A GM-CSF/CD40L Producing Cell Augments Anti-tumor T Cell Responses

Dessureault, Sophie; Alsarraj, Marwan; McCarthy, Susan; Hunter, Terri B.; Noyes, David; Lee, David; Harkins, Jennifer; Seigne, John D.; Jennings, Ron; Antonia, Scott

doi:10.1016/j.jss.2004.11.036

Cited by 18 publications

(18 citation statements)

References 32 publications

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“…In a murine model, in vivo delivery of an activating anti-CD40 antibody has been reported to overcome the immunosuppressive mechanism of tumours and support specific T-cell priming [33]. Similarly, we have previously reported that a bystander cell line expressing CD40 ligand promotes a specific anti-tumour T-cell response in vitro [14]. CD40 ligand has also been shown to inhibit tumour-induced apoptosis of DC [34,35] as well as tumour-secreted IL-10-mediated abrogation of DC function [36].…”

Section: Discussionmentioning

confidence: 63%

“…The ligation of CD40 induces full maturation of DC, including the up-regulation of surface molecules requisite for the complete stimulation and activation of T cells [12,13]. Our laboratory has previously demonstrated that DC cultured with a bystander cell line engineered to express CD40 ligand display a mature phenotype and the bystander line promotes specific anti-tumour T-cell responses in vitro [14]. Based on this knowledge, we tested an agonist antibody specific for CD40 (CP-870,893) for its ability to promote anti-tumour immune responses through the DC activation.…”

Section: Introductionmentioning

confidence: 99%

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An Agonist Antibody Specific for CD40 Induces Dendritic Cell Maturation and Promotes Autologous Anti‐tumour T‐cell Responses in an In vitro Mixed Autologous Tumour Cell/Lymph Node Cell Model

et al. 2007

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CD40‐mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen‐presenting cells, namely dendritic cells (DC), by CD40L leads to maturation and up‐regulation of co‐stimulatory molecules B7.1 and B7.2 (CD80 and CD86). These molecules are requisite to subsequent antigen‐specific activation of T cells. T‐cell activation is a critical aspect of specific anti‐tumour immune responses that have become the focus of a variety of cancer immunotherapy approaches. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40, CP‐870,893, has been developed. A fully autologous mixed tumour cell/lymph node cell model was utilized to demonstrate that CP‐870,893 promotes the responsiveness of lymph node‐derived T cells to autologous tumour. Specifically, T cells from the tumour‐draining lymph nodes are not responsive to autologous tumour cells; however, in the presence of CP‐870,893, this unresponsiveness is reversed, as indicated by lymph node cell proliferation and cytokine secretion. Monocyte‐derived DC treated with CP‐870,893 consistently display a mature phenotype: up‐regulation of CD80, CD83, CD86 and HLA‐DR expression, increased Mip1α and IL‐12 secretion, and the loss of exogenous antigen‐presenting capability subsequent to treatment with the antibody. These data indicate that CP‐870,893 binds to and activates DC, ultimately driving a specific anti‐tumour T‐cell response.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

An Agonist Antibody Specific for CD40 Induces Dendritic Cell Maturation and Promotes Autologous Anti‐tumour T‐cell Responses in an In vitro Mixed Autologous Tumour Cell/Lymph Node Cell Model

et al. 2007

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“…15,20 The combination of GM-CSF-based cancer vaccines with other immunostimulatory factors is under development in order to enhance the anti-tumor response induced by GM-CSF. Some of these factors include CD40L 21 or TLR-ligands e.g. CpG 22 that stimulate activation of dendritic cell (DC) or anti-cytotoxic T-cell (CTL)A4 that can inhibit the induction of immune suppression.…”

