate complement in carcinogenesis.MethodsWe evaluated the role of three protein inhibitors of complement—cobra venom factor, humanized cobra venom factor, and recombinant staphylococcus aureus superantigen-like protein 7—in the setting of a transplantable murine colon cancer model. Outcomes were evaluated by monitoring tumor growth, and flow cytometry, ELISPOT, and quantitative real-time PCR were used to determine the impact of complement inhibition on the host immune response.ResultsComplement inhibitors were effective at depleting complement component C3 in tumor bearing mice and this was temporally correlated with a decreased rate of tumor growth during the establishment of tumors. Treatment with cobra venom factor resulted in increased CD8+ T cells as a percentage of tumor-infiltrating cells as well as a reduced immunosuppressive environment evidenced by decreased myeloid derived suppressor cells in splenocytes of treated mice. Complement inhibition resulted in increased expression of the chemoattractive cytokines CCL5, CXCL10, and CXCL11.DiscussionComplement depletion represents a promising mode of immunotherapy in cancer by its ability to impair tumor growth by increasing the host’s effective immune response to tumor and diminishing the immunosuppressive effect created by the tumor microenvironment and ultimately could be utilized as a component of combination immunotherapy.

Ex-Th17 Foxp3+ T cells - a novel subset of Foxp3+ T cells induced in cancer

Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg misbalance associates with inflammation. We demonstrate that in addition to natural (n)Treg and induced (i)Treg cells developed from naive precursors, Th17 cells are a novel source of Foxp3+ cells by converting into ex-Th17 Foxp3+ cells, and this helps to reconcile the contradictory information about the relevance in particularly of Th17 subset in immune surveillance. We identified IL-17A+Foxp3+ double-positive and ex-IL-17-producing IL-17A-Foxp3+ T cells to be the underlying mechanism of immune regulation in mesenchymal stem cell-mediated prolonged allograft survival. Further, we identified accumulation of IL17A+Foxp3+ and ex-Th17 Foxp3+ cells in tumor bearing mice, indicating progressive direct Th17-into-Treg cell conversion as a novel phenomenon in cancer. Moreover, we determined the importance of the Th17 cell plasticity for tumor induction and/or progression in ROR-g-/- mice. Our data indicate that RORgt is required not only for Th17 development, but also for effective Treg cell induction. TGF-b1 induced Foxp3 expression was reduced in ROR-g -/- cells. Further, tumor bearing ROR-g-/- mice showed significantly less Foxp3+ Treg cells, but higher IFNg+ Tcells compared to wild type animals. Increased infiltration of IL17+ and FoxP3+ CD4+ T cells in the human ovarian cancer ascites, with the presence of a distinct IL17+FoxP3+ subset, and a significant correlation between tumor-associated Th17 and Treg cells demonstrates the existence of Th17-Foxp3+ T cell inter-relationship in cancer patients. Yin-yang of IL17+ and Foxp3+ is important principle for improved clinical approaches targeting responses against self, allo and/or neo-self.

