Transferrin-Liposome-Mediated Systemic p53 Gene Therapy in Combination with Radiation Results in Regression of Human Head and Neck Cancer Xenografts

Xu, Liang; Pirollo, Kathleen F.; Tang, Wilkin; Rait, Antonina; Chang, Esther H.

doi:10.1089/10430349950016357

Cited by 207 publications

(184 citation statements)

References 25 publications

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“…26 Indeed, we have shown that the restoration of p53 function via SGT-53, a tumor-targeted nanomedicine, could inhibit tumor growth and sensitize xenografts of human tumors in nude mice lacking T cells to both chemotherapy 27,28 and radiotherapy. 29 Nonetheless, it has become clear that p53 also participates in various aspects of immune modulation in cancer. 30 In the present study, we are reporting that introducing functional wtp53 gene via SGT-53 can induce immunogenic changes of cancer cells, effectively promote anti-tumor immunity, and reduce tumor-induced immunosuppression in the TME.…”

Section: Discussionmentioning

confidence: 99%

“…The p53 expression plasmid pCMV-p53 contains the 1.7 kb human wtp53 cDNA under the control of the CMV promoter, followed by the SV40 polyadenylation signal. 29 As a control treatment, scL-GFP or scL-vec nanocomplexes were prepared using either GFP expression plasmid pCMV-GFP or empty plasmid pCMV, respectively. After incubation for 4 h at 37°C, the medium was replaced with complete medium and the cells were further incubated.…”

Section: Methodsmentioning

confidence: 99%

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Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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The tumor suppressor p53 responds to genotoxic and oncogenic stresses by inducing cell cycle arrest and apoptosis. Recent studies suggest that p53 also participates in the regulation of cellular immune responses. Here, we have investigated the potential of p53 gene therapy to augment immune checkpoint inhibition by combining an anti-programmed cell death protein 1 (PD1) antibody with SGT-53, our investigational nanomedicine carrying a plasmid encoding human wild-type p53. In three syngeneic mouse tumor models examined including a breast cancer, a non-small cell lung carcinoma, and a glioblastoma, SGT-53 sensitized otherwise refractory tumors to anti-PD1 antibody. The involvement of p53 in enhancing anti-PD1 immunotherapy appears to be multifaceted, since SGT-53 treatment increased tumor immunogenicity, enhanced both innate and adaptive immune responses, and reduced tumor-induced immunosuppression in a 4T1 breast tumor model. In addition, SGT-53 alleviates a fatal xenogeneic hypersensitivity associated with the anti-PD1 antibody in this model. Our data suggest that restoring p53 function by SGT-53 is able to boost anti-tumor immunity to augment anti-PD1 therapy by sensitizing tumors otherwise insensitive to anti-PD1 immunotherapy while reducing immune-related adverse events.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

et al. 2018

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“…Transferrin has also been used to target plasmids for tumor delivery. 18,[36][37][38] In order to identify a suitable cell line for preparing a mouse xenograft tumor model, the relative levels of transferrin uptake in three human carcinoma cell lines (A2780, HT-29 and HeLa) was determined (Fig. 5).…”

Section: Discussionmentioning

confidence: 99%

Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles

Pun

Tack

Bellocq

et al. 2004

Cancer Biology & Therapy

185

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“…Notably, transferrin incorporated into liposomes can substantially enhance efficiency of gene transfer mediated by the liposome. 29,30 Several groups, including our own, have used recombinant antibody fragments (Fab and ScFv ) as ligands in the design of targeted nonviral gene transfer vectors. 13,14,19 The bifunctional nonviral vector we previously reported is of human origin, but difficulty in large -scale isolation of the Fab protamine fusion proteins was felt to restrict its further development.…”

Section: Discussionmentioning

confidence: 99%

Single-chain antibody-mediated gene delivery into ErbB2-positive human breast cancer cells

Stuckert

Bosch

et al. 2001

Cancer Gene Ther

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Targeted gene transfer by nonviral vectors can be achieved through incorporation of specific ligand( s ) into the vectors. In this study, the effects of incorporation of an anti -ErbB2 single -chain antibody fragment ( ScFv ) into nonviral vectors for targeted gene delivery were investigated. The ML39 ScFv, selected from a human ScFv phage display library and affinity matured in vitro ( K d =1Â10 À 9 M ), was used as ligand specific for the extracellular domain of the tumor surface protein, ErbB2. Two approaches were taken: ( a ) development of a vector that is composed of a bifunctional fusion protein capable of binding DNA with the ErbB2 -specific ML39 ScFv at its N -terminus and a truncated form of human protamine at its C -terminus, and ( b ) formulation and evaluation of delivery vectors consisting of three independent components including ML39 ScFv, protamine, and cationic lipids. We demonstrate that fusion proteins comprised of the ML39 ScFv and a truncated form of protamine, denoted as ScFv -P -S, can selectively deliver exogenous DNA into ErbB2( + ) cells, with an 8 -to 10 -fold increase in expression levels of the luciferase reporter gene in ErbB2( + ) cells as compared to ErbB2( À ) cells. In addition, vectors formulated by appropriately mixing DNA, ScFv, protamine, and lipids in vitro could even more efficiently deliver the reporter gene into ErbB2( + ) cells with approximately 5 -fold increase in gene expression in ErbB2( + ) cell as compared to ErbB2( À ) cells. Expression and refolding of the ScFv fusion proteins, in addition to determination of optimal conditions for vector development using these approaches, are discussed.

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Transferrin-Liposome-Mediated Systemic p53 Gene Therapy in Combination with Radiation Results in Regression of Human Head and Neck Cancer Xenografts

Cited by 207 publications

References 25 publications

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Targeted delivery of RNA-cleaving DNA enzyme (DNAzyme) to tumor tissue by transferrin-modified, cyclodextrin-based particles

Single-chain antibody-mediated gene delivery into ErbB2-positive human breast cancer cells

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