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First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells

BACKGROUND: ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stro...

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Autores principales: Minev, Boris R., Lander, Elliot, Feller, John F., Berman, Mark, Greenwood, Bernadette M., Minev, Ivelina, Santidrian, Antonio F., Nguyen, Duong, Draganov, Dobrin, Killinc, Mehmet O., Vyalkova, Anna, Kesari, Santosh, McClay, Edward, Carabulea, Gabriel, Marincola, Francesco M., Butterfield, Lisa H., Szalay, Aladar A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699108/
https://www.ncbi.nlm.nih.gov/pubmed/31426803
http://dx.doi.org/10.1186/s12967-019-2011-3
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author Minev, Boris R.
Lander, Elliot
Feller, John F.
Berman, Mark
Greenwood, Bernadette M.
Minev, Ivelina
Santidrian, Antonio F.
Nguyen, Duong
Draganov, Dobrin
Killinc, Mehmet O.
Vyalkova, Anna
Kesari, Santosh
McClay, Edward
Carabulea, Gabriel
Marincola, Francesco M.
Butterfield, Lisa H.
Szalay, Aladar A.
author_facet Minev, Boris R.
Lander, Elliot
Feller, John F.
Berman, Mark
Greenwood, Bernadette M.
Minev, Ivelina
Santidrian, Antonio F.
Nguyen, Duong
Draganov, Dobrin
Killinc, Mehmet O.
Vyalkova, Anna
Kesari, Santosh
McClay, Edward
Carabulea, Gabriel
Marincola, Francesco M.
Butterfield, Lisa H.
Szalay, Aladar A.
author_sort Minev, Boris R.
collection PubMed
description BACKGROUND: ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML). METHODS: Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 10(6) plaque-forming units (PFU) to 1.8 × 10(7) PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment. RESULTS: No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days—an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients’ blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition. CONCLUSIONS: Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility. Trial registration Retrospectively registered (ISRCTN#10201650) on October 22, 2018.
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spelling pubmed-66991082019-08-26 First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells Minev, Boris R. Lander, Elliot Feller, John F. Berman, Mark Greenwood, Bernadette M. Minev, Ivelina Santidrian, Antonio F. Nguyen, Duong Draganov, Dobrin Killinc, Mehmet O. Vyalkova, Anna Kesari, Santosh McClay, Edward Carabulea, Gabriel Marincola, Francesco M. Butterfield, Lisa H. Szalay, Aladar A. J Transl Med Research BACKGROUND: ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML). METHODS: Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 10(6) plaque-forming units (PFU) to 1.8 × 10(7) PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment. RESULTS: No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days—an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients’ blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition. CONCLUSIONS: Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility. Trial registration Retrospectively registered (ISRCTN#10201650) on October 22, 2018. BioMed Central 2019-08-19 /pmc/articles/PMC6699108/ /pubmed/31426803 http://dx.doi.org/10.1186/s12967-019-2011-3 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Minev, Boris R.
Lander, Elliot
Feller, John F.
Berman, Mark
Greenwood, Bernadette M.
Minev, Ivelina
Santidrian, Antonio F.
Nguyen, Duong
Draganov, Dobrin
Killinc, Mehmet O.
Vyalkova, Anna
Kesari, Santosh
McClay, Edward
Carabulea, Gabriel
Marincola, Francesco M.
Butterfield, Lisa H.
Szalay, Aladar A.
First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells
title First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells
title_full First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells
title_fullStr First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells
title_full_unstemmed First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells
title_short First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells
title_sort first-in-human study of tk-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699108/
https://www.ncbi.nlm.nih.gov/pubmed/31426803
http://dx.doi.org/10.1186/s12967-019-2011-3
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