In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the α1,3galactosyltransferase gene

Deriy, Ludmila V.; Ogawa, Hideoki; Gao, Guangping; Galili, Uri

doi:10.1038/sj.cgt.7700812

Cited by 25 publications

(31 citation statements)

References 63 publications

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“…The ability of B16 cells expressing ␣-gal epitopes to function as endogenous vaccines is also in accord with our previous studies (34,42) and those of other investigators (58,59). These studies on the immunogenicity of B16 cells expressing ␣-gal epitopes indicated that the immunization of KO mice with irradiated B16 cells engineered to express ␣-gal epitopes by transfection or transduction with the ␣1,3GT gene results in the induction of a protective antitumor immune response.…”

Section: Discussionsupporting

confidence: 77%

“…These studies on the immunogenicity of B16 cells expressing ␣-gal epitopes indicated that the immunization of KO mice with irradiated B16 cells engineered to express ␣-gal epitopes by transfection or transduction with the ␣1,3GT gene results in the induction of a protective antitumor immune response. The method presented here differs from those of previous studies (34,42,58,59) in that it enables the expression of ␣-gal epitopes in situ within the tumor lesions rather than using tumor cells processed in vitro to express ␣-gal epitopes. The present method achieves both the destruction of the treated lesion and its conversion into vaccine and, thus, may be beneficial to patients with multiple lesions that are refractory to standard treatments.…”

Section: Discussionmentioning

confidence: 61%

“…The 6-wk-old mice received three weekly intraperitoneal immunizations of 50 mg of pig kidney membrane (PKM) homogenate for inducing anti-Gal production in titers similar to those in humans (31,34,35). AntiGal production was confirmed by ELISA with synthetic ␣-gal epitopes linked to BSA as a solid phase Ag (31,35).…”

Section: Micementioning

confidence: 99%

“…After washes, cells were incubated for 1 h at 4 o C with 10 g/ml mouse anti-Gal (31,34,35,42) in PBS containing 1% BSA followed by incubation at 4°C for 30 min with FITC-coupled anti-mouse IgG. Washed cells were fixed with 1% paraformaldehyde and analyzed by flow cytometry (BD Biosciences).…”

Section: Identification Of Cell Inserted ␣-Gal Glycolipidsmentioning

confidence: 99%

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Intratumoral Injection of α-gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines

Galili

Wigglesworth²,

Abdel-Motal³

2007

The Journal of Immunology

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134

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This study describes a novel cancer immunotherapy treatment that exploits the natural anti-Gal Ab to destroy tumor lesions and convert them into an endogenous vaccine targeted to APC via FcγR. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts specifically with α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). The binding of anti-Gal to α-gal epitopes on pig cells mediates xenograft rejection. The proposed method uses glycolipid micelles with multiple α-gal epitopes (α-gal glycolipids). These glycolipids are extracted from rabbit red cell membranes and are comprised of ceramides with carbohydrate chains containing 5–25 carbohydrates, all capped with α-gal epitopes. Efficacy of this treatment was demonstrated in α1,3-galactosyltransferase knockout mice producing anti-Gal and bearing B16 melanoma or B16/OVA producing OVA as a surrogate tumor Ag. These mice are unique among nonprimate mammals in that, similar to humans, they lack α-gal epitopes and can produce the anti-Gal Ab. Intratumoral injection of α-gal glycolipids results in local inflammation mediated by anti-Gal binding to the multiple α-gal epitopes and activation of complement. These glycolipids spontaneously insert into tumor cell membranes. The binding of anti-Gal to α-gal expressing tumor cells induces the destruction of treated lesions as in anti-Gal-mediated xenograft rejection. Anti-Gal further opsonizes tumor cells within the lesion and, thus, targets them for effective uptake by APC that transport the tumor Ags to draining lymph nodes. APC further cross-present immunogenic tumor Ag peptides and elicit a systemic anti-tumor immune response. Similar intratumoral injection of α-gal glycolipids in humans is likely to induce the destruction of treated lesions and elicit a protective immune response against micrometastases.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 61%

Section: Micementioning

confidence: 99%

Section: Identification Of Cell Inserted ␣-Gal Glycolipidsmentioning

confidence: 99%

See 2 more Smart Citations

Intratumoral Injection of α-gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines

