Effects of Postoperative Intravenous Cyclosporine Treatment on the Survival and Functional Performance Status of Patients With Glioblastoma: A Randomized, Triple-Blinded, Placebo-Controlled Clinical Trial.

BACKGROUND: Glioblastoma is associated with low median survival time irrespective of maximal treatment. Previous in vitro studies have revealed tumor inhibitory effect of cyclosporine A. However, whether the addition of cyclosporine could improve survival among patients with glioblastoma is unknown. This study aimed to determine the impact of postoperation treatment with cyclosporine on the survival and performance status. METHODS: In this randomized, triple-blinded, placebo-controlled trial, 118 patients with glioblastoma who underwent surgery were treated with standard chemoradiotherapy regimen. Patients were randomized to receive intravenous cyclosporine for 3 days postoperatively or placebo during the same period. The primary endpoint was the short-term effect of intravenous cyclosporine on survival and Karnofsky performance scores. Secondary endpoints were chemoradiotherapy toxicity and neuroimaging features. RESULTS: The overall survival (OS) in the cyclosporine (17.03 ± 5.8, 95% confidence interval: 11-17.37 months) group was statistically lower than in the placebo (30.53 ± 4.9, 95% confidence interval: 8-32.3 months) groups (P = 0.049). However, compared to the placebo group, a statistically higher percentage of patients in the cyclosporine group were alive at 12 months follow-up. Also, progression-free survival in the cyclosporine group was significantly prolonged than in the placebo group (6.3 ± 4.07 months vs. 3.4 ± 2.98 months, P < 0.001). In the multivariate analysis, age <50 years (P = 0.022) and gross total resection (P = 0.03) were significantly associated with OS. CONCLUSIONS: Our study results demonstrated that administering postoperative cyclosporine does not improve OS and functional performance status. Notably, the survival rate was significantly dependent on the patient age and the extent of glioblastoma resection.

Dendritic Cells Pulsed with Cytokine-Adjuvanted Tumor Membrane Vesicles Inhibit Tumor Growth in HER2-Positive and Triple Negative Breast Cancer Models.

Dendritic cells (DCs) are the most effective antigen presenting cells for the development of T cell responses. The only FDA approved DC-based immunotherapy to date is Sipuleucel-T, which utilizes a fusion protein to stimulate DCs ex vivo with GM-CSF and simultaneously deliver the antigen PAP for prostate cancer. This approach is restricted by the breadth of immunity elicited to a single antigen, and to cancers that have a defined tumor associated antigen. Other multi-antigen approaches have been restricted by poor efficacy of vaccine adjuvants. We have developed a vaccine platform that consists of autologous DCs pulsed with cytokine-adjuvanted tumor membrane vesicles (TMVs) made from tumor tissue, that encapsulate the antigenic landscape of individual tumors. Here we test the efficacy of DCs pulsed with TMVs incorporated with glycolipid-anchored immunostimulatory molecules (GPI-ISMs) in HER2-positive and triple negative breast cancer murine models. Pulsing of DCs with TMVs containing GPI-ISMs results in superior uptake of vesicles, DC activation and cytokine production. Adaptive transfer of TMV-pulsed DCs to tumor bearing mice results in the inhibition of tumor growth, reduction in lung metastasis, and an increase in immune cell infiltration into the tumors. These observations suggest that DCs pulsed with TMVs containing GPI-GM-CSF and GPI-IL-12 can be further developed to be used as a personalized immunotherapy platform for cancer treatment.

Glioblastoma Multiforme: an Advanced Analysis of 153 Patients and Review of the Literature

