Highlights • We discuss the complex link between indoleamine 2,3 dioxygenase 1 (IDO1), tryptophan (Trp) and kynurenine (Kyn) in glioblastoma (GBM) patients. • We identify a potential new prognostic ...tool for GBM patient stratification. • We found that differences in the Kyn/Trp ratio appear ⩾10 weeks post-surgery. • We introduce novel physiologically-relevant clinical data from GBM patients.
Abstract
Ovarian cancer is the fifth leading cause of death and the most lethal gynecological cancer among women in the United States. Persistent activation of signal transducer and activator of ...transcription 3 (STAT3), a cytoplasmic transcription factor, is frequently detected in EOC. STAT3 transduces signals from cytokines such as interleukin 6 (IL-6) via interactions with the IL-6 receptor and Janus kinases (JAK). JAK2 activates STAT3 by phosphorylation, leading to dimerization and translocation of STAT3 to the nucleus where it activates transcription of target genes regulating proliferation, survival and motility. Importantly, in addition to tumor cells, STAT3 signaling is also critical for immune cell activity and, in particular, inflammatory response. The inflammatory tumor microenvironment is important for ovarian cancer progression; therefore, we hypothesized that disruption of the STAT3 pathway would block ovarian tumor progression by: 1) directly inhibiting the growth of tumor cells; and 2) reducing a pro-tumorigenic inflammatory microenvironment. To target JAK2-mediated activation of STAT3 we used AZD1480, a JAK2-selective small molecule inhibitor. The effects of AZD1480 treatment on cell proliferation, apoptosis, adhesion and motility were evaluated in cultured human ovarian carcinoma cells. To study the effects of AZD1480 in vivo, we used MISIIR-TAg mice, a transgenic mouse model of ovarian carcinoma. Tumor growth in MISIIR-TAg mice was monitored and quantified in mice by weekly magnetic resonance imaging (MRI). Drug treatment-mediated alterations in gene expression were evaluated by microarray analysis and changes in the inflammatory response were evaluated by flow cytometry analysis of cells extracted from ovarian tumors, spleens and peritoneal washes. AZD1480 treatment significantly reduced primary ovarian tumor growth in transgenic mice. Microarray analysis showed changes in expression of genes involved in the acute immune response, such as Gbp6, Ifi44, Irgm, Igtp, Gzmb and Cd69. Analysis of immune cell populations by flow cytometry showed a significant decrease in the number and percent of T helper and T regulatory cells present in the peritoneal cavity of drug-treated mice compared to controls. As T regulatory cells are associated with a poor prognosis in ovarian cancer patients, the decrease of this subpopulation in drug-treated mice suggests a change in the tumor microenvironment that may contribute to reduced tumor growth. Taken together, these results indicate that targeting JAK2/STAT3 impedes ovarian tumor growth through complex mechanisms, including the reduction of primary tumor growth and inflammation in the tumor microenvironment. These findings highlight the potential utility of targeting the JAK2/STAT3 pathway for the treatment of ovarian cancer patients.
Citation Format: Galina Gritsina, Fang Xiao, Shane W. O'Brien, Marisa A. Maglaty, Ren-Huan Xu, Luis J. Sigal, Samuel Litwin, Denise C. Connolly. Targeting the JAK2/STAT3 pathway in ovarian cancer. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1113. doi:10.1158/1538-7445.AM2014-1113
Abstract
Glioblastoma (GBM) is the most common primary brain tumor, accounting for 54% of malignant glioma diagnoses. Over the course of the past 30 years, a diagnosis of GBM has remained fatal even ...after maximum surgical resection, radiotherapy (RT), and chemotherapy, with a median overall survival of 14.6 months. The immunosuppressive microenvironment of GBM is a major contributor to the poor patient outcome. Expression of IDO1, as well as the accumulation of tumor-infiltrating regulatory T cells contribute to the avoidance of immune surveillance. Although current immunotherapies have had some success in extending patient survival, combinatorial treatment approaches addressing both tumor growth and the potent immunosuppression may prove to be more effective. This work aimed to determine the efficacy of a novel, pharmaceutical-grade, blood brain barrier-penetrating small molecule IDO1 inhibitor, BGB-5777, in combination with PD-1 blockade and/or whole brain radiation in an immunocompetent mouse GBM model. METHODS/RESULTS: All mice were intracranially-engrafted 2×105 GL261 (syngeneic to B6 background) cells to recapitulate brain tumors. At 14 days post-intracranial injection (dp-ic.), mice were treated with IgG alone as a control (n = 7), 2Gy RT for 5 days (n = 8), 500 ug (loading dose), followed by three 200 ug maintenance doses given every 3 days, of PD-1 mAb (J43) (n = 8), or 100mg/kg BGB-5777 for 4 weeks (n = 10), with a median overall survival (OS) of 25, 25, 32, and 26.5 days, respectively. Mice treated with dual therapies including RT and PD-1 mAb (n = 10), RT and BGB-5777 (n = 8), or PD-1 mAb and BGB-5777 (n = 9), had a median OS of 30, 39, and 32 days, respectively. All mice treated with mono- or dual-therapy succumbed to tumor burden. In contrast, mice treated with concurrent RT, PD-1 mAb and BGB-5777 (n = 9) showed a significant increase in median OS to 53 days (P<0.0001) with 33% of mice demonstrating a durable survival benefit of more than 150 days. Importantly, mice treated with the triple therapy and co-administered CD4 (n = 9)-, but not CD8 (n = 9)- or NK1.1 (n = 9)-depleting mAb, significantly decreased median OS to 29 days (P<0.001) confirming the requirement of CD4+ T cells for efficacy of this immunotherapeutic approach. CONCLUSION: The data indicate that combining the standard of care agent, RT, with PD-1 blockade and the novel IDO1 inhibitor, BGB-5777, synergistically increases OS in a mouse GBM model. Unexpectedly, CD4+, rather than CD8+ T cells, are required for immunotherapeutic efficacy. Understanding how CD4+ T cells coordinate anti-GBM immunity, the kinetics of PD-1 and IDO1 expression after RT, and determining why CD8+ T cells are dispensable under these conditions, are current areas of active investigation in our laboratory. Ultimately, these data suggest that using radiation to induce potential immunogenicity and/or inflammation in GBM, while co-inhibiting immunosuppression, is a rational and potentially clinically-beneficial pursuit.
Citation Format: Erik Ladomersky, Lijie Zhai, Galina Gritsina, Kristen L. Lauing, Matthew Genet, C. David James, Derek A. Wainwright. A novel IDO1 inhibitor combined with targeted immunotherapy durably increases survival in a mouse model of glioblastoma abstract. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B018.
The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a ...median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored. We conclude by proposing new strategies that are built on current vaccine technologies and improved upon with novel combinatorial approaches.
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