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Your search keyword '"Kirn, David H."' showing total 23 results
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23 results on '"Kirn, David H."'

1. Oncolytic Vaccinia Virus Gene Modification and Cytokine Expression Effects on Tumor Infection, Immune Response, and Killing

Author

Inoue, Tomoyoshi, Byrne, Thomas, Inoue, Mitsuko, Tait, Madeline E, Wall, Patrick, Wang, Annabel, Dermyer, Michael R, Laklai, Hanane, Binder, Joseph J, Lees, Clare, Hollingsworth, Robert, Maruri-Avidal, Liliana, Kirn, David H, and McDonald, Donald M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Gene Therapy, Genetics, Rare Diseases, Vaccine Related, Infectious Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Infection, Animals, Apoptosis, CD8-Positive T-Lymphocytes, Cell Proliferation, Cytokines, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Immunity, Interleukin-2, Killer Cells, Natural, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neuroendocrine Tumors, Oncolytic Virotherapy, Pancreatic Neoplasms, Tumor Cells, Cultured, Vaccinia virus, Pharmacology and Pharmaceutical Sciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Oncolytic vaccinia viruses have promising efficacy and safety profiles in cancer therapy. Although antitumor activity can be increased by manipulating viral genes, the relative efficacy of individual modifications has been difficult to assess without side-by-side comparisons. This study sought to compare the initial antitumor activity after intravenous administration of five vaccinia virus variants of the same Western Reserve backbone and thymidine kinase gene deletion in RIP-Tag2 transgenic mice with spontaneous pancreatic neuroendocrine tumors. Tumors had focal regions of infection at 5 days after all viruses. Natural killer (NK) cells were restricted to these sites of infection, but CD8+ T cells and tumor cell apoptosis were widespread and varied among the viruses. Antitumor activity of virus VV-A34, bearing amino acid substitution A34K151E to increase viral spreading, and virus VV-IL2v, expressing a mouse IL2 variant (mIL2v) with attenuated IL2 receptor alpha subunit binding, was similar to control virus VV-GFP. However, antitumor activity was significantly greater after virus VV-A34/IL2v, which expressed mIL2v together with A34K151E mutation and viral B18R gene deletion, and virus VV-GMCSF that expressed mouse GM-CSF. Both viruses greatly increased expression of CD8 antigens Cd8a/Cd8b1 and cytotoxicity genes granzyme A, granzyme B, Fas ligand, and perforin-1 in tumors. VV-A34/IL2v led to higher serum IL2 and greater tumor expression of death receptor ligand TRAIL, but VV-GMCSF led to higher serum GM-CSF, greater expression of leukocyte chemokines and adhesion molecules, and more neutrophil recruitment. Together, the results show that antitumor activity is similarly increased by viral expression of GM-CSF or IL2v combined with additional genetic modifications.

Published
2021

2. Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies

Author

Salabarria, Stephanie M., Corti, Manuela, Coleman, Kirsten E., Wichman, Megan B., Berthy, Julie A., D'Souza, Precilla, Tifft, Cynthia J., Herzog, Roland W., Elder, Melissa E., Shoemaker, Lawrence R., Leon-Astudillo, Carmen, Tavakkoli, Fatemeh, Kirn, David H., Schwartz, Jonathan D., and Byrne, Barry J.

Subjects
Control, Identification and classification, Diagnosis, Care and treatment, Genetic aspects, Patient outcomes, Health aspects, Gene therapy -- Patient outcomes, Immune response -- Health aspects, Thrombocytopenic purpura -- Diagnosis -- Care and treatment -- Genetic aspects, Adenoviruses -- Identification and classification -- Control
Abstract

Introduction Adeno-associated virus-mediated (AAV-mediated) gene therapy has emerged as a promising treatment approach for a spectrum of monogenic genetic disorders (1-4). With the approval of the first recombinant AAV vector-based [...], BACKGROUND. Systemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome- like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity. METHODS. We describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation. RESULTS. Group 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation. CONCLUSIONS. This study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.

Published
2024
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3. Amplification of oncolytic vaccinia virus widespread tumor cell killing by sunitinib through multiple mechanisms

Author

Kim, Minah, Nitschké, Maximilian, Sennino, Barbara, Murer, Patrizia, Schriver, Brian J, Bell, Alexander, Subramanian, Aishwarya, McDonald, Corry E, Wang, Jiahu, Cha, Howard, Bourgeois-Daigneault, Marie-Claude, Kirn, David H, Bell, John C, De Silva, Naomi, Breitbach, Caroline J, and McDonald, Donald M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Rare Diseases, Digestive Diseases, Cancer, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Infection, Animals, Antineoplastic Agents, Humans, Mice, Mice, Transgenic, Oncolytic Virotherapy, Oncolytic Viruses, Sunitinib, Vaccinia virus, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors that developed spontaneously and progressed as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8+ T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multitargeted receptor tyrosine kinase inhibitor. These effects were not mimicked by selective inhibition of VEGFR2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells and greater influx of activated CD8+ T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8+ T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by coadministration of sunitinib.Significance: These findings reveal multiple unrecognized features of the antitumor properties of oncolytic vaccinia viruses, all of which can be amplified by the multitargeted kinase inhibitor sunitinib. Cancer Res; 78(4); 922-37. ©2017 AACR.

