Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model

Leah A. Mitchell, Fernando Lopez Espinoza, Daniel Mendoza, Yuki Kato, Akihito Inagaki, Kei Hiraoka, Noriyuki Kasahara, Harry E. Gruber, Douglas J. Jolly, Joan M. Robbins

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background. Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding an optimized yeast cytosine deaminase (CD). Tumor-selective expression of CD converts the prodrug, 5-fluorocytosine (5-FC), into the active chemotherapeutic, 5-fluorouracil (5-FU). This therapeutic approach is being tested in a randomized phase II/III trial in recurrent glioblastoma and anaplastic astrocytoma (NCT0241416). The aim of this study was to identify the immune cell subsets contributing to antitumor immune responses following treatment with 5-FC in Toca 511-expressing gliomas in a syngeneic mouse model. Methods. Flow cytometry was utilized to monitor and characterize the immune cell infiltrate in subcutaneous Tu-2449 gliomas in B6C3F1 mice treated with Toca 511 and 5-FC. Results. Tumor-bearing animals treated with Toca 511 and 5-FC display alterations in immune cell populations within the tumor that result in antitumor immune protection. Attenuated immune subsets were exclusive to immunosuppressive cells of myeloid origin. Depletion of immunosuppressive cells temporally preceded a second event which included expansion of T cells which were polarized away from Th2 and Th17 in the CD4+ T cell compartment with concomitant expansion of interferon gamma-expressing CD8+ T cells. Immune alterations correlated with clearance of Tu-2449 subcutaneous tumors and T cell-dependent protection from future tumor challenge. Conclusions. Treatment with Toca 511 and 5-FC has a concentrated effect at the site of the tumor which causes direct tumor cell death and alterations in immune cell infiltrate, resulting in a tumor microenvironment that is more permissive to establishment of a T cell mediated antitumor immune response.

Original languageEnglish (US)
Pages (from-to)930-939
Number of pages10
JournalNeuro-Oncology
Volume19
Issue number7
DOIs
StatePublished - Jul 1 2017

Fingerprint

Flucytosine
Prodrugs
Glioma
Immunity
T-Lymphocytes
Genes
Cytosine Deaminase
Neoplasms
Immunosuppressive Agents
Tumor Microenvironment
Cytoprotection
Astrocytoma
Myeloid Cells
Glioblastoma
Fluorouracil
Interferon-gamma
Flow Cytometry
Cell Death
Yeasts
Population

Keywords

  • 5-fluorouracil
  • cytosine deaminase
  • immunotherapy
  • myeloid-derived suppressor cell
  • retroviral gene transfer

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Mitchell, L. A., Lopez Espinoza, F., Mendoza, D., Kato, Y., Inagaki, A., Hiraoka, K., ... Robbins, J. M. (2017). Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. Neuro-Oncology, 19(7), 930-939. https://doi.org/10.1093/neuonc/nox037

Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. / Mitchell, Leah A.; Lopez Espinoza, Fernando; Mendoza, Daniel; Kato, Yuki; Inagaki, Akihito; Hiraoka, Kei; Kasahara, Noriyuki; Gruber, Harry E.; Jolly, Douglas J.; Robbins, Joan M.

In: Neuro-Oncology, Vol. 19, No. 7, 01.07.2017, p. 930-939.

Research output: Contribution to journalArticle

Mitchell, LA, Lopez Espinoza, F, Mendoza, D, Kato, Y, Inagaki, A, Hiraoka, K, Kasahara, N, Gruber, HE, Jolly, DJ & Robbins, JM 2017, 'Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model', Neuro-Oncology, vol. 19, no. 7, pp. 930-939. https://doi.org/10.1093/neuonc/nox037
Mitchell, Leah A. ; Lopez Espinoza, Fernando ; Mendoza, Daniel ; Kato, Yuki ; Inagaki, Akihito ; Hiraoka, Kei ; Kasahara, Noriyuki ; Gruber, Harry E. ; Jolly, Douglas J. ; Robbins, Joan M. / Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. In: Neuro-Oncology. 2017 ; Vol. 19, No. 7. pp. 930-939.
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abstract = "Background. Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding an optimized yeast cytosine deaminase (CD). Tumor-selective expression of CD converts the prodrug, 5-fluorocytosine (5-FC), into the active chemotherapeutic, 5-fluorouracil (5-FU). This therapeutic approach is being tested in a randomized phase II/III trial in recurrent glioblastoma and anaplastic astrocytoma (NCT0241416). The aim of this study was to identify the immune cell subsets contributing to antitumor immune responses following treatment with 5-FC in Toca 511-expressing gliomas in a syngeneic mouse model. Methods. Flow cytometry was utilized to monitor and characterize the immune cell infiltrate in subcutaneous Tu-2449 gliomas in B6C3F1 mice treated with Toca 511 and 5-FC. Results. Tumor-bearing animals treated with Toca 511 and 5-FC display alterations in immune cell populations within the tumor that result in antitumor immune protection. Attenuated immune subsets were exclusive to immunosuppressive cells of myeloid origin. Depletion of immunosuppressive cells temporally preceded a second event which included expansion of T cells which were polarized away from Th2 and Th17 in the CD4+ T cell compartment with concomitant expansion of interferon gamma-expressing CD8+ T cells. Immune alterations correlated with clearance of Tu-2449 subcutaneous tumors and T cell-dependent protection from future tumor challenge. Conclusions. Treatment with Toca 511 and 5-FC has a concentrated effect at the site of the tumor which causes direct tumor cell death and alterations in immune cell infiltrate, resulting in a tumor microenvironment that is more permissive to establishment of a T cell mediated antitumor immune response.",
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T1 - Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model

