Interferon‐γ Therapy: Evaluation of Routes of Administration and Delivery Systems

Younes, Husam M.; Amsden, Brian G.

doi:10.1002/jps.10007

Cited by 56 publications

(31 citation statements)

References 131 publications

(133 reference statements)

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“…Many attempts have been made to deliver IFNg to tumors using liposomes, polymer gels, microspheres and nanoparticles (32)(33)(34). In these approaches, however, cellselective targeting is lacking which might result in systemic side effects in long-term treatment.…”

Section: Discussionmentioning

confidence: 99%

Selective Targeting of Interferon γ to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth

Bansal

Tomar

Östman

et al. 2012

Molecular Cancer Therapeutics

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New approaches to block the function of tumor stromal cells such as cancer-associated fibroblasts and pericytes is an emerging field in cancer therapeutics as these cells play a crucial role in promoting angiogenesis and tumor growth via paracrine signals. Because of immunomodulatory and other antitumor activities, IFNg, a pleiotropic cytokine, has been used as an anticancer agent in clinical trials. Unfortunately only modest beneficial effects, but severe side effects, were seen. In this study, we delivered IFNg to stromal fibroblasts and pericytes, considering its direct antifibrotic activity, using our platelet-derived growth factor-beta receptor (PDGFbR)-binding carrier (pPB-HSA), as these cells abundantly express PDGFbR. We chemically conjugated IFNg to pPB-HSA using a heterobifunctional PEG linker. In vitro in NIH3T3 fibroblasts, pPB-HSA-IFNg conjugate activated IFNg-signaling (pSTAT1a) and inhibited their activation and migration. Furthermore, pPB-HSA-IFNg inhibited fibroblasts-induced tube formation of H5V endothelial cells. In vivo in B16 tumor-bearing mice, pPB-HSA-IFNg rapidly accumulated in tumor stroma and pericytes and significantly inhibited the tumor growth while untargeted IFNg and pPB-HSA carrier were ineffective. These antitumor effects of pPB-HSA-IFNg were attributed to the inhibition of tumor vascularization, as shown with a-SMA and CD-31 staining. Moreover, pPB-HSA-IFNg induced MHC-II expression specifically in tumors compared with untargeted IFNg, indicating the specificity of this approach. This study thus shows the impact of drug targeting to tumor stromal cells in cancer therapy as well as provides new opportunities to use cytokines for therapeutic application.

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Section: Discussionmentioning

confidence: 99%

Selective Targeting of Interferon γ to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth

Bansal

Tomar

Östman

et al. 2012

Molecular Cancer Therapeutics

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“…The strategy could protect the cytokine from rapid enzymatic degradation and clearance and then improve the activities of the cytokines at lower doses, which would allow their toxicity to be avoided (32). A gross body of evidence from previous reports has evidenced the benefits of targeting antimicrobial agents directly to macrophages through their association with lipidic or polymeric particles (2,16).…”

Section: Discussionmentioning

confidence: 99%

“…However, the therapeutic potential of IFN-␥ may be limited by its rapid clearance from the circulation and, thus, a brief duration of the activating effect on macrophages. This fact implies that frequent and high doses, which often result in severe systemic side effects, must be used (32).…”

mentioning

confidence: 99%

Gamma Interferon Loaded onto Albumin Nanoparticles: In Vitro and In Vivo Activities against Brucella abortus

Segura

Gamazo

Irache

et al. 2007

Antimicrob Agents Chemother

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The aim of this study was to evaluate the activity of gamma interferon (IFN-␥) when it was either adsorbed onto or loaded into albumin nanoparticles. Brucella abortus-infected macrophages and infected BALB/c mice were selected as the models for testing of the therapeutic potentials of these cytokine delivery systems, in view of the well-established role of IFN-␥-activated macrophages for the control of Brucella sp. infections. Whereas the encapsulation of IFN-␥ inside the matrix of nanoparticles completely abrogated its activity, adsorbed IFN-␥ increased by 0.75 log unit the bactericidal effect induced by RAW macrophages activated with free IFN-␥, along with a higher level of production of nitric oxide. In infected BALB/c-mice, IFN-␥ adsorbed onto nanoparticles was also more active than free cytokine in reducing the number of bacteria in the spleens, and the effect was mediated by an increased ratio of IFN-␥-secreting (Th1) to interleukin-4-secreting (Th2) cells. Overall, albumin nanoparticles would be suitable as carriers that target IFN-␥ to macrophages and, thus, potentiate their therapeutic activity.

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“…Being aware of their respectively short half-life in vivo, [28][29][30] we were interested to examine their potential role in the initiation of a systemic antitumor immune response after immunization. Therefore, the pharmacokinetics for both cytokines after i.p.…”

Section: Increased Serum Concentrations Of Both Gm-csf and Ifnc Aftermentioning

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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Interferon‐γ Therapy: Evaluation of Routes of Administration and Delivery Systems

Cited by 56 publications

References 131 publications

Selective Targeting of Interferon γ to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth

Selective Targeting of Interferon γ to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth

Gamma Interferon Loaded onto Albumin Nanoparticles: In Vitro and In Vivo Activities against Brucella abortus

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

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Interferon‐γ Therapy: Evaluation of Routes of Administration and Delivery Systems

Cited by 56 publications

References 131 publications

Selective Targeting of Interferon γ to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth

Selective Targeting of Interferon γ to Stromal Fibroblasts and Pericytes as a Novel Therapeutic Approach to Inhibit Angiogenesis and Tumor Growth

Gamma Interferon Loaded onto Albumin Nanoparticles: In Vitro and In Vivo Activities against Brucella abortus

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

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Product

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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