Published
2018

4. Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies

Author

Salabarria, Stephanie M., primary, Corti, Manuela, additional, Coleman, Kirsten E., additional, Wichman, Megan B., additional, Berthy, Julie A., additional, D'Souza, Precilla, additional, Tifft, Cynthia J., additional, Herzog, Roland W., additional, Elder, Melissa E., additional, Shoemaker, Lawrence R., additional, Leon-Astudillo, Carmen, additional, Tavakkoli, Fatemeh, additional, Kirn, David H., additional, Schwartz, Jonathan D., additional, and Byrne, Barry J., additional

Published
2023
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5. Supplemental methods from Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms

Author

Kim, Minah, primary, Nitschké, Maximilian, primary, Sennino, Barbara, primary, Murer, Patrizia, primary, Schriver, Brian J., primary, Bell, Alexander, primary, Subramanian, Aishwarya, primary, McDonald, Corry E., primary, Wang, Jiahu, primary, Cha, Howard, primary, Bourgeois-Daigneault, Marie-Claude, primary, Kirn, David H., primary, Bell, John C., primary, De Silva, Naomi, primary, Breitbach, Caroline J., primary, and McDonald, Donald M., primary

Published
2023
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6. Supplemental Figures 1-9 from Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms

Author

Kim, Minah, primary, Nitschké, Maximilian, primary, Sennino, Barbara, primary, Murer, Patrizia, primary, Schriver, Brian J., primary, Bell, Alexander, primary, Subramanian, Aishwarya, primary, McDonald, Corry E., primary, Wang, Jiahu, primary, Cha, Howard, primary, Bourgeois-Daigneault, Marie-Claude, primary, Kirn, David H., primary, Bell, John C., primary, De Silva, Naomi, primary, Breitbach, Caroline J., primary, and McDonald, Donald M., primary

Published
2023
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7. Data from Amplification of Oncolytic Vaccinia Virus Widespread Tumor Cell Killing by Sunitinib through Multiple Mechanisms

Author

Kim, Minah, primary, Nitschké, Maximilian, primary, Sennino, Barbara, primary, Murer, Patrizia, primary, Schriver, Brian J., primary, Bell, Alexander, primary, Subramanian, Aishwarya, primary, McDonald, Corry E., primary, Wang, Jiahu, primary, Cha, Howard, primary, Bourgeois-Daigneault, Marie-Claude, primary, Kirn, David H., primary, Bell, John C., primary, De Silva, Naomi, primary, Breitbach, Caroline J., primary, and McDonald, Donald M., primary

Published
2023
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8. Supplementary Figure 3 from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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9. Supplementary Methods from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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10. Data from Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

Author

Tai, Lee-Hwa, primary, de Souza, Christiano Tanese, primary, Bélanger, Simon, primary, Ly, Lundi, primary, Alkayyal, Almohanad A., primary, Zhang, Jiqing, primary, Rintoul, Julia L., primary, Ananth, Abhirami A., primary, Lam, Tiffany, primary, Breitbach, Caroline J., primary, Falls, Theresa J., primary, Kirn, David H., primary, Bell, John C., primary, Makrigiannis, Andrew P., primary, and Auer, Rebecca A., primary

Published
2023
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11. Supplementary Figure 1 from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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12. Supplementary Figure 4 from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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13. Supplementary Table 1 from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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14. Supplementary Figure 1 from Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

Author

Tai, Lee-Hwa, primary, de Souza, Christiano Tanese, primary, Bélanger, Simon, primary, Ly, Lundi, primary, Alkayyal, Almohanad A., primary, Zhang, Jiqing, primary, Rintoul, Julia L., primary, Ananth, Abhirami A., primary, Lam, Tiffany, primary, Breitbach, Caroline J., primary, Falls, Theresa J., primary, Kirn, David H., primary, Bell, John C., primary, Makrigiannis, Andrew P., primary, and Auer, Rebecca A., primary

Published
2023
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15. Supplementary Figure Legend from Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

Author

Tai, Lee-Hwa, primary, de Souza, Christiano Tanese, primary, Bélanger, Simon, primary, Ly, Lundi, primary, Alkayyal, Almohanad A., primary, Zhang, Jiqing, primary, Rintoul, Julia L., primary, Ananth, Abhirami A., primary, Lam, Tiffany, primary, Breitbach, Caroline J., primary, Falls, Theresa J., primary, Kirn, David H., primary, Bell, John C., primary, Makrigiannis, Andrew P., primary, and Auer, Rebecca A., primary

Published
2023
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16. Supplementary Figure 2 from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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17. Data from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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18. Supplementary Video 2 from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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19. Supplementary Video 1 from Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Author

Breitbach, Caroline J., primary, Arulanandam, Rozanne, primary, De Silva, Naomi, primary, Thorne, Steve H., primary, Patt, Richard, primary, Daneshmand, Manijeh, primary, Moon, Anne, primary, Ilkow, Carolina, primary, Burke, James, primary, Hwang, Tae-Ho, primary, Heo, Jeong, primary, Cho, Mong, primary, Chen, Hannah, primary, Angarita, Fernando A., primary, Addison, Christina, primary, McCart, J. Andrea, primary, Bell, John C., primary, and Kirn, David H., primary

Published
2023
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20. VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection

Author

Arulanandam, Rozanne, Batenchuk, Cory, Angarita, Fernando A., Ottolino-Perry, Kathryn, Cousineau, Sophie, Mottashed, Amelia, Burgess, Emma, Falls, Theresa J., De Silva, Naomi, Tsang, Jovian, Howe, Grant A., Bourgeois-Daigneault, Marie-Claude, Conrad, David P., Daneshmand, Manijeh, Breitbach, Caroline J., Kirn, David H., Raptis, Leda, Sad, Subash, Atkins, Harold, Huh, Michael S., Diallo, Jean-Simon, Lichty, Brian D., Ilkow, Carolina S., Le Boeuf, Fabrice, Addison, Christina L., McCart, J. Andrea, and Bell, John C.

Published
2015
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