Section: Increased Numbers Of Cd11bmentioning

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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“…Owing to biosafety concerns, this genetic modification method is preferable over a retroviral infection approach because retroviral infection involves risks of development of competent recombinant retroviral particles in vivo. K562-hGM-CSF cells secreted approximately 3000 ng per 10 6 cells every 24 h, which is higher than previously reported values that range from 42 to 1403 ng per 10 6 cells every 24 h. 19,22,41,42,44,45,47 Although the GM-CSF threshold for an effective immunostimulation effect has been evaluated to be 36 ng per 10 6 cells every 24 h, 48 there are no clearly defined values reported for the site of cell injection. On the other hand, Serafini et al 49 reported that a high-dose of GM-CSF could impair the immune response through the recruitment of myeloid suppressor cells.…”

Section: Discussionmentioning

confidence: 59%

“…10,15,19,[21][22][23][41][42][43] The inability to obtain reproducible levels of the cytokine, and the labor-intensive requirements for individualized genetic engineering, led to the development of allogeneic bystander cells for the local delivery of GM-CSF, such as the K562 human erythroleukemia cell line. [44][45][46] However, despite their undetectable expression of human leukocyte antigen class I and II, the high sensitivity of allogeneic K562 cells to natural killer cytotoxicity prevented continuous release of the cytokine for several days. In this context, the encapsulation technology has the advantage of allowing a sustained release of the cytokine at the implantation site by the allogeneic cells being physically isolated from the host immune response.…”

Section: Discussionmentioning

confidence: 99%

Cell encapsulation technology as a novel strategy for human anti-tumor immunotherapy

et al. 2011

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant in autologous cell-based anti-tumor immunotherapy has recently been approved for clinical application. To avoid the need for individualized processing of autologous cells, we developed a novel strategy based on the encapsulation of GM-CSF-secreting human allogeneic cells. GM-CSF-producing K562 cells showed high, stable and reproducible cytokine secretion when enclosed into macrocapsules. For clinical development, the cryopreservation of these devices is critical. Thawing of capsules frozen at different time points displayed differences in GM-CSF release shortly after thawing. However, similar secretion values to those of non-frozen control capsules were obtained 8 days after thawing at a rate of >1000 ng GM-CSF per capsule every 24 h. For future human application, longer and reinforced capsules were designed. After irradiation and cryopreservation, these capsules produced >300 ng GM-CSF per capsule every 24 h 1 week after thawing. The in vivo implantation of encapsulated K562 cells was evaluated in mice and showed preserved cell survival. Finally, as a proof of principle of biological activity, capsules containing B16-GM-CSF allogeneic cells implanted in mice induced a prompt inflammatory reaction. The ability to reliably achieve high adjuvant release using a standardized procedure may lead to a new clinical application of GM-CSF in cell-based cancer immunization

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A GM-CSF/CD40L Producing Cell Augments Anti-tumor T Cell Responses

Cited by 18 publications

References 32 publications

An Agonist Antibody Specific for CD40 Induces Dendritic Cell Maturation and Promotes Autologous Anti‐tumour T‐cell Responses in an In vitro Mixed Autologous Tumour Cell/Lymph Node Cell Model

An Agonist Antibody Specific for CD40 Induces Dendritic Cell Maturation and Promotes Autologous Anti‐tumour T‐cell Responses in an In vitro Mixed Autologous Tumour Cell/Lymph Node Cell Model

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

Cell encapsulation technology as a novel strategy for human anti-tumor immunotherapy

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A GM-CSF/CD40L Producing Cell Augments Anti-tumor T Cell Responses

Cited by 18 publications

References 32 publications

An Agonist Antibody Specific for CD40 Induces Dendritic Cell Maturation and Promotes Autologous Anti‐tumour T‐cell Responses in an In vitro Mixed Autologous Tumour Cell/Lymph Node Cell Model

An Agonist Antibody Specific for CD40 Induces Dendritic Cell Maturation and Promotes Autologous Anti‐tumour T‐cell Responses in an In vitro Mixed Autologous Tumour Cell/Lymph Node Cell Model

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

Cell encapsulation technology as a novel strategy for human anti-tumor 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