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Retargeting Oncolytic Vesicular Stomatitis Virus to Human T-Cell Lymphotropic Virus Type 1-Associated Adult T-Cell Leukemia.

Betancourt D, Ramos JC, Barber GN - J. Virol. (2015)

Bottom Line: VSV-gp160G was further noted to be highly attenuated and did not replicate efficiently in or induce significant cell death of primary CD4(+) T cells.Importantly, VSV-gp160G effectively exerted potent oncolytic activity in patient-derived ATL transplanted into NSG mice and facilitated a significant survival benefit.This effect greatly reduced neurotoxic risk associated with VSV infection while still allowing VSV to effectively target ATL cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.

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VSV-gp160G is nonpathogenic within immunodeficient NSG mice and mediates tumor burden relief in ATL bearing hosts. (A) Survival curve of NSG mice (n = 7) inoculated with various doses of VSV-gp160G, VSV-XN2, or heat-inactivated VSV-XN2. VSV vectors were prepared in PBS and delivered intranasally to anesthetized NSG mice. (B) Survival curve of NSG (n = 7) mice were inoculated with 4 × 105 TLO-m1-luc i.p. on day 0 and treated with two injections of VSV-gp160G with 2 × 106 PFU on day 3 and 1 × 107 PFU on day18 (*, P = 0.039, log-rank test). (C) Control or VSV-gp160G-treated mice from panel B were anesthetized and injected with a luciferin substrate i.p., and the uciferase activity was detected on days 3, 7, 15, and 22 using IVIS. The average flux (p/s) emitted is an indicator of tumor burden and was quantified using Living Image software (*, P = 0.014; Student t test two tailed, equal variance). (D) Representative images acquired on day 30 of the experiment when statistical significance was achieved. (E) Numbers of NSG mice inoculated with TLO-m1-luc that developed luciferase activity in areas other than the primary injection site, indicative of significant metastasis. (F) The luciferase activity detected in the metastatic lesions for each group was quantified using Living Image software with control mice (n = 7) and VSV-gp160G-treated mice (n = 3).
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Figure 6: VSV-gp160G is nonpathogenic within immunodeficient NSG mice and mediates tumor burden relief in ATL bearing hosts. (A) Survival curve of NSG mice (n = 7) inoculated with various doses of VSV-gp160G, VSV-XN2, or heat-inactivated VSV-XN2. VSV vectors were prepared in PBS and delivered intranasally to anesthetized NSG mice. (B) Survival curve of NSG (n = 7) mice were inoculated with 4 × 105 TLO-m1-luc i.p. on day 0 and treated with two injections of VSV-gp160G with 2 × 106 PFU on day 3 and 1 × 107 PFU on day18 (*, P = 0.039, log-rank test). (C) Control or VSV-gp160G-treated mice from panel B were anesthetized and injected with a luciferin substrate i.p., and the uciferase activity was detected on days 3, 7, 15, and 22 using IVIS. The average flux (p/s) emitted is an indicator of tumor burden and was quantified using Living Image software (*, P = 0.014; Student t test two tailed, equal variance). (D) Representative images acquired on day 30 of the experiment when statistical significance was achieved. (E) Numbers of NSG mice inoculated with TLO-m1-luc that developed luciferase activity in areas other than the primary injection site, indicative of significant metastasis. (F) The luciferase activity detected in the metastatic lesions for each group was quantified using Living Image software with control mice (n = 7) and VSV-gp160G-treated mice (n = 3).

Mentions: To evaluate the safety of VSV-gp160G in immunocompromised hosts, we performed preliminary toxicity assays using NSG (NOD/Shi-scid, IL-2Rγ-c-) mice. NSG mice are severely immunocompromised, lacking mature T cells, B cells, and functional NK cells. They are also deficient in cytokine signaling. All of which makes them both highly susceptible to VSV infection and excellent recipients for engraftment of human cells. NSG animals (n = 7) were inoculated intranasally with either 3 × 105 PFU of VSV-gp160G or with 1 × 103 or 3 × 105 PFU of VSV-XN2. We observed that NSG mice inoculated with VSV-XN2 at the higher dose succumbed rapidly to neurotoxicity, while the lower dose resulted in ca. 60% survival. In contrast, mice inoculated with VSV-gp160G did not experience any symptoms, and there were no mortalities (Fig. 6A).


