ABSTRACT
Activation of immune checkpoint pathways and limited T- cell infiltration result in immunological escape of tumors. Although immune checkpoint inhibitors are currently approved for several types of cancers, the response rate is often limited by the lack of tumor specific T-cells within the malignant tissue. Therefore, new combinatorial strategies are needed to enhance the clinical benefit of immune checkpoint inhibitors. We have previously developed PeptiCRAd, an oncolytic vaccine platform capable of directing the immune response toward tumor epitopes. In this study, we evaluated whether the platform could be used to increase the response rate to checkpoint inhibitors in both highly immunogenic and poorly immunogenic tumors, such as melanoma and triple negative breast cancer (TNBC). We report here that anti-PD-L1 therapy in combination with PeptiCRAd significantly reduced the growth of melanomas and increased the response rate to checkpoint inhibition. In fact, we registered a higher rate of complete responses among mice treated with the combination. This approach promoted the presence of non-exhausted antigen-specific T-cells within the tumor in comparison to anti-PD-L1 monotherapy. Furthermore, we found that targeting both MHC-I and II restricted tumor epitopes was necessary to decrease the growth of the poorly immunogenic TNBC model 4T1 and that combination with PD-L1 blockade increased the number of responders to checkpoint inhibition. Finally, the described strategy was validated in a translational in vitro model using HLA matched human PBMCs and tumor cell lines. Consistent to our previous results, improved cytotoxicity was observed with combination of PeptiCRAd and anti-PD-L1. These results demonstrate that oncolytic virus based cancer vaccine can significantly improve the response rate to checkpoint blocking antibodies in the context of immunogenic and non-immunogenic tumors.
ABSTRACT
UNLABELLED: The incidence rate of invasive infections due to Candida species has increased drastically in the last 20 years, causing a 40% mortality rate in hospitalized patients. In order to comprehend the epidemiology of Candida bloodstream infection, the study was carried out. MATERIALS AND METHODS: A retrospective study was done based on microbiology laboratory reports from five terciary care hospitals from the city of Cordoba between January 2010 and August 2012. RESULTS: 158 patients had candidemia, the average age was 55,8 years, and 54% of patients were in the intensive care unit. Candida albicans (44%), Candida parapsilosis (22%) and Candida tropicalis (12%) were the main fungi isolated. Candida parapsilosis was commonly associated with catether infections. CONCLUSIONS: The data from the city of Cordoba showed that C. albicans, C. parapsilosis y C. tropicalis were the more frequent species isolated from blood cultures. This is similar to what is seen in other series published from Argentina and Latinamerica. This study may have implications when it comes to deciding which empiric antifugal agent is best for the treatment of candidemia.
La incidencia de infecciones invasivas por Candida ha aumentado en forma dramática en los últimos 20 años, siendo causa importante de mortalidad en torno al 40% en los pacientes hospitalizados. Material y métodos: Se realizó un estudio retrospectivo, basado en reportes de laboratorio de cinco hospitales de tercer nivel de la ciudad de Córdoba entre enero de 2010 y agosto de 2012, con el objetivo de conocer la epidemiología regional. Resultados: 158 pacientes con candidemia, edad promedio de 55.8 años, el 60% internados en unidades de cuidados intensivos. Candida albicans 44%, Candida parapsilosis 22% y Candida tropicalis 12% fueron las principales especies aisladas. Candida parapsilosis estuvo comúnmente asociada a infecciones relacionadas a catéteres. Conclusiones: Esta serie local de la ciudad de Córdoba muestra que C. albicans, C. parapsilosis y C. tropicalis son las especies mas frecuentes coincidente con el perfil de las series publicadas en Argentina y Latinoamérica. Esto puede tener implicancias para decidir que agente antifúngico usar empíricamente para tratar las candidemias.
Subject(s)
Candidemia/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Argentina/epidemiology , Candidemia/microbiology , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infant, Newborn , Male , Middle Aged , Population Surveillance , Retrospective Studies , Young AdultABSTRACT
UNLABELLED: The incidence rate of invasive infections due to Candida species has increased drastically in the last 20 years, causing a 40
mortality rate in hospitalized patients. In order to comprehend the epidemiology of Candida bloodstream infection, the study was carried out. MATERIALS AND METHODS: A retrospective study was done based on microbiology laboratory reports from five terciary care hospitals from the city of Cordoba between January 2010 and August 2012. RESULTS: 158 patients had candidemia, the average age was 55,8 years, and 54
of patients were in the intensive care unit. Candida albicans (44
), Candida parapsilosis (22
) and Candida tropicalis (12
) were the main fungi isolated. Candida parapsilosis was commonly associated with catether infections. CONCLUSIONS: The data from the city of Cordoba showed that C. albicans, C. parapsilosis y C. tropicalis were the more frequent species isolated from blood cultures. This is similar to what is seen in other series published from Argentina and Latinamerica. This study may have implications when it comes to deciding which empiric antifugal agent is best for the treatment of candidemia.
ABSTRACT
UNLABELLED: The incidence rate of invasive infections due to Candida species has increased drastically in the last 20 years, causing a 40
mortality rate in hospitalized patients. In order to comprehend the epidemiology of Candida bloodstream infection, the study was carried out. MATERIALS AND METHODS: A retrospective study was done based on microbiology laboratory reports from five terciary care hospitals from the city of Cordoba between January 2010 and August 2012. RESULTS: 158 patients had candidemia, the average age was 55,8 years, and 54
of patients were in the intensive care unit. Candida albicans (44
) and Candida tropicalis (12
) were the main fungi isolated. Candida parapsilosis was commonly associated with catether infections. CONCLUSIONS: The data from the city of Cordoba showed that C. albicans, C. parapsilosis y C. tropicalis were the more frequent species isolated from blood cultures. This is similar to what is seen in other series published from Argentina and Latinamerica. This study may have implications when it comes to deciding which empiric antifugal agent is best for the treatment of candidemia.
Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Young Adult , Candidemia/epidemiology , Argentina/epidemiology , Population Surveillance , Incidence , Retrospective Studies , Candidemia/microbiologyABSTRACT
AIMS AND METHODS: This study assessed incidence, predictive factors, and outcome of Epstein-Barr virus (EBV) DNAemia in 100 recipients of allogeneic hematopoietic stem cell transplant. A total of 68 patients received anti-thymocyte globulin before unrelated grafts. RESULTS: Cumulative incidence of high-load EBV DNAemia defined by levels >10,000 copies/mL was 14% at 12 months. In multivariate analysis, a CD4+ T-lymphocyte count >50 µL at day +30 was the only factor significantly associated with a reduced risk of high-load EBV DNAemia. Thirteen of 16 patients with high viral loads were preemptively treated with rituximab and achieved EBV DNA negativity. Three patients had already developed post-transplant lymphoproliferative disorder (PTLD) at the time of detection of high EBV DNA loads, and they obtained complete response after rituximab infusions and chemotherapy. Patients with high EBV DNA load had a significantly higher transplant-related mortality (TRM) compared with patients with negative or low viral load (54% vs. 16%, P = 0.009) and a trend to lower overall survival (55% vs. 29%, P = 0.060). CONCLUSION: We conclude that CD4+ cell count at day +30 is a predictive factor for EBV DNAemia and may help identify patients requiring closer monitoring. Although only 3% of patients progressed to PTLD and were all successfully managed, EBV reactivation was associated with higher TRM, mainly because of infections.
