Incorporation of porcine adenovirus 4 fiber protein enhances infectivity of adenovirus vector on dendritic cells: Implications for immune-mediated cancer therapy

One strategy in cancer immunotherapy is to capitalize on the key immunoregulatory and antigen presenting capabilities of dendritic cells (DCs). This approach is dependent on efficient delivery of tumor specific antigens to DCs, which subsequently induce an anti-tumor T-cell mediated immune response. Human adenovirus serotype 5 (HAdV5) has been used in human studies for gene delivery, but has limited infection in DCs, which lack the proper receptors. Addition of the porcine fiber knob (PK) from porcine adenovirus type 4 to HAdV5 allows the virus to deliver genetic material via binding to glycosylated surface proteins and bypasses the coxsackie-and-adenovirus receptor required by wild-type HAdV5. In this study we explored the potential therapeutic applications of an adenovirus with PK-based tropism against cancers expressing mesothelin. Infectivity and gene transfer assays were used to compare Ad5-PK to wild-type HAdV5. Mouse models were used to demonstrate peptide specificity and T-cell responses. We show that the PK modification highly augmented infection of DCs, including the CD141+ DC subset, a key subset for activation of naïve CD8+ T-cells. We also show that Ad5-PK increases DC infectivity and tumor specific antigen expression. Finally, vaccination of mice with the Ad5-PK vector resulted in enhanced T-cell-mediated interferon gamma (IFN-γ) release in response to both mesothelin peptide and a tumor line expressing mesothelin. Ad5-PK is a promising tool for cancer immunotherapy as it improves infectivity, gene transfer, protein expression, and subsequent T-cell activation in DCs compared to wild-type HAdV5 viruses

Memory-like differentiation enhances NK cell responses to melanoma

PURPOSE: Treatment of advanced melanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell-refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined. EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK cells from healthy donors (HD) and patients with advanced melanoma were evaluated for their ability to produce IFNγ and kill melanoma targets RESULTS: NK cells in advanced melanoma exhibited a decreased cytotoxic potential compared with blood NK cells. ML NK cells differentiated from HD and patients with advanced melanoma displayed enhanced IFNγ production and cytotoxicity against melanoma targets. This included ML differentiation enhancing melanoma patients\u27 NK-cell responses against autologous targets. The ML NK-cell response against melanoma was partially dependent on the NKG2D- and NKp46-activating receptors. Furthermore, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared with conventional NK cells. CONCLUSIONS: Blood NK cells from allogeneic HD or patients with advanced melanoma can be differentiated into ML NK cells for use as a novel immunotherapeutic treatment for advanced melanoma, which warrants testing in early-phase clinical trials

Sigma-2 receptor ligands potentiate conventional chemotherapies and improve survival in models of pancreatic adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>We have previously reported that the sigma-2 receptor is highly expressed in pancreas cancer. Furthermore, we have demonstrated that sigma-2 receptor specific ligands induce apoptosis in a dose-dependent fashion. Here, we examined whether sigma-2 receptor ligands potentiate conventional chemotherapies such as gemcitabine and paclitaxel.</p> <p>Methods</p> <p>Mouse (Panc-02) and human (CFPAC-1, Panc-1, AsPC-1) pancreas cancer cell lines were used in this study. Apoptosis was determined by FACS or immunohistochemical analysis after TUNEL and Caspase-3 staining. Combination therapy with the sigma-2 ligand SV119 and the conventional chemotherapies gemcitabine and paclitaxel was evaluated in an allogenic animal model of pancreas cancer.</p> <p>Results</p> <p>SV119, gemcitabine, and paclitaxel induced apoptosis in a dose-dependent fashion in all pancreas cancer cell lines tested. Combinations demonstrated increases in apoptosis. Mice were treated with SV119 (1 mg/day) which was administered in combination with paclitaxel (300 μg/day) over 7 days to mice with established tumors. A survival benefit was observed with combination therapy (p = 0.0002). Every other day treatment of SV119 (1 mg/day) in combination with weekly treatment of gemcitabine (1.5 mg/week) for 2 weeks also showed a survival benefit (p = 0.046). Animals tolerated the combination therapy and no gross toxicity was noted in serum biochemistry data or on necropsy.</p> <p>Conclusion</p> <p>SV119 augments tumoricidal activity of paclitaxel and gemcitabine without major side effects. These results highlight the potential utility of the sigma-2 ligand as an adjuvant treatment in pancreas cancer.</p

