Interest in cancer immunotherapy has been bolstered by the recent success of T cell checkpoint blockade with specific antibodies. This approach might be especially effective if combined with methods for enhancing tumor immunogenicity, eg injection of dendritic cells (DC) expressing tumor antigens. Currently, DC therapy is successful in only a small proportion of patients, perhaps reflecting poor homing of injected DC. To overcome this problem, we have generated cell-surface membrane nanovesicles from in vitro-generated bone-marrow-derived mature DC. When loaded with specific peptide, the vesicles are stimulatory for naïve TCR transgenic CD8 T cells in vitro without APC, though only with aggregated vesicles and not with vesicles dispersed into nano-vesicles by sonication. By contrast, after IV injection in vivo, the nanovesicles are much more immunogenic than aggregates and generate strong proliferation and effector function of CD8 cells in both spleen and LN, reflecting widespread distribution of the vesicles and uptake by host APC. Preliminary work has shown that injection of the vesicles can be used vaccinate against tumor growth and also reject established tumours in mice.

Monoclonal antibody (mAb) and chimeric antigen receptor (CAR) T-cell therapies have demonstrated promising clinical outcomes treating hematological malignancies. However, disease relapse remains problematic and likely caused by loss of therapeutic targets on tumors.1 Thus, novel immunotherapies against alternative targets are urgently needed. We developed a new therapeutic mAb against B-cell activating factor receptor (BAFF-R), a tumor necrosis factor primarily expressed on B cells and B-cell lymphoma and leukemia.2 The mAb induced antibody-dependent cellular cytotoxicity against a panel of human B-cell tumor lines and primary tumors including samples from relapse after rituximab treatment. Potent in vivo antitumor effects were observed on two drug-resistant human lymphoma models (rituximab- and ibrutinibresistant lymphomas) resulting in eradication of implanted tumors and long-term, tumor-free survival (P<0.001).3 Adapting the antibody binding domain, we developed a BAFF-R CAR containing CD3 and 4-1BB intracellular signaling domains. BAFF-R CAR-T cells had significant activation and killing against various malignant B-cell lines and primary tumors (NHLs, acute lymphoblastic leukemias, and chronic lymphocytic leukemias), in vitro. Tumor eradication and tumor-free survival was repeatedly observed in human lymphoma xenograft models including mantle cell (JeKo-1, Z-138) and Burkitt (Raji) lymphomas in NSG mice (P<0.01). Moreover, our BAFF-R CAR-T therapy eradicated CD19KO Z-138 tumors that is resistant to CD19-CAR treatment in NSG mice (*P<0.01 Figure). Altogether, our results strongly support the translational significance of our novel BAFF-R targeting immunotherapies, particularly for the major unmet clinical need of drug-resistant relapses in B-cell lymphoma and leukemia

miRNAs have a prominent position in the negative control of gene expression and are involved in many cellular processes including carcinogenesis. Analysis and published results of high throughput miRNA profiles lack a robust approach to describe their findings with a real integrative approach. We examined the whole miRNome using a high throughput microarray platform including 2578 mature miRNAs in 12 samples of primary human retinoblastoma, an intraocular malignant tumor of early childhood and probably the most robust clinical model of genetic predisposition to develop cancer.This work delineates the miRNA landscape in human retinoblastoma samples with a non-biased approach using detection call scores as an approximation to expressed/not-expressed state for each miRNA. With this approach we discovered a central cluster of 30 miRNAs highly expressed in all the cases, a cluster of 993 not expressed in all cases and 1022 variably detected in the samples accounting for inter tumor heterogeneity. We further explored mRNA targets, pathways and biological processes affected by some of these miRNAs.The 30 miRs core represent a shared miRNA machinery in retinoblastoma affecting most pathways considered hallmarks of cancer. We identified miR-3613 as a potential down regulator hub, because is highly expressed by all the samples and has at least 36 tumor suppressor genes as potential mRNA targets including the RB1 gene itself. Our results indicate that human retinoblastoma share a common and fundamental miRNA expression profile regardless of heterogeneity.miRNAs have a prominent position in the negative control of gene expression and are involved in many cellular processes including carcinogenesis. Analysis and published results of high throughput miRNA profiles lack a robust approach to describe their findings with a real integrative approach. We examined the whole miRNome using a high throughput microarray platform including 2578 mature miRNAs in 12 samples of primary human retinoblastoma, an intraocular malignant tumor of early childhood and probably the most robust clinical model of genetic predisposition to develop cancer.This work delineates the miRNA landscape in human retinoblastoma samples with a non-biased approach using detection call scores as an approximation to expressed/not-expressed state for each miRNA. With this approach we discovered a central cluster of 30 miRNAs highly expressed in all the cases, a cluster of 993 not expressed in all cases and 1022 variably detected in the samples accounting for inter tumor heterogeneity. We further explored mRNA targets, pathways and biological processes affected by some of these miRNAs.The 30 miRs core represent a shared miRNA machinery in retinoblastoma affecting most pathways considered hallmarks of cancer. We identified miR-3613 as a potential down regulator hub, because is highly expressed by all the samples and has at least 36 tumor suppressor genes as potential mRNA targets including the RB1 gene itself. Our results indicate that human retinoblastoma share a common and fundamental miRNA expression profile regardless of heterogeneity.

