Effects of irradiated tumor vaccine and infusion of granulocyte-macrophage colony-stimulating factor and interleukin-12 on established gliomas in rats

Chen, Jin Cherng; Chen, Yun; Wu, Jiann Ming; Su, Yen‐Hao; Tai, Kuang-Yen; Tseng, Sheng Hong

doi:10.1007/s00262-005-0077-7

Cited by 8 publications

(8 citation statements)

References 43 publications

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“…High systemic concentration of GM-CSF, on the other hand, has been shown to induce immune suppression through the activation of myeloid suppressor cells, CD11c 1 /Gr1 1 . 25 To ensure continuous and prolonged GM-CSF secretion and also to avoid degradation of the cytokines, others have implanted miniosmotic pumps 5,12 or used GM-CSF modified with PEG. 8,26 However, our results show that a continuous or prolonged GM-CSF administration is not necessary for successful immunotherapy when combining both GM-CSF-transduced tumor cells and IFNg.…”

Section: Discussionmentioning

confidence: 99%

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Smith

Janelidze

Visse

et al. 2006

Intl Journal of Cancer

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Glioblastoma multiforme is the most common malignant primary brain tumor and also one of the most therapy-resistant tumors. Because of the dismal prognosis, various therapies modulating the immune system have been developed in experimental models. Previously, we have shown a 37-70% cure in a rat glioma model where rats were peripherally immunized with tumor cells producing IFNc. On the basis of these results, we wanted to investigate whether a combination of GM-CSF and IFNc could improve the therapeutic effect in a mouse glioma model, GL261 (GL-wt). Three biweekly intraperitoneal (i.p.) immunizations with irradiated GM-CSF-transduced GL261 cells (GL-GM) induced a 44% survival in mice with intracranial glioma. While treatment of GLwt and GL-GM with IFNc in vitro induced upregulation of MHC I and MHC II on the tumor cells, it could not enhance survival after immunization. However, immunizations with GL-GM combined with recombinant IFNc at the immunization site synergistically enhanced survival with a cure rate of 88%. Tumors from mice receiving only 1 immunization on Day 10 after tumor inoculation were sectioned on Day 20 for analysis of leukocyte infiltration. Tumor volume was reduced and the infiltration of macrophages was denser in mice immunized with GL-GM combined with IFNc compared with that of both wildtype and nonimmunized mice. To our knowledge, this is the first study to demonstrate a synergy between GM-CSF and IFNc in experimental immunotherapy of tumors, by substantially increasing survival as well as inducing a potent anti-tumor response after only 1 postponed immunization. ' 2006 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Smith

Janelidze

Visse

et al. 2006

Intl Journal of Cancer

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“…gliomas. 6 GM-CSF secreting cancer vaccines have shown promising results, both in experimental [7][8][9] as well as in clinical trials. 10,11 The immunological effect induced systemically by the peripheral administration of GM-CSF is due to an increase in maturation and migration of myeloid progenitor cells from the bone marrow to the site of immunization as well as to local draining lymph nodes.…”

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confidence: 99%

Cure of established GL261 mouse gliomas after combined immunotherapy with GM‐CSF and IFNγ is mediated by both CD8⁺ and CD4⁺ T‐cells

Smith

Fritzell

Badn

et al. 2008

Intl Journal of Cancer

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We were the first to demonstrate that combined immunotherapy with GM-CSF producing GL261 cells and recombinant IFNc of preestablished GL261 gliomas could cure 90% of immunized mice. To extend these findings and to uncover the underlying mechanisms, the ensuing experiments were undertaken. We hypothesized that immunizations combining both GM-CSF and IFNc systemically would increase the number of immature myeloid cells, which then would mature and differentiate into dendritic cells (DCs) and macrophages, thereby augmenting tumor antigen presentation and T-cell activation. Indeed, the combined therapy induced a systemic increase of both immature and mature myeloid cells but also an increase in T regulatory cells (T-regs). Cytotoxic anti-tumor responses, mirrored by an increase in Granzyme B-positive cells as well as IFNc-producing T-cells, were augmented after immunizations with GM-CSF and IFNc. We also show that the combined therapy induced a long-term memory with rejection of intracerebral (i.c.) rechallenges. Depletion of Tcells showed that both CD4 1 and CD8 1 T-cells were essential for the combined GM-CSF and IFNc effect. Finally, when immunizations were delayed until day 5 after tumor inoculation, only mice receiving immunotherapy with both GM-CSF and IFNc survived. We conclude that the addition of recombinant IFNc to immunizations with GM-CSF producing tumor cells increased the number of activated tumoricidal T-cells, which could eradicate established intracerebral tumors. These results clearly demonstrate that the combination of cytokines in immunotherapy of brain tumors have synergistic effects that have implications for clinical immunotherapy of human malignant brain tumors.