Regional Delivery of Oncolytic Vaccinia Virus: It’s Time for Clinical Trials

Malignant peritoneal mesothelioma is both rare and deadly with very poor overall long-term survival. Historically, therapies have offered little survival benefit, but recent advances in surgical therapy—a combination of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC)—have shown promise and demonstrate a role for regional, intraperitoneal treatment.1 This regional delivery needs to be employed with other agents, including biologic therapies such as oncolytic viruses, to continue to improve survival for this disease. In this month’s issue, Acuna et al. describe the use of an oncolytic vaccinia virus (vvDD) for regional, intraperitoneal therapy in a murine model of peritoneal mesothelioma. The authors have been instrumental in the design, construction, and pre-clinical development of this exciting, tumor-selective mutated virus over the last 13 years, and in this manuscript they perform important translational studies to demonstrate the efficacy of this virus as a regional treatment for peritoneal mesothelioma. They establish the selective cytotoxic effects of double-deleted vaccinia virus (vvDD) against two different mesothelioma cell lines and demonstrate improved survival in two different orthotopic murine models of malignant peritoneal mesothelioma after regional (intraperitoneal) treatment with vvDD. The authors verify the remarkable selectivity of the virus, with replication only in the tumor and the ovary. In a model, believed by the authors to be a surrogate for cytoreductive surgery (removal of all macroscopic disease), mice with only microscopic disease achieved a significant survival benefit when treated with vvDD compared to controls. Fifty percent of the mice were cured after a single intraperitoneal injection of 1 × 109 plaque-forming units (pfu) of vvDD. Oncolytic viral therapy has been studied as a local, regional, and systemic therapy in various human cancers. Adenovirus led the way, but was limited by its inefficiency in vivo and the clinical results were disappointing. Clinical trials using oncolytic herpes virus and measles virus have established viral replication in tumors, but the clinical results have been equally disappointing. The most encouraging results have been from the use of oncolytic vaccinia virus expressing granulocyte–macrophage colony-stimulating factor (GmCSF) in patients with hepatocellular cancer. Intralesional vaccinia-GMCSF therapy resulted in a 15 % response rate utilizing modified response evaluation criteria in solid tumors and a prolongation in survival (14.1 months versus 6.7 months; p = 0.02) comparing high dose (109 pfu) with low dose (108 pfu) intralesional treatment.2 Several different oncolytic viruses including adenovirus, measles virus, and vaccinia virus have shown promise in treating human mesothelioma cell lines and in models of pleural mesothelioma.3–5 Although no human trials have been reported to date, we know of three ongoing Phase I trials that are utilizing oncolytic vaccinia, measles, or herpes virus for pleural mesothelioma. vvDD is an efficient, tumor selective virus due to its deletion of both the thymidine kinase and vaccinia growth factor genes, and it has been shown to be both tumor selective and a potent oncolytic agent.6 We have recently completed clinical trials of intralesional and intravenous delivery of vvDD (unpublished) and realize that poor delivery and premature immune clearance of the virus limits systemic efficacy. Other oncolytic viruses have been delivered intraperitoneally in clinical trials to enhance delivery and improve viral infection.7–10 Regional delivery of vvDD into the peritoneal cavity leads to direct exposure of high concentration of virus to the tumor and productive infection of the malignant cells, avoiding the antibody and complement mediated clearance of the virus. Because peritoneal mesothelioma is superficially exposed within the peritoneal cavity, it is the perfect opportunity for this delivery approach. The clinical implications of the study by Acuna et al. are potentially two-fold. First, similar to work that has been done using HIPEC for mesothelioma treatment, the authors validate the efficacy of regional therapy for what is typically a diffuse process that is difficult to completely eradicate surgically. Second, the authors’ findings suggest that there may be a role for a combination of cytoreductive surgery and regional therapy with oncolytic viral treatment. Additionally, the authors note the possibility of combining oncolytic viral therapy with the expression of tumor antigens or with chemotherapy. However, other methods of immune modulation, such as expression of proinflammatory cytokines or chemokines, may also enhance viral efficacy, especially because vaccinia can be a potent immune stimulant, in addition to having oncolytic effects. The lack of a suitable animal model for cytoreductive surgery is a major limitation of these experiments, which is addressed by the authors. Until a better model can be developed, it will be difficult to conclude that the combination of cytoreductive surgery and vvDD treatment improve survival compared with cytoreductive surgery or vvDD treatment alone. The model of “microscopic disease” is imperfect, as it represents an early tumor microenvironment instead of a mature microenvironment that has been surgically treated. In a sense, the authors are examining the role of vvDD treatment in preventing tumor progression, instead of treating a diffusely progressed disease with multimodal therapy. The issues of the optimal timing of virus delivery after cytoreduction and the possibility that surgical scarring prevents dissemination of vvDD in the peritoneal cavity have not been addressed. The complexity and safety of delivering a live virus in the immediate postoperative period when anastomoses need to heal and other inflammatory responses are being endured by the patient also needs to be addressed. Despite the imperfect model, the findings still demonstrate the efficacy of vvDD as regional therapy in the treatment of both microscopic and macroscopic malignant peritoneal mesothelioma representing a significant finding in a disease with such poor overall survival. Malignant peritoneal mesothelioma is a lethal disease that presents a surgical challenge given its diffuse nature and the reality that microscopic disease is left behind after cytoreductive treatment. It has been shown that regional therapy, in the form of HIPEC, is beneficial to these patients. Acuna et al. are the first to demonstrate that in an orthotopic animal model of peritoneal mesothelioma, local oncolytic viral therapy with vvDD is effective for improving median and overall survival. These promising results should be confirmed in a clinical trial where vvDD may provide a significant survival benefit to patients in dire need of new therapies.