Tricistronic viral vectors co-expressing interleukin-12 (IL-12) and CD80 (B7-1) for the immunotherapy of cancer: Preclinical studies in myeloma

Xiao Yan Wen, Saul Mandelbaum, Zhi H. Li, Mary Hitt, Frank L. Graham, Teresa S. Hawley, Robert G. Hawley, Alexander Keith Stewart

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Synergy between interleukin-12 (IL-12) and B7-1 (CD80) for cancer immunotherapy has previously been demonstrated in animal models of breast cancer, lymphoma, and multiple myeloma. With a view to human clinical application, tricistronic retroviral and adenovirus vectors co-expressing IL-12 (IL-12p40 plus IL-12p35) and CD80 were constructed by utilizing two internal ribosome entry site (IRES) sequences to link the three cDNAs. A murine stem cell virus (MSCV)-based retroviral vector (MSCV-hIL12.B7) utilized distinct IRES sequences from the encephalomyocarditis virus (EMCV) and the foot-and-mouth disease virus (FMCV), whereas Ad5-based adenovirus vectors contained transcriptional units with two EMCV IRES sequences under the control of murine (AdMh12.B7) or human (AdHh12.B7) cytomegalovirus promoters. AdMh12.B7 was found to consistently direct higher levels of IL-12 and CD80 expression than AdHh12.B7 following infection of a number of human tumor cell lines. In preclinical studies, the human myeloma cell line U266 was infected with MSCV-hIL12.B7 and a resulting clonal cell line, U/MSCV-h12.B7, was generated with stable expression of CD80 and secreting IL-12 at 1 ng/24 h/106 cells. By comparison, following AdMh12.B7 infection, 81% of infected U266 cells (U/AdMh12.B7) expressed CD80 and secreted IL-12 at 25-50 ng/24 h/106 cells. Both engineered myeloma cell lines stimulated enhanced allogeneic mixed lymphocyte proliferation and provoked increases in cytotoxic T-lymphocyte responses and γ-interferon release from normal donor lymphocytes exposed to parental U266 cells. These results suggest potential clinical utility of AdMh12.B7 in immunotherapy strategies for the treatment of multiple myeloma and other cancers.

Original languageEnglish (US)
Pages (from-to)361-370
Number of pages10
JournalCancer Gene Therapy
Volume8
Issue number5
DOIs
StatePublished - 2001
Externally publishedYes

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Interleukin-12
Immunotherapy
Stem Cells
Encephalomyocarditis virus
Viruses
Neoplasms
Multiple Myeloma
Adenoviridae
Cell Line
Interleukin-12 Subunit p35
Interleukin-12 Subunit p40
Lymphocytes
Foot-and-Mouth Disease Virus
Cytotoxic T-Lymphocytes
Infection
Tumor Cell Line
Cytomegalovirus
Interferons
Lymphoma
Animal Models

Keywords

  • Adenovirus and gene therapy
  • CD80
  • IL-12
  • Immunotherapy
  • Myeloma

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Tricistronic viral vectors co-expressing interleukin-12 (IL-12) and CD80 (B7-1) for the immunotherapy of cancer : Preclinical studies in myeloma. / Wen, Xiao Yan; Mandelbaum, Saul; Li, Zhi H.; Hitt, Mary; Graham, Frank L.; Hawley, Teresa S.; Hawley, Robert G.; Stewart, Alexander Keith.

In: Cancer Gene Therapy, Vol. 8, No. 5, 2001, p. 361-370.