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“…Other methods implicate the isolation of a patient's own tumour cells by culture or the use of wellestablished glioma cell lines as a source of TAAs. In this regard, these whole tumour cell vaccines, either irradiated (Mahaley et al 1983), co-injected with adjuvants such as granulocyte monocyte colony stimulating factor (GM-CSF) (Borrello and Pardoll 2002;Menei et al 2002;Jean et al 2004;Chen et al 2006), fused with dendritic cells (Kikuchi et al 2001;Kikuchi et al 2004), genetically modified in vitro to increase their immunogenicity (Parney et al 1997;Okada et al 2001;Smith et al 2007;Ma et al 2008), or used in dendritic cell-based immunotherapy (Liau et al 2005;Zhang et al 2007), showed promising data in several animal experiments and clinical trials. The use of autologous tumour cells (ATC) or well-established glioma cell lines as tumour cell vaccines needs to cultivate these cells in vitro.…”

Section: Introductionmentioning

confidence: 96%

Human glioma cell culture: two FCS-free media could be recommended for clinical use in immunotherapy

Clavreul

Jean

Preisser

et al. 2009

In Vitro Cell.Dev.Biol.-Animal

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Immunotherapy, particularly active vaccination, may be developed as an effective and safe treatment modality for malignant gliomas, which continue to have a poor prognosis, despite advances in surgical techniques and adjuvant chemotherapy and radiotherapy. Since no glioma-specific tumor-associated antigens (TAAs) have been discovered, autologous tumor cells or well-established glioma cell lines could be used in future vaccination protocols to induce antitumour immunity against unknown TAAs. One obstacle for clinical use of these tumour cell vaccines is related to foetal calf serum (FCS). Efforts are currently being directed toward developing FCS-free media and serum-free alternatives to culture these cell vaccines. In this study, a medium containing human serum and one serum-free medium (UltraCulture), supplemented or not with epidermal growth factor, were tested on morphology, survival, DNA content and TAA expression of human glioma cell lines and glioma biopsy primary cultures. Their effects were compared on FCS-containing medium. Results show that, whatever the medium used, no significant variations in morphology and survival were observed. Furthermore, human serum-containing medium or UltraCulture preserved at early passage cultures the cell population of interest present in the biopsies before culture. In addition, the expression profile of eight TAAs was similar between these media. These data indicate that human serum-containing medium and UltraCulture serum-free medium could be promising candidates to produce tumour-cell vaccines.

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Effects of irradiated tumor vaccine and infusion of granulocyte-macrophage colony-stimulating factor and interleukin-12 on established gliomas in rats

Cited by 8 publications

References 43 publications

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Cure of established GL261 mouse gliomas after combined immunotherapy with GM‐CSF and IFNγ is mediated by both CD8⁺ and CD4⁺ T‐cells

Human glioma cell culture: two FCS-free media could be recommended for clinical use in immunotherapy

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Effects of irradiated tumor vaccine and infusion of granulocyte-macrophage colony-stimulating factor and interleukin-12 on established gliomas in rats

Cited by 8 publications

References 43 publications

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Synergism between GM–CSF and IFNγ: Enhanced immunotherapy in mice with glioma

Cure of established GL261 mouse gliomas after combined immunotherapy with GM‐CSF and IFNγ is mediated by both CD8+ and CD4+ T‐cells

Human glioma cell culture: two FCS-free media could be recommended for clinical use in immunotherapy

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Cure of established GL261 mouse gliomas after combined immunotherapy with GM‐CSF and IFNγ is mediated by both CD8⁺ and CD4⁺ T‐cells