Objective Glioblastoma multiforme (GBM) is an aggressive primary tumor with frequent recurrences that leaves patients with a short survival time and a low quality of life. The aim of this study was to review the prognostic factors in patients with glioblastoma multiforme. Material and Methods The focus of this retrospective study was a group of 153 patients with supratentorial GBM tumors, who were admitted to a tertiary-care referral academic center from 2005 to 2013. The factors associated with survival and local recurrence were assessed using the hazard ratio (HR) function of Cox proportional hazards regression and neural network analysis. Results Out of the 153 patients, 99 (64.7%) weremale. The average age of the patients was 55.69 15.10 years. The median overall survival (OS) and progression-free survival (PFS) rates were 14.0 and 7.10 months respectively. In the multivariate analysis, age (HR » 2.939, p < 0.001), operative method (HR » 7.416, p < 0.001), temozolomide (TMZ, HR » 11.723, p < 0.001), lomustine (CCNU, HR » 8.139, p < 0.001), occipital lobe involvement (HR » 3.088, p < 0.001) and Karnofsky Performance Status (KPS, HR » 4.831, p < 0.001) scores were shown to be significantly associated with a higher OS rate. Furthermore, higher KPS (HR » 7.292, p < 0.001) readings, the operative method (HR » 0.493, p » 0.005), the use of CCNU (HR » 2.047, p » 0.003) and resection versus chemotherapy (HR » 0.171, p < 0.001) were the significant factors associated with the local recurrence of the tumor. Conclusion Our findings suggest that the use of CCNU and TMZ, the operative method and higher KPS readings are associated with both higher survival and lower local recurrence rates.

Objetivo Glioblastoma multiforme (GBM) é um tumor primário agressivo com recorrências frequentes que deixam pacientes com uma curta sobrevida e baixa qualidade de vida. O objetivo deste estudo é rever fatores de prognóstico em pacientes com glioblastoma multiforme. Material e Métodos O foco deste estudo retrospectivo foi um grupo de 153 pacientes com tumores GBM supratentoriais, os quais deram entrada em um centro acadêmico de atendimento de referência de 2005 a 2013. Fatores associados com a sobrevivência e a recorrência local foram avaliados usando a razão de risco (RR) da regressão de risco proporcional de Cox e análise de redes neurais. Resultados Dos 153 pacientes, 99 (64,7%) eram homens. A média de idade foi de 55,69 15,10 anos. A sobrevida geral (SG) mediana e a sobrevida de livre progressão (SLP) foram 14,0 e 7,10 meses, respectivamente. Na análise multivariada, idade (RR » 2,939, p < 0,001), método operatório (RR » 7,416, p < 0,001), temozolomida (TMZ, RR » 11,723, p < 0,001), lomustina (CCNU, RR » 8,139, p < 0,001), envolvimento do lobo occipital (RR » 3,088, p < 0,001) e Índice de Desempenho de Karnofsky (IDK, RR » 4,831, p < 0,001) foram identificados como significativamente associados a uma SG maior. Além disso, leituras maiores de IDK (RR » 7,292, p < 0,001), o método operatório (RR » 0,493, p » 0,005), o uso de CCNU (RR » 2,047, p » 0,003) e ressecção versus quimioterapia (RR » 0,171, p < 0,001) foram fatores significativos associados à recorrência local de tumor. Conclusão Nossos resultados sugerem que o uso de CCNU e TMZ, o método operatório e leituras maiores de IDK estão associados tanto à maior sobrevida quanto à menor recorrência local.

Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-12.

Immunotherapeutic approaches have emerged as promising strategies to treat various cancers, including breast cancer. A single approach, however, is unlikely to effectively combat the complex, immune evasive strategies found within the tumor microenvironment, thus novel, effective combination treatments must be explored. In this study, we investigated the efficacy of a combination therapy consisting of PD-L1 immune checkpoint blockade and whole cell vaccination in a HER-2 positive mouse model of breast cancer. We demonstrate that tumorigenicity is completely abrogated when adjuvanted with immune stimulatory molecules (ISMs) B7-1 and a cell-surface anchored (GPI) form of IL-12 or GM-CSF. Irradiated cellular vaccines expressing the combination of adjuvants B7-1 and GPI-IL-12 completely inhibited tumor formation which was correlative with robust HER-2 specific CTL activity. However, in a therapeutic setting, both cellular vaccination and PD-L1 blockade induced only 10-20% tumor regression when administered alone but resulted in 50% tumor regression as a combination therapy. This protection was significantly hindered following CD4 or CD8 depletion indicating the essential role played by cellular immunity. Collectively, these pre-clinical studies provide a strong rationale for further investigation into the efficacy of combination therapy with tumor cell vaccines adjuvanted with membrane-anchored ISMs along with PD-L1 blockade for the treatment of breast cancer.