AU - Mitchell, Leah A.

AU - Lopez Espinoza, Fernando

AU - Mendoza, Daniel

AU - Kato, Yuki

AU - Inagaki, Akihito

AU - Hiraoka, Kei

AU - Kasahara, Noriyuki

AU - Gruber, Harry E.

AU - Jolly, Douglas J.

AU - Robbins, Joan M.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Background. Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding an optimized yeast cytosine deaminase (CD). Tumor-selective expression of CD converts the prodrug, 5-fluorocytosine (5-FC), into the active chemotherapeutic, 5-fluorouracil (5-FU). This therapeutic approach is being tested in a randomized phase II/III trial in recurrent glioblastoma and anaplastic astrocytoma (NCT0241416). The aim of this study was to identify the immune cell subsets contributing to antitumor immune responses following treatment with 5-FC in Toca 511-expressing gliomas in a syngeneic mouse model. Methods. Flow cytometry was utilized to monitor and characterize the immune cell infiltrate in subcutaneous Tu-2449 gliomas in B6C3F1 mice treated with Toca 511 and 5-FC. Results. Tumor-bearing animals treated with Toca 511 and 5-FC display alterations in immune cell populations within the tumor that result in antitumor immune protection. Attenuated immune subsets were exclusive to immunosuppressive cells of myeloid origin. Depletion of immunosuppressive cells temporally preceded a second event which included expansion of T cells which were polarized away from Th2 and Th17 in the CD4+ T cell compartment with concomitant expansion of interferon gamma-expressing CD8+ T cells. Immune alterations correlated with clearance of Tu-2449 subcutaneous tumors and T cell-dependent protection from future tumor challenge. Conclusions. Treatment with Toca 511 and 5-FC has a concentrated effect at the site of the tumor which causes direct tumor cell death and alterations in immune cell infiltrate, resulting in a tumor microenvironment that is more permissive to establishment of a T cell mediated antitumor immune response.

AB - Background. Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding an optimized yeast cytosine deaminase (CD). Tumor-selective expression of CD converts the prodrug, 5-fluorocytosine (5-FC), into the active chemotherapeutic, 5-fluorouracil (5-FU). This therapeutic approach is being tested in a randomized phase II/III trial in recurrent glioblastoma and anaplastic astrocytoma (NCT0241416). The aim of this study was to identify the immune cell subsets contributing to antitumor immune responses following treatment with 5-FC in Toca 511-expressing gliomas in a syngeneic mouse model. Methods. Flow cytometry was utilized to monitor and characterize the immune cell infiltrate in subcutaneous Tu-2449 gliomas in B6C3F1 mice treated with Toca 511 and 5-FC. Results. Tumor-bearing animals treated with Toca 511 and 5-FC display alterations in immune cell populations within the tumor that result in antitumor immune protection. Attenuated immune subsets were exclusive to immunosuppressive cells of myeloid origin. Depletion of immunosuppressive cells temporally preceded a second event which included expansion of T cells which were polarized away from Th2 and Th17 in the CD4+ T cell compartment with concomitant expansion of interferon gamma-expressing CD8+ T cells. Immune alterations correlated with clearance of Tu-2449 subcutaneous tumors and T cell-dependent protection from future tumor challenge. Conclusions. Treatment with Toca 511 and 5-FC has a concentrated effect at the site of the tumor which causes direct tumor cell death and alterations in immune cell infiltrate, resulting in a tumor microenvironment that is more permissive to establishment of a T cell mediated antitumor immune response.

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