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Ryuya Yamanaka, Susan A. Zullo, Ryuichi Tanaka, Michael Blaese, and Kleanthis G. Xanthopoulos

Object. The aim of this study was to further investigate dendritic cell (DC)—based immunotherapy for malignant glioma to improve its therapeutic efficacy.

Methods. Dendritic cells were isolated from the bone marrow and pulsed with phosphate-buffered saline, tumor RNA, tumor lysate, Semliki Forest virus (SFV)-LacZ, SFV-mediated B16 complementary (c)DNA, or SFV-mediated 203 glioma cDNA, respectively, to treat mice bearing tumors of the 203 glioma cell line. The results indicated that preimmunization with DCs pulsed with the same type of cDNA as in the tumor by a self-replicating RNA vector (that is, SFV) protected mice from tumor challenge, and that therapeutic immunization prolonged the survival of mice with established tumors. The SFV induced apoptosis in DCs and their death facilitated the uptake of apoptotic cells by other DCs, thus providing a potential mechanism for enhanced immunogenicity.

Conclusions. Therapy with DCs that have been pulsed with SFV-mediated tumor cDNA may be an excellent procedure for the development of new cancer vaccines.

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Ryuya Yamanaka, Susan A. Zullo, Ryuichi Tanaka, Jay Ramsey, Michael Blaese, and Kleanthis G. Xanthopoulos

Object

The authors investigated immunogene therapy for malignant glioma to determine whether its therapeutic efficacy could be improved.

Methods

Four groups of 203-glioma–bearing mice were treated with injections of phosphate-buffered saline, Semliki Forest virus (SFV)–LacZ, retrovirus vector DFG–interleukin (IL)–12, and SFV-IL12, respectively.

The results indicated that therapeutic immunization with SFV-IL12 prolonged the survival of mice with established tumors. Semliki Forest virus induces apoptotic death to glioma cells, which facilitates the uptake of apoptotic cells by dendritic cells, providing a potential mechanism for enhanced immunogenicity.

Conclusions

Immunogene therapy with IL-12 via SFV may be an excellent candidate for the development of new cancer vaccines.

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Ryuya Yamanaka, Naoki Yajima, Naoto Tsuchiya, Junpei Honma, Ryuichi Tanaka, Jay Ramsey, Michael Blaese, and Kleanthis G. Xanthopoulos

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy.

Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored.

The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial.

Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

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Ryuya Yamanaka, Susan A. Zullo, Jay Ramsey, Naoki Yajima, Naoto Tsuchiya, Ryuichi Tanaka, Michael Blaese, and Kleanthis G. Xanthopoulos

Object. The authors evaluated dendritic cell (DC)—based immunotherapy for malignant brain tumor to improve its therapeutic efficacy.

Methods. Dendritic cells were isolated from bone marrow and pulsed with phosphate-buffered saline, Semliki Forest virus (SFV)—LacZ, retrovirus vector GCsap—interleukin (IL)-12, and SFV—IL-12, respectively, to treat mice bearing brain tumors of the B16 cell line. The results indicated that therapeutic immunization with DCs pulsed with SFV—IL-12 prolonged the survival of mice with established tumors. Semliki Forest virus induced apoptosis in DCs, which in turn facilitated the uptake of apoptotic cells by other DCs, thus providing a potential mechanism for enhanced immunogenicity.

Conclusions. Therapy with DCs that have been pulsed with SFV-mediated IL-12 may be an excellent step in the development of new cancer vaccines. Intratumorally injected DCs that have been transiently transduced with IL-12 do not require pulsing of a source of tumor antigens to induce tumor regression.

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Ryuya Yamanaka, Naoto Tsuchiya, Naoki Yajima, Junpei Honma, Hitoshi Hasegawa, Ryuichi Tanaka, Jay Ramsey, R. Michael Blaese, and Kleanthis G. Xanthopoulos

Object. The aim of this study was to investigate further immunogene treatment of malignant brain tumor to improve its therapeutic efficacy.

Methods. Intratumoral dendritic cells pulsed with Semliki Forest virus (SFV)—interleukin-18 (IL-18) and/or systemic IL-12 were injected into mice bearing the B16 brain tumor. To study the immune mechanisms involved in tumor regression, we monitored the growth of implanted B16 brain tumor cells in T cell—depleted mice and IFNγ-neutralized mice. To analyze the protective immunity created by tumor inoculation, B16 cells were injected into the left thighs of mice that had received an inoculation, and tumor growth was monitored.

The local delivery of dendritic cells pulsed with IL-18 bound by SFV combined with the systemic administration of IL-12 enhanced the induction of the T helper type 1 response from tumor-specific CD4+ and CD8+ T cells and natural killer cells as well as antitumor immunity. Interferon-γ is partly responsible for this IL-18—mediated antitumor immunity. Furthermore, the protective immunity is mediated mainly by CD8+ T cells.

Conclusions. Immunogene therapy that combines the local administration of dendritic cells pulsed with IL-18 bound by SFV and the systemic administration of IL-12 may be an excellent candidate for the development of a new treatment protocol. A self-replicating SFV system may therefore open a novel approach for the treatment of malignant brain tumor.