A vaccine is a biological preparation that improves immunity to a particular microorganism. The working principle is to stimulate the body's immune system to recognize the agent as foreign, destroy it, and "remember" it. Vaccines are recognized for highly potent tool of public health. Accurate diagnostic and surveillance with better understanding of genetic and immunologic background of host specific response and pathogen evolution drives adapted vaccine research. Pandemics, drug resistance and neglected diseases framing health as a “global security issue”.  The list was drawn up in a bid to guide and promote research and development (R&D) of new antibiotics, as part of WHO’s efforts to address growing global AMR (27th Feb 2017) and it highlights in particular the threat of gram-negative bacteria. Although initially omitted from the list, tuberculosis (MDR/XDR) and latent tuberculosis represent still a major issue to tackle. XDR tuberculosis has evolved in several tuberculosis endemic countries to drug incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). BCG vaccine successfully helped to interrupt transmission cycle and large reduction of mortality. HIV/AIDS has known link with tuberculosis but other risk factors have also emerged in recent years as important determinants of the TB epidemic, one of which is diabetes mellitus. Noted risk or new emerging and re-emerging pathogens originated from animals after having crossed the species barrier (e.g Ebola) and re-appearance of “old diseases” like pertussis, measles. Finally, neglected tropical diseases represent a vast area where innovative vaccines might have strong economic impact. Live attenuated vaccines elicit a broad immune response (humoral and cellular) and there is a strongly expected disease nonspecific effect to be looked in depth. This direction along with improving of host immune system capacities (known microbiota and immune cell “training” and immune cell metabolic profiling) seems to be a promising path to explore further.

Monoclonal antibody (mAb) and chimeric antigen receptor (CAR) T-cell therapies have demonstrated promising clinical outcomes treating hematological malignancies. However, disease relapse remains problematic and likely caused by loss of therapeutic targets on tumors.1 Thus, novel immunotherapies against alternative targets are urgently needed. We developed a new therapeutic mAb against B-cell activating factor receptor (BAFF-R), a tumor necrosis factor primarily expressed on B cells and B-cell lymphoma and leukemia.2 The mAb induced antibody-dependent cellular cytotoxicity against a panel of human B-cell tumor lines and primary tumors including samples from relapse after rituximab treatment. Potent in vivo antitumor effects were observed on two drug-resistant human lymphoma models (rituximab- and ibrutinibresistant lymphomas) resulting in eradication of implanted tumors and long-term, tumor-free survival (P<0.001).3 Adapting the antibody binding domain, we developed a BAFF-R CAR containing CD3 and 4-1BB intracellular signaling domains. BAFF-R CAR-T cells had significant activation and killing against various malignant B-cell lines and primary tumors (NHLs, acute lymphoblastic leukemias, and chronic lymphocytic leukemias), in vitro. Tumor eradication and tumor-free survival was repeatedly observed in human lymphoma xenograft models including mantle cell (JeKo-1, Z-138) and Burkitt (Raji) lymphomas in NSG mice (P<0.01). Moreover, our BAFF-R CAR-T therapy eradicated CD19KO Z-138 tumors that is resistant to CD19-CAR treatment in NSG mice (*P<0.01 Figure). Altogether, our results strongly support the translational significance of our novel BAFF-R targeting immunotherapies, particularly for the major unmet clinical need of drug-resistant relapses in B-cell lymphoma and leukemia. 

Monoclonal antibody (mAb) and chimeric antigen receptor (CAR) T-cell therapies have demonstrated promising clinical outcomes treating hematological malignancies. However, disease relapse remains problematic and likely caused by loss of therapeutic targets on tumors.1 Thus, novel immunotherapies against alternative targets are urgently needed. We developed a new therapeutic mAb against B-cell activating factor receptor (BAFF-R), a tumor necrosis factor primarily expressed on B cells and B-cell lymphoma and leukemia.2 The mAb induced antibody-dependent cellular cytotoxicity against a panel of human B-cell tumor lines and primary tumors including samples from relapse after rituximab treatment. Potent in vivo antitumor effects were observed on two drug-resistant human lymphoma models (rituximab- and ibrutinibresistant lymphomas) resulting in eradication of implanted tumors and long-term, tumor-free survival (P<0.001).3 Adapting the antibody binding domain, we developed a BAFF-R CAR containing CD3 and 4-1BB intracellular signaling domains. BAFF-R CAR-T cells had significant activation and killing against various malignant B-cell lines and primary tumors (NHLs, acute lymphoblastic leukemias, and chronic lymphocytic leukemias), in vitro. Tumor eradication and tumor-free survival was repeatedly observed in human lymphoma xenograft models including mantle cell (JeKo-1, Z-138) and Burkitt (Raji) lymphomas in NSG mice (P<0.01). Moreover, our BAFF-R CAR-T therapy eradicated CD19KO Z-138 tumors that is resistant to CD19-CAR treatment in NSG mice (*P<0.01 Figure). Altogether, our results strongly support the translational significance of our novel BAFF-R targeting immunotherapies, particularly for the major unmet clinical need of drug-resistant relapses in B-cell lymphoma and leukemia.