Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor
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 checkpoi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2018-10-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2018.1484982 |
| _version_ | 1818203347192119296 |
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| author | Sang-Soo Kim Joe B. Harford Manish Moghe Antonina Rait Esther H. Chang |
| author_facet | Sang-Soo Kim Joe B. Harford Manish Moghe Antonina Rait Esther H. Chang |
| author_sort | Sang-Soo Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T03:23:54Z |
| format | Article |
| id | doaj.art-bb4300d60ed1479ba1938f754e3a5d91 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-12T03:23:54Z |
| publishDate | 2018-10-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-bb4300d60ed1479ba1938f754e3a5d912022-12-22T00:40:06ZengTaylor & Francis GroupOncoImmunology2162-402X2018-10-0171010.1080/2162402X.2018.14849821484982Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitorSang-Soo Kim0Joe B. Harford1Manish Moghe2Antonina Rait3Esther H. Chang4Georgetown University Medical CenterSynerGene Therapeutics, IncGeorgetown University Medical CenterGeorgetown University Medical CenterGeorgetown University Medical CenterThe 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.http://dx.doi.org/10.1080/2162402X.2018.1484982checkpoint inhibitorgene therapynanomedicinep53tumor-targeted delivery |
| spellingShingle | Sang-Soo Kim Joe B. Harford Manish Moghe Antonina Rait Esther H. Chang Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor OncoImmunology checkpoint inhibitor gene therapy nanomedicine p53 tumor-targeted delivery |
| title | Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor |
| title_full | Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor |
| title_fullStr | Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor |
| title_full_unstemmed | Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor |
| title_short | Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor |
| title_sort | combination with sgt 53 overcomes tumor resistance to a checkpoint inhibitor |
| topic | checkpoint inhibitor gene therapy nanomedicine p53 tumor-targeted delivery |
| url | http://dx.doi.org/10.1080/2162402X.2018.1484982 |
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