An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53

Nikitina, Ekaterina Yu.; Chada, Sunil; Muro-Cacho, Carlos; Fang, Bingliang; Zhang, R.; Roth, Jack A.; Gabrilovich, Dmitry I.

doi:10.1038/sj.gt.3301670

Cited by 40 publications

(31 citation statements)

References 35 publications

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“…Because both adenovirus-and p53-derived antigens are presented on the same DC, evaluation of antiadenovirus immunity may serve as a correlate for functional activity of DC. These data are consistent with the results obtained in animal models that showed a limited antiadenovirus response after immunization of mice with DCs transduced with different adenoviral constructs which did not affect antigen-specific CTL activity (14,36).…”

Section: Discussionsupporting

confidence: 82%

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

Antonia

Mirza

Fricke

et al. 2006

Clinical Cancer Research

391

272

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Purpose: The initial goal of this study was to test the immunologic and clinical effects of a new cancer vaccine consisting of dendritic cells (DC) transduced with the full-length wild-type p53 gene delivered via an adenoviral vector in patients with extensive stage small cell lung cancer. Experimental Design: Twenty-nine patients with extensive stage small cell lung cancer were vaccinated repeatedly at 2-week intervals. Most of the patients received three immunizations. p53-specific responses were evaluated, and phenotype and function of Tcells, DCs, and immature myeloid cells were analyzed and correlated with antigen-specific immune responses. Objective clinical response to vaccination as well as subsequent chemotherapy was evaluated.Results: p53-specificTcell responses to vaccination were observed in 57.1% of patients. Immunologic responses to vaccination were positively associated with a moderate increase in the titer of antiadenovirus antibodies, and negatively with an accumulation of immature myeloid cells. One patient showed a clinical response to vaccination whereas most of the patients had disease progression. However, we observed a high rate of objective clinical responses to chemotherapy (61.9%) that immediately followed vaccination. Clinical response to subsequent chemotherapy was closely associated with induction of immunologic response to vaccination. Conclusions: This study provides clinical support for an emerging paradigm in cancer immunotherapy, wherein optimal use of vaccination might be more effective, not as a separate modality, but in direct combination with chemotherapy.

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Section: Discussionsupporting

confidence: 82%

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

Antonia

Mirza

Fricke

et al. 2006

Clinical Cancer Research

391

272

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“…This cell-based approach has been suggested as an effective technique for avoiding antiviral responses that occur with direct and repeated delivery of the virus itself. 32,33 There may be several reasons for this. First, as no free virus is administered, transduced cells escape the effects of pre-existing neutralizing antibodies directed against the viral capsid.…”

Section: Helper-dependent Adenovirus Enhanced Vaccine Responses a Harmentioning

confidence: 99%

Vaccination with helper-dependent adenovirus enhances the generation of transgene-specific CTL

et al. 2004

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Recombinant adenoviral vectors (AdV) have been used experimentally as vaccines to present antigenic transgenes in vivo. However, administration of first-generation vectors (FG-AdV) is often limited by their induction of antiviral immunity. To address this limitation, helper-dependent vectors (HD-AdV) were developed that lack viral coding regions. While the administration of HD-AdV results in longterm gene expression in vivo, their utility as immunogens has never been examined. Direct vaccination with 10 8 blueforming units (BFU) of HD-AdV injected into C57BL/6 mice lead to superior transgene-specific CTL and antibody responses when compared to the same amount of a FGAdV. The antibody responses to viral antigens were high in response to both the vectors. As a mechanism to reduce viral exposure, dendritic cells (DC) were transduced with HD-AdV in vitro and then used as a cell-based vaccine. DC transduced with HD-AdV expressed higher levels of transgene-specific mRNA and up to 1200-fold higher levels of transgene protein than did DC transduced with a FG-AdV. In addition, HD-AdV-transduced DC stimulated superior transgene-specific CTL responses when administered in vivo, an effect that was further enhanced by maturing the DC with LPS prior to administration. In contrast to direct immunization with HD-AdV, vaccination with HD-AdV-transduced DC was associated with limited antibody responses against the AdV. We conclude that HD-AdV stimulates superior transgenespecific immune responses when compared to a FG-AdV, and that immunization with a DC-based vaccine maintains this efficacy while limiting antiviral reactivity.

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“…The replication-deficient adenoviral vector has many superior characters including wide host range, high titer of amplification, ability to infect quiescent cells, and a lower potential for oncogenesis and teratogenesis than with retroviral vectors because there is no insertion of DNA into the host genome (Tauber and Dobner 2001). In 1999, Jesse, a patient with ornithine transcarbamylase (OTC) deficiency, died of multiple organ failure after his hepatic artery was injected with genetically altered adenovirus (Adv), so increasing attention has been paid to the effect of host immune responses against adenovirus-mediated gene therapy (Harvey et al 1999, Stein et al 2000, Rahman et al 2001, Nikitina et al 2002. It has been reported that intradermal administration of an adenoviral vector to humans induced local cellular responses and systemic Adv5-specific lymphocyte proliferation (Harvey et al 1999).…”

mentioning

confidence: 99%

Immune response and effect of adenovirus-mediated human BMP-2 gene transfer on the repair of segmental tibial bone defects in goats

Tang

Dai

et al. 2005

Acta Orthopaedica

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(2005) Immune response and effect of adenovirus-mediated human BMP-2 gene transfer on the repair of segmental tibial bone defects in goats, Acta Orthopaedica, 76:5, 637-646, DOI: 10.1080 Background Tissue-engineered bone may be used for filling bone defects. There are, however, no reports on this technique used in large animals.Methods We evaluated the effectiveness of, and immune response in repairing diaphyseal bone defects by gene transfer using bone morphogenetic proteins (BMPs). We used adenovirus-mediated human BMP-2 (Adv-hBMP-2) gene-transduced bone marrow stromal cells (BMSCs) to repair 2.1-cm segmental tibial bone defects in goats (group I, n = 7). An Adv-ßgal-transduced BMSC group (group II, n = 5), a non-transduced BMSC group (group III, n = 5), and an untreated group (group IV, n = 2) were used as controls. Self-secreted extracellular matrix was used as cellular carrier.Results Radiographic and histomorphometric examination demonstrated more callus in the bone defects of group I compared to other groups.Week 24 after implantation, the defect healing rates of groups I, II, III, and IV were 6/7, 1/5, 2/5, and 0/2, respectively. The maximum compressive strength of new tissue in the bone defects of group I was higher than those of groups II and III. Temporary cellular and persistent humoral immune responses against adenovirus were detected after hBMP-2 gene transfer.Interpretation We found that Adv-hBMP-2 genetransduced BMSCs had superior osteoinductivity in the repair of tibial bone defects in goats, but it could cause temporary cellular and persistent humoral immune responses against adenovirus.

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An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53

Abstract: P53-based immunization is an attractive approach to

Cited by 40 publications

References 35 publications

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

Combination of p53 Cancer Vaccine with Chemotherapy in Patients with Extensive Stage Small Cell Lung Cancer

Vaccination with helper-dependent adenovirus enhances the generation of transgene-specific CTL

Immune response and effect of adenovirus-mediated human BMP-2 gene transfer on the repair of segmental tibial bone defects in goats

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