Research output: Contribution to journalArticle

Wen, Xiao Yan ; Mandelbaum, Saul ; Li, Zhi H. ; Hitt, Mary ; Graham, Frank L. ; Hawley, Teresa S. ; Hawley, Robert G. ; Stewart, Alexander Keith. / Tricistronic viral vectors co-expressing interleukin-12 (IL-12) and CD80 (B7-1) for the immunotherapy of cancer : Preclinical studies in myeloma. In: Cancer Gene Therapy. 2001 ; Vol. 8, No. 5. pp. 361-370.
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abstract = "Synergy between interleukin-12 (IL-12) and B7-1 (CD80) for cancer immunotherapy has previously been demonstrated in animal models of breast cancer, lymphoma, and multiple myeloma. With a view to human clinical application, tricistronic retroviral and adenovirus vectors co-expressing IL-12 (IL-12p40 plus IL-12p35) and CD80 were constructed by utilizing two internal ribosome entry site (IRES) sequences to link the three cDNAs. A murine stem cell virus (MSCV)-based retroviral vector (MSCV-hIL12.B7) utilized distinct IRES sequences from the encephalomyocarditis virus (EMCV) and the foot-and-mouth disease virus (FMCV), whereas Ad5-based adenovirus vectors contained transcriptional units with two EMCV IRES sequences under the control of murine (AdMh12.B7) or human (AdHh12.B7) cytomegalovirus promoters. AdMh12.B7 was found to consistently direct higher levels of IL-12 and CD80 expression than AdHh12.B7 following infection of a number of human tumor cell lines. In preclinical studies, the human myeloma cell line U266 was infected with MSCV-hIL12.B7 and a resulting clonal cell line, U/MSCV-h12.B7, was generated with stable expression of CD80 and secreting IL-12 at 1 ng/24 h/106 cells. By comparison, following AdMh12.B7 infection, 81{\%} of infected U266 cells (U/AdMh12.B7) expressed CD80 and secreted IL-12 at 25-50 ng/24 h/106 cells. Both engineered myeloma cell lines stimulated enhanced allogeneic mixed lymphocyte proliferation and provoked increases in cytotoxic T-lymphocyte responses and γ-interferon release from normal donor lymphocytes exposed to parental U266 cells. These results suggest potential clinical utility of AdMh12.B7 in immunotherapy strategies for the treatment of multiple myeloma and other cancers.",
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AU - Hawley, Robert G.

AU - Stewart, Alexander Keith

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AB - Synergy between interleukin-12 (IL-12) and B7-1 (CD80) for cancer immunotherapy has previously been demonstrated in animal models of breast cancer, lymphoma, and multiple myeloma. With a view to human clinical application, tricistronic retroviral and adenovirus vectors co-expressing IL-12 (IL-12p40 plus IL-12p35) and CD80 were constructed by utilizing two internal ribosome entry site (IRES) sequences to link the three cDNAs. A murine stem cell virus (MSCV)-based retroviral vector (MSCV-hIL12.B7) utilized distinct IRES sequences from the encephalomyocarditis virus (EMCV) and the foot-and-mouth disease virus (FMCV), whereas Ad5-based adenovirus vectors contained transcriptional units with two EMCV IRES sequences under the control of murine (AdMh12.B7) or human (AdHh12.B7) cytomegalovirus promoters. AdMh12.B7 was found to consistently direct higher levels of IL-12 and CD80 expression than AdHh12.B7 following infection of a number of human tumor cell lines. In preclinical studies, the human myeloma cell line U266 was infected with MSCV-hIL12.B7 and a resulting clonal cell line, U/MSCV-h12.B7, was generated with stable expression of CD80 and secreting IL-12 at 1 ng/24 h/106 cells. By comparison, following AdMh12.B7 infection, 81% of infected U266 cells (U/AdMh12.B7) expressed CD80 and secreted IL-12 at 25-50 ng/24 h/106 cells. Both engineered myeloma cell lines stimulated enhanced allogeneic mixed lymphocyte proliferation and provoked increases in cytotoxic T-lymphocyte responses and γ-interferon release from normal donor lymphocytes exposed to parental U266 cells. These results suggest potential clinical utility of AdMh12.B7 in immunotherapy strategies for the treatment of multiple myeloma and other cancers.

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