Adenovirus MART-1–engineered Autologous Dendritic Cell Vaccine for Metastatic Melanoma

Butterfield, Lisa H.; Comin-Anduix, Begoñya; Vujanović, Lazar; Lee, Yohan; Dissette, Vivian B.; Yang, Jin-Quan; Vu, Hong Tien; Seja, Elizabeth; Oseguera, Denise K; Potter, Douglas M.; Glaspy, John A.; Economou, James S.; Ribas, Antoni

doi:10.1097/cji.0b013e31816a8910

Cited by 104 publications

(95 citation statements)

References 59 publications

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“…In particular, the secretion of the immunostimulatory cytokine IL-12p70 was significantly more pronounced and three-fold higher in DC-1 compared with DC-2, whereas the secretion of the immunosuppressive IL-10 was more characteristic of DC-2 in comparison to DC-1. High secretion levels of IL-12p70 are one of the most important features of therapeutic cancer vaccines as it has clearly been demonstrated in various experimental and clinical studies (22)(23)(24)(25). IL-12p70 drives and maintains the generation of Th1-polarized immune responses which are the key players in the detection and elimination of cancer (26).…”

Section: Discussionmentioning

confidence: 99%

Expression of tolerogenic potential-representing markers on clinical-grade therapeutic dendritic cell-based cancer vaccines

Dobrovolskiene¹,

Strioga²,

Liudkevičienė³

et al. 2014

AML

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Background. Currently a particular interest is given to specific active cancer immunotherapy (therapeutic cancer vaccination) strategies such as treatment with specially “educated” autologous dendritic cells (DCs). The purpose of these vaccines is to enhance antitumor immune responses against the existing tumor. DC vaccines are composed of tumor antigen-loaded mature DCs, which are produced for each cancer patient individually. However, recent data indicate that there are at least two types of mature DCs – immunogenic, which activate antitumor immune responses, and tolerogenic, which suppress immune responses, thereby interfering with effector mechanisms of protective antitumor immunity. Hence, the aim of our study was to assess the expression of immunogenic and tolerogenic potential-representing markers on the surface of therapeutic DC vaccines generated using two different maturation approaches. Materials and methods. Two different DC maturation approaches were investigated: Cocktail 1, composed of lipopolysaccharide (200 ng/ mL) and interferon-γ (50 ng/mL), and Cocktail 2, composed of IL1β (10 ng/mL), IL-6 (10 ng/mL), TNF-α (10 ng/mL), PGE2 (1 μg/mL). Secretion of two basic cytokines – the immunostimulatory IL-12p70 and the immunosuppressive IL-10 – has also been investigated. Results. We show that a subset of immature DCs expressed tolerogenic markers. Importantly their expression profile considerably differed on mature DCs, depending on the maturation approach used. Conclusions. In particular, our results indicate that Cocktail 1 is superior to Cocktail 2 for the production of clinical-grade therapeutic cancer DC vaccines, both in terms of immunophenotypical attributes of DC tolerogenicity and their cytokine secretory profile.

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Section: Discussionmentioning

confidence: 99%

Expression of tolerogenic potential-representing markers on clinical-grade therapeutic dendritic cell-based cancer vaccines

Dobrovolskiene¹,

Strioga²,

Liudkevičienė³

et al. 2014

AML

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“…20,21 They acquire an intermediate level of maturation based on the expression of cell-surface maturation markers, cytokine secretion, and antigen-presenting machinery, and increased ability to stimulate antigen-specific CD4 ϩ and CD8 ϩ T-cell responses. [22][23][24] The effectiveness of Ad.DC-based vaccines may be dependent on the ability of Ad.DCs to crosstalk with NK cells and bridge innate and adaptive immunity.…”

Section: Introductionmentioning

confidence: 99%

Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15

Vujanović

Szymkowski

Alber³

et al. 2010

Blood

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“…22 We have previously demonstrated upregulation of TAAs in p53 null and p73-expressing MM-AN cells after T-oligo treatment. 8 In this study, we investigated the expression of TAAs in these cells after T-oligo treatment with/without knockdown of p73.…”

Section: T-oligo Increases Expression Of Taas In Vitromentioning

confidence: 88%

Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy

Uppada¹,

Erickson²,

Wojdyla³

et al. 2013

IJN

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Oligonucleotides homologous to 3′-telomere overhang (T-oligos) trigger inherent telomere-based DNA damage responses mediated by p53 and/or ATM and induce senescence or apoptosis in various cancerous cells. However, T-oligo has limited stability in vivo due to serum and intracellular nucleases. To develop T-oligo as an innovative, effective therapeutic drug and to understand its mechanism of action, we investigated the antitumor effects of T-oligo or T-oligo complexed with a novel cationic alpha helical peptide, PVBLG-8 (PVBLG), in a p53 null melanoma cell line both in vitro and in vivo. The uptake of T-oligo by MM-AN cells was confirmed by immunofluorescence, and fluorescence-activated cell sorting analysis indicated that the T-oligo-PVBLG nanocomplex increased uptake by 15-fold. In vitro results showed a 3-fold increase in MM-AN cell growth inhibition by the T-oligo-PVBLG nanocomplex compared with T-oligo alone. Treatment of preformed tumors in immunodeficient mice with the T-oligo-PVBLG nanocomplex resulted in a 3-fold reduction in tumor volume compared with T-oligo alone. This reduction in tumor volume was associated with decreased vascular endothelial growth factor expression and induction of thrombospondin-1 expression and apoptosis. Moreover, T-oligo treatment downregulated procaspase-3 and procaspase-7 and increased catalytic activity of caspase-3 by 4-fold in MM-AN cells. Furthermore, T-oligo induced a 10-fold increase of senescence and upregulated the melanoma tumor-associated antigens MART-1, tyrosinase, and thrombospondin-1 in MM-AN cells, which are currently being targeted for melanoma immunotherapy. Interestingly, siRNA-mediated knockdown of p73 (4–10-fold) abolished this upregulation of tumor-associated antigens. In summary, we suggest a key role of p73 in mediating the anticancer effects of T-oligo and introduce a novel nanoparticle, the T-oligo-PVBLG nanocomplex, as an effective anticancer therapeutic.

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Adenovirus MART-1–engineered Autologous Dendritic Cell Vaccine for Metastatic Melanoma

Cited by 104 publications

References 59 publications

Expression of tolerogenic potential-representing markers on clinical-grade therapeutic dendritic cell-based cancer vaccines

Expression of tolerogenic potential-representing markers on clinical-grade therapeutic dendritic cell-based cancer vaccines

Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15

Novel delivery system for T-oligo using a nanocomplex formed with an alpha helical peptide for melanoma therapy

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