GM-CSF and B7-1 (CD80) co-stimulatory signals co-operate in the induction of effective anti-tumor immunity in syngeneic mice

Sumimoto, Hidetoshi; Tani, Kenzaburo; Nakazaki, Yukoh; Tanabe, Tsuyoshi; Hibino, Hironori; Hamada, Hirofumi; Azuma, Miyuki; Asano, Shigetaka

doi:10.1002/(sici)1097-0215(19971114)73:4<556::aid-ijc17>3.0.co;2-7

Cited by 24 publications

(5 citation statements)

References 15 publications

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“…29 Thus, vaccination with irradiated GM-CSF secreting tumor cells generates the potent, specific, and long-lasting cellular and humoral immunity in several murine cancer models, including the LLC. 13 In our present studies, GM-CSF-transduced tumor vaccine elicits T-dependent and tumor-specific cellular immunity against lung cancers. However, tumor-specific IgG antibodies are not induced by LLC-1/ GM-CSF vaccine, but induced by LLC-1/FasL/GM-CSF (Fig.…”

Section: Discussionmentioning

confidence: 67%

“…11 GM-CSF-based cancer cell vaccines have been shown to be potent inducers of antitumor immunity in several murine tumor models. [12][13][14][15] Vaccination of C57BL/6 mice with irradiated GM-CSF-transduced Lewis lung carcinoma (LLC) cells inhibited growth of LLC-1 cells in subsequent challenge. 16 Nevertheless, the antitumor effect of GM-CSF on established LLC-1 tumors is limited.…”

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confidence: 99%

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Combination of Fasl and GM‐CSF confers synergistic antitumor immunity in an in vivo model of the murine Lewis lung carcinoma

Ho¹,

Sun²,

Leu³

et al. 2008

Intl Journal of Cancer

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Gene transfer of Fas ligand (FasL) to tumor cells has been demonstrated to inhibit tumor growth in vivo, and neutrophils are primarily responsible for this immunoprotection. The granulocyte–macrophage colony stimulating factor (GM‐CSF) secreted by tumor vaccine can recruit dendritic cells (DCs) for efficient antigen presentation to T cells that generate the tumor‐specific response. To investigate whether the combination of FasL and GM‐CSF can efficiently suppress tumor growth, we have established Lewis lung carcinoma (LLC‐1) cells that are transduced with GM‐CSF (LLC/GM‐CSF), FasL (LLC/FasL) or both genes (LLC/FasL/GM‐CSF) to test their tumorigenic potential in vivo. Mice inoculated with LLC/GM‐CSF display high survival rates along with reduction of tumor growth. In contrast, none of the mice injected with LLC/FasL or LLC/FasL/GM‐CSF develop tumors. Specific memory immune response and delayed LLC‐1 tumor growth are found in mice immunized with LLC‐1/FasL or LLC‐1/FasL/GM‐CSF. Furthermore, therapeutic effects are observed only when LLC‐1/FasL/GM‐CSF tumor vaccine is employed to retard growth of preexisting LLC‐1 tumors. Tumor growth is also completely suppressed in mice injected with a mixture of LLC‐1 and LLC‐1/FasL/GM‐CSF. In addition, IL‐12 production, cytotoxic T‐cell activity and IgG against LLC‐1 are manifested in mice injected with LLC/FasL/GM‐CSF. Our data show that FasL‐induced pathway triggers expression of proinflammatory cytokines, including IL‐1β, IL‐6, MIP‐2 and MCP‐1, while GM‐CSF‐dependent pathway promotes functional maturation and activation of DCs. Taken together, the results indicate that dual gene‐based delivery with FasL and GM‐CSF may serve as a more effective tumor vaccine to suppress lung cancer cell growth in vivo. © 2008 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

Combination of Fasl and GM‐CSF confers synergistic antitumor immunity in an in vivo model of the murine Lewis lung carcinoma

Ho¹,

Sun²,

Leu³

et al. 2008

Intl Journal of Cancer

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“…The activation of naive T cells depends on the costimulatory signal transduced by the engagement of CD80 on antigen-presenting cells (APCs) with CD28 on T cells that results in the production of IL-2, synthesis of high-affinity IL-2 receptor (IL-2R), and T cell proliferation (Allison and Krummel, 1995). Tumor cells genetically modified to express costimulatory molecules, therefore, have been shown to induce potent antitumor responses when used for cancer immunotherapy in preclinical and limited clinical studies (Sumimoto et al, 1997;Felzmann et al, 1999;Guinn et al, 1999;Antonia and Seigne, 2000;Mazzocchi et al, 2001;Wilcox et al, 2002;Antonia et al, 2004). In particular, the successful use of tumor cells genetically modified to express the costimulatory molecule CD80 for immunotherapy in preclinical studies (Sumimoto et al, 1997;Joki et al, 1999;Martin-Fontecha et al, 2000;Briones et al, 2003;Singh et al, 2003) has led to testing of this approach in several phase I and II clinical trials (Antonia and Seigne, 2000;Horig et al, 2000;Antonia et al, 2002Antonia et al, , 2004Dols et al, 2003;Raez et al, 2003Raez et al, , 2004.…”