The World-Class Multiversity: Global commonalities and national characteristics

World-Class Universities (WCUs) are nationally embedded comprehensive higher education institutions (HEIs) that are closely engaged in the global knowledge system. The article reviews the conditions of possibility and evolution of WCUs. Three interpretations are used to explain worldwide higher education: neoliberal theory, institutional theory, and critical political economy, which give greater recognition than the other theories to the role of the state and variations between states. World higher education is evolving under conditions of globalization, organizational modernization (the New Public Management), and in some countries, marketization. These larger conditions have become manifest in higher education in three widespread tendencies: massification, the WCU movement, and organizational expansion. The last includes the strengthening of the role of the large multi-disciplinary multi-purpose HEIs ("multiversities"), in the form of both research-intensive WCUs with significant global presence, and other HEIs. The role of binary sector and specialist HEIs has declined. Elite WCUs gain status and strategic advantage in both quantity and quality: through growth and the expansion of scope, and through selectivity and research concentration. The balance between quantity and quality is now resolved at larger average size and broader scope than before. The final section of the article reviews WCUs in China and considers whether they might constitute a distinctive university model

Incorporation of Porcine Adenovirus 4 Fiber Protein Enhances Infectivity of Adenovirus Vector on Dendritic Cells: Implications for Immune-Mediated Cancer Therapy

One strategy in cancer immunotherapy is to capitalize on the key immunoregulatory and antigen presenting capabilities of dendritic cells (DCs). This approach is dependent on efficient delivery of tumor specific antigens to DCs, which subsequently induce an anti-tumor T-cell mediated immune response. Human adenovirus serotype 5 (HAdV5) has been used in human studies for gene delivery, but has limited infection in DCs, which lack the proper receptors. Addition of the porcine fiber knob (PK) from porcine adenovirus type 4 to HAdV5 allows the virus to deliver genetic material via binding to glycosylated surface proteins and bypasses the coxsackie-and-adenovirus receptor required by wild-type HAdV5. In this study we explored the potential therapeutic applications of an adenovirus with PK-based tropism against cancers expressing mesothelin. Infectivity and gene transfer assays were used to compare Ad5-PK to wild-type HAdV5. Mouse models were used to demonstrate peptide specificity and T-cell responses. We show that the PK modification highly augmented infection of DCs, including the CD141+ DC subset, a key subset for activation of naïve CD8+ T-cells. We also show that Ad5-PK increases DC infectivity and tumor specific antigen expression. Finally, vaccination of mice with the Ad5-PK vector resulted in enhanced T-cell-mediated interferon gamma (IFN-γ) release in response to both mesothelin peptide and a tumor line expressing mesothelin. Ad5-PK is a promising tool for cancer immunotherapy as it improves infectivity, gene transfer, protein expression, and subsequent T-cell activation in DCs compared to wild-type HAdV5 viruses

Ad5GFP-PK infects both CD141⁺ and CD141^- DCs.

<p>Human PBMCs were infected with either Ad5GFP1 or Ad5GFP1-PK and analyzed by flow cytometry for expression of GFP in CD141⁺ and CD141^- DCs after 24 hours. The DC population was identified by first selecting the CD11c⁺/Lin1^- population of live PBMCs (top and middle panel). CD141⁺ DCs were then selected from the CD11c⁺/Lin1^- cohort and are outlined in red in the gating schema (bottom panel). All CD11c⁺/Lin1^- cells that express GFP are outlined in black in the bottom panel. There was no significant difference in percent DCs or percent CD141⁺ cells between groups (p = .15).</p

Ad5-9SCT-PK confers specific T cell reactivity.

<p>A. Splenocytes from mice vaccinated with Ad5-9SCT or Ad5-9SCT-PK were tested for reactivity against the SCT-encoded 9mer peptide, an irrelevant peptide, or no peptide. Splenocytes from mice injected with Ad5-9SCT-PK had a two-fold increase in the number of IFN-γ-producing cells compared to splenocytes from mice injected with Ad5-9SCT (p = .001) based on ELISpot. B. Mice were primed <i>in vivo</i> with HAd5V-containing full length mesothelin. Splenocytes were boosted <i>ex vivo</i> with either Ad5-9SCT or Ad5-9SCT-PK infected DCs. Cells boosted with Ad5-9SCT-PK had a 1.5-fold greater IFN-γ response to HLA-A2⁺, mesothelin expressing ovarian cancer cells than Ad5-9SCT (p = .0005).</p