Retargeting Oncolytic Vesicular Stomatitis Virus to Human T-Cell Lymphotropic Virus Type 1-Associated Adult T-Cell Leukemia.

Betancourt D, Ramos JC, Barber GN - J. Virol. (2015)

VSV-gp160G is nonpathogenic within immunodeficient NSG mice and mediates tumor burden relief in ATL bearing hosts. (A) Survival curve of NSG mice (n = 7) inoculated with various doses of VSV-gp160G, VSV-XN2, or heat-inactivated VSV-XN2. VSV vectors were prepared in PBS and delivered intranasally to anesthetized NSG mice. (B) Survival curve of NSG (n = 7) mice were inoculated with 4 × 105 TLO-m1-luc i.p. on day 0 and treated with two injections of VSV-gp160G with 2 × 106 PFU on day 3 and 1 × 107 PFU on day18 (*, P = 0.039, log-rank test). (C) Control or VSV-gp160G-treated mice from panel B were anesthetized and injected with a luciferin substrate i.p., and the uciferase activity was detected on days 3, 7, 15, and 22 using IVIS. The average flux (p/s) emitted is an indicator of tumor burden and was quantified using Living Image software (*, P = 0.014; Student t test two tailed, equal variance). (D) Representative images acquired on day 30 of the experiment when statistical significance was achieved. (E) Numbers of NSG mice inoculated with TLO-m1-luc that developed luciferase activity in areas other than the primary injection site, indicative of significant metastasis. (F) The luciferase activity detected in the metastatic lesions for each group was quantified using Living Image software with control mice (n = 7) and VSV-gp160G-treated mice (n = 3).
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Related In: Results  -  Collection

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Figure 6: VSV-gp160G is nonpathogenic within immunodeficient NSG mice and mediates tumor burden relief in ATL bearing hosts. (A) Survival curve of NSG mice (n = 7) inoculated with various doses of VSV-gp160G, VSV-XN2, or heat-inactivated VSV-XN2. VSV vectors were prepared in PBS and delivered intranasally to anesthetized NSG mice. (B) Survival curve of NSG (n = 7) mice were inoculated with 4 × 105 TLO-m1-luc i.p. on day 0 and treated with two injections of VSV-gp160G with 2 × 106 PFU on day 3 and 1 × 107 PFU on day18 (*, P = 0.039, log-rank test). (C) Control or VSV-gp160G-treated mice from panel B were anesthetized and injected with a luciferin substrate i.p., and the uciferase activity was detected on days 3, 7, 15, and 22 using IVIS. The average flux (p/s) emitted is an indicator of tumor burden and was quantified using Living Image software (*, P = 0.014; Student t test two tailed, equal variance). (D) Representative images acquired on day 30 of the experiment when statistical significance was achieved. (E) Numbers of NSG mice inoculated with TLO-m1-luc that developed luciferase activity in areas other than the primary injection site, indicative of significant metastasis. (F) The luciferase activity detected in the metastatic lesions for each group was quantified using Living Image software with control mice (n = 7) and VSV-gp160G-treated mice (n = 3).
Mentions: To evaluate the safety of VSV-gp160G in immunocompromised hosts, we performed preliminary toxicity assays using NSG (NOD/Shi-scid, IL-2Rγ-c-) mice. NSG mice are severely immunocompromised, lacking mature T cells, B cells, and functional NK cells. They are also deficient in cytokine signaling. All of which makes them both highly susceptible to VSV infection and excellent recipients for engraftment of human cells. NSG animals (n = 7) were inoculated intranasally with either 3 × 105 PFU of VSV-gp160G or with 1 × 103 or 3 × 105 PFU of VSV-XN2. We observed that NSG mice inoculated with VSV-XN2 at the higher dose succumbed rapidly to neurotoxicity, while the lower dose resulted in ca. 60% survival. In contrast, mice inoculated with VSV-gp160G did not experience any symptoms, and there were no mortalities (Fig. 6A).

Bottom Line: VSV-gp160G was further noted to be highly attenuated and did not replicate efficiently in or induce significant cell death of primary CD4(+) T cells.Importantly, VSV-gp160G effectively exerted potent oncolytic activity in patient-derived ATL transplanted into NSG mice and facilitated a significant survival benefit.This effect greatly reduced neurotoxic risk associated with VSV infection while still allowing VSV to effectively target ATL cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.

Show MeSH
Related in: MedlinePlus