Section: Introductionmentioning

confidence: 99%

Primary Tumor Cells Resected from Cancer Patients and Decorated with a Novel Form of CD80 Protein Serve as Effective Antigen-Presenting Cells for the Induction of Autologous T Cell Immune Responses Ex Vivo

Singh

Miller²,

Yolcu³

et al. 2006

Human Gene Therapy

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Vaccination with autologous tumor cells genetically modified to express costimulatory molecules has shown utility for cancer immunotherapy in preclinical and limited clinical settings. Given the complicated nature of gene therapy, a practical alternative approach has been designed that relies on modification of the cell membrane with biotin and its "decoration" with a chimeric protein composed of the functional portion of human CD80 and core streptavidin (CD80-SA). We tested whether primary tumor cells resected from cancer patients can be decorated with CD80-SA and whether such cells serve as antigen-presenting cells (APCs) to generate autologous T cell responses ex vivo. Tumors and peripheral blood lymphocytes (PBLs) were collected from 14 lung, 9 colon, and 2 breast "treatment-naive" cancer patients presenting various clinical stages of the disease. Tumors were mechanically processed, irradiated, decorated with CD80-SA or control streptavidin (SA) protein, and used as APCs in ex vivo autologous T cell-proliferative and cytotoxicity assays. All tumor samples were modified with CD80-SA, albeit with various degrees of decoration ranging from 21.8 to 100%. CD80- SA-decorated cells generated significant proliferative responses in autologous T cells from 9 of 16 evaluable patients (p < 0.05). Proliferative responses were CD80-SA specific and heterogeneous, with stimulation indices ranging from 0.25 to 45. In 15 of 15 evaluable patients, CD80-SA-specific cytotoxic T cell responses against autologous tumors were generated, 11 of which were significant, with specific killing ranging from 5 to 70%. Taken together, these data demonstrate that primary tumor cells can be effectively decorated with CD80-SA and that such cells serve as APCs to induce autologous antitumor T cell responses.

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“…CD80, however, has been used to stimulate immune responses to infections and tumors 18–21. Tumor cells genetically modified to express CD80 were shown to induce effective antitumor immune responses with therapeutic efficacy in various animal cancer models and limited clinical settings 19,22‐28…”

Section: Introductionmentioning

confidence: 99%

ProtEx™: A Novel Technology to Display Exogenous Proteins on the Cell Surface for Immunomodulation

Singh

2005

Annals of the New York Academy of Sciences

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Gene therapy as an immunomodulatory approach has the potential to treat various inherited and acquired immune-based human diseases. However, its clinical application has several challenges, varying from the efficiency of gene transfer, control of gene expression, cell and tissue targeting, and safety concerns associated with the introduction of exogenous DNA into cells/tissues. Gene therapy is also a time- and labor-intensive procedure. As an alternative, we recently developed a novel technology, ProtEx, that allows for rapid, efficient, and durable display of exogenous proteins on the surface of cells, tissues, and organs without detectable toxicity. This technology exploits the strong binding affinity (Kd = 10(-15) M) of streptavidin with biotin and involves generation of chimeric molecules composed of the extracellular portions of immunological proteins of interest and a modified form of streptavidin, biotinylation of biological surfaces, and decoration of the modified surface with chimeric proteins. Biotin persists on the cell surface for weeks both in vitro and in vivo, thereby providing a platform to display exogenous proteins with extended cell surface kinetics. Two chimeric proteins, rat FasL (SA-FasL) and human CD80 (CD80-SA), were generated and tested for cell surface display and immunomodulatory functions. SA-FasL and CD80-SA molecules persisted on the surface of various cell types for extended periods, varying from days to weeks in vitro and in vivo. The cell surface kinetics, however, were protein and cell type dependent. SA-FasL showed potent apoptotic activity against Fas+ cells as a soluble protein or displayed on the cell surface and effectively blocked alloreactive responses. The display of CD80-SA on the surface of tumor cells, however, converted them into antigen-presenting cells for effective stimulation of autologous and allogeneic T-cell responses. ProtEx technology, therefore, represents a practical and effective alternative to DNA-based gene therapy for immunomodulation.

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GM-CSF and B7-1 (CD80) co-stimulatory signals co-operate in the induction of effective anti-tumor immunity in syngeneic mice

Cited by 24 publications

References 15 publications

Combination of Fasl and GM‐CSF confers synergistic antitumor immunity in an in vivo model of the murine Lewis lung carcinoma

Combination of Fasl and GM‐CSF confers synergistic antitumor immunity in an in vivo model of the murine Lewis lung carcinoma

Primary Tumor Cells Resected from Cancer Patients and Decorated with a Novel Form of CD80 Protein Serve as Effective Antigen-Presenting Cells for the Induction of Autologous T Cell Immune Responses Ex Vivo

ProtEx™: A Novel Technology to Display Exogenous Proteins on the Cell Surface for Immunomodulation

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