Galili

Wigglesworth²,

Abdel-Motal³

2007

The Journal of Immunology

Self Cite

134

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show abstract

“…In fact, antiGal is the only antibody in humans that can serve the purpose of targeting antigens to APC, because it is the only natural antibody known to be produced ubiquitously in large amounts in humans (10,17). Therefore, any particulate or soluble antigen that has ␣-Gal epitopes will form immune complexes with anti-Gal and will be targeted for effective uptake by APC (1,8,18,30).…”

mentioning

confidence: 99%

Immunogenicity of Influenza Virus Vaccine Is Increased by Anti-Gal-Mediated Targeting to Antigen-Presenting Cells

Abdel-Motal¹,

Guay

Wigglesworth³

et al. 2007

J Virol

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124

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This study describes a method for increasing the immunogenicity of influenza virus vaccines by exploiting the natural anti-Gal antibody to effectively target vaccines to antigen-presenting cells (APC). This method is based on enzymatic engineering of carbohydrate chains on virus envelope hemagglutinin to carry the ␣-Gal epitope (Gal␣1-3Gal␤1-4GlcNAc-R). This epitope interacts with anti-Gal, the most abundant antibody in humans (1% of immunoglobulins). Influenza virus vaccine expressing ␣-Gal epitopes is opsonized in situ by anti-Gal immunoglobulin G. The Fc portion of opsonizing anti-Gal interacts with Fc␥ receptors on APC and induces effective uptake of the vaccine virus by APC. APC internalizes the opsonized virus to transport it to draining lymph nodes for stimulation of influenza virus-specific T cells, thereby eliciting a protective immune response. The efficacy of such an influenza vaccine was demonstrated in ␣1,3galactosyltransferase (␣1,3GT) knockout mice, which produce anti-Gal, using the influenza virus strain A/Puerto Rico/8/34-H1N1 (PR8). Synthesis of ␣-Gal epitopes on carbohydrate chains of PR8 virus (PR8 ␣gal ) was catalyzed by recombinant ␣1,3GT, the glycosylation enzyme that synthesizes ␣-Gal epitopes in cells of nonprimate mammals. Mice immunized with PR8 ␣gal displayed much higher numbers of PR8-specific CD8 ؉ and CD4؉ T cells (determined by intracellular cytokine staining and enzyme-linked immunospot assay) and produced anti-PR8 antibodies with much higher titers than mice immunized with PR8 lacking ␣-Gal epitopes. Mice immunized with PR8 ␣gal also displayed a much higher level of protection than PR8 immunized mice after being challenged with lethal doses of live PR8 virus. We suggest that a similar method for increasing immunogenicity may be applicable to avian influenza vaccines.

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Therapeutics targeting tumor immune escape: Towards the development of new generation anticancer vaccines

Mocellin

Nitti

2007

Medicinal Research Reviews

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Despite the evidence that immune effectors can play a significant role in controlling tumor growth under natural conditions or in response to therapeutic manipulation, it is clear that malignant cells evade immune surveillance in most cases. Considering that anticancer vaccination has reached a plateau of results and currently no vaccination regimen is indicated as a standard anticancer therapy, the dissection of the molecular events underlying tumor immune escape is the necessary condition to make anticancer vaccines a therapeutic weapon effective enough to be implemented in the routine clinical setting. Recent years have witnessed significant advances in our understanding of the molecular mechanisms underlying tumor immune escape. These mechanistic insights are fostering the development of rationally designed therapeutics aimed at reverting the immunosuppressive circuits that undermine an effective antitumor immune response. In this review, the best characterized mechanisms that allow cancer cells to evade immune surveillance are overviewed and the most debated controversies constellating this complex field are highlighted. In addition, the latest therapeutic strategies devised to overcome tumor immune escape are described, with special regard to those entering clinical phase investigation.

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In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the α1,3galactosyltransferase gene

Cited by 25 publications

References 63 publications

Intratumoral Injection of α-gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines

Intratumoral Injection of α-gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines

Immunogenicity of Influenza Virus Vaccine Is Increased by Anti-Gal-Mediated Targeting to Antigen-Presenting Cells

Therapeutics targeting tumor immune escape: Towards the development of new generation anticancer vaccines

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