Preclinical Safety Evaluation of Recombinant Human Interleukin-10

Rosenblum, Ira; Johnson, Rebecca; Schmahai, Theodore J.

doi:10.1006/rtph.2001.1504

Cited by 32 publications

(34 citation statements)

References 20 publications

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“…Functional mechanisms investigated include activation of natural killer (NK) cells (17) that have been associated with tumor clearance in murine models of breast and colorectal cancer (18); inhibition of angiogenesis; enhancement of macrophage infiltration into tumors (19); and prevention of metastasis by inhibition of matrix metalloproteinase-2 (20). A number of preclinical (21) and clinical trials have consistently demonstrated safety of IL10 administration in treatment of diseases, including psoriasis (22), Crohn disease (23), and chronic hepatitis C infection (24), which make a strong case for its use as a therapeutic modality in cancer. IL10 has been reported to enhance the therapeutic effectiveness of a vaccinia virus-based vaccine against murine cancer cells (25), which may be connected to its ability to enhance the growth and proliferation of T cells (26) or its role as a chemotactic agent for CD8 þ T cells.…”

Section: Introductionmentioning

confidence: 99%

A Vaccinia Virus Armed with Interleukin-10 Is a Promising Therapeutic Agent for Treatment of Murine Pancreatic Cancer

Chard

Maniati

Wang

et al. 2015

Clinical Cancer Research

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Purpose: Vaccinia virus has strong potential as a novel therapeutic agent for treatment of pancreatic cancer. We investigated whether arming vaccinia virus with interleukin-10 (IL10) could enhance the antitumor efficacy with the view that IL10 might dampen the host immunity to the virus, increasing viral persistence, thus maximizing the oncolytic effect and antitumor immunity associated with vaccinia virus.Experimental Design: The antitumor efficacy of IL10-armed vaccinia virus (VVLDTK-IL10) and control VVDTK was assessed in pancreatic cancer cell lines, mice bearing subcutaneous pancreatic cancer tumors and a pancreatic cancer transgenic mouse model. Viral persistence within the tumors was examined and immune depletion experiments as well as immunophenotyping of splenocytes were carried out to dissect the functional mechanisms associated with the viral efficacy.Results: Compared with unarmed VVLDTK, VVLDTK-IL10 had a similar level of cytotoxicity and replication in vitro in murine pancreatic cancer cell lines, but rendered a superior antitumor efficacy in the subcutaneous pancreatic cancer model and a K-ras-p53 mutant-transgenic pancreatic cancer model after systemic delivery, with induction of long-term antitumor immunity. The antitumor efficacy of VVLDTK-IL10 was dependent on CD4 þ and CD8 þ , but not NK cells. Clearance of VVLDTK-IL10 was reduced at early time points compared with the control virus. Treatment with VVLDTK-IL10 resulted in a reduction in virus-specific, but not tumor-specific CD8 þ cells compared with VVLDTK. Conclusions: These results suggest that VVLDTK-IL10 has strong potential as an antitumor therapeutic for pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

A Vaccinia Virus Armed with Interleukin-10 Is a Promising Therapeutic Agent for Treatment of Murine Pancreatic Cancer

Chard

Maniati

Wang

et al. 2015

Clinical Cancer Research

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“…[8][9][10][11][12] However, these effects have not yet been established in vivo and it remains to be seen whether targeting of the CD40 molecule and stimulation with IL-4 and IL-10 are tolerated and therapeutically effective in humans. 13,14 Immunomodulatory intervention with low doses of IL-2 has shown promise in vivo, despite insufficient evidence and proof of safety to support its routine use. [15][16][17][18] Human interleukin-21 (IL-21) is a 4-helix-bundle cytokine of the ␥ c family that is expressed exclusively by activated CD4 ϩ T cells, including the recently discovered Th17 cells.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency

Borte

Pan‐Hammarström

Liu

et al. 2009

Blood

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“…It has been shown that the rate of elimination of IL-10 is inversely proportional to circulating [IL10](t) [51]. This phenomenon is captured by a down-regulating function, f DN IL10IL10 (t), coupled with the parameter d IL10 , as shown in Equation (22).…”

Section: Mathematical Model Of Acute Inflammationmentioning

confidence: 99%

“…This was achieved by introducing the down-regulating function, f DN IL10IL10 (Equation (24)). The down-regulation in the model is physiologically motivated by studies showing that elevated levels of [IL10] reduce its own rate of elimination from the blood stream [51]. An alternate version of Equation (22) without the f DN IL10IL10 function can be written as (AV-6):…”

Section: Appendix A2 Model Selection Comparisonsmentioning

confidence: 99%

Modeling and Hemofiltration Treatment of Acute Inflammation

et al. 2016

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Abstract:The body responds to endotoxins by triggering the acute inflammatory response system to eliminate the threat posed by gram-negative bacteria (endotoxin) and restore health. However, an uncontrolled inflammatory response can lead to tissue damage, organ failure, and ultimately death; this is clinically known as sepsis. Mathematical models of acute inflammatory disease have the potential to guide treatment decisions in critically ill patients. In this work, an 8-state (8-D) differential equation model of the acute inflammatory response system to endotoxin challenge was developed. Endotoxin challenges at 3 and 12 mg/kg were administered to rats, and dynamic cytokine data for interleukin (IL)-6, tumor necrosis factor (TNF), and IL-10 were obtained and used to calibrate the model. Evaluation of competing model structures was performed by analyzing model predictions at 3, 6, and 12 mg/kg endotoxin challenges with respect to experimental data from rats. Subsequently, a model predictive control (MPC) algorithm was synthesized to control a hemoadsorption (HA) device, a blood purification treatment for acute inflammation. A particle filter (PF) algorithm was implemented to estimate the full state vector of the endotoxemic rat based on time series cytokine measurements. Treatment simulations show that: (i) the apparent primary mechanism of HA efficacy is white blood cell (WBC) capture, with cytokine capture a secondary benefit; and (ii) differential

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Preclinical Safety Evaluation of Recombinant Human Interleukin-10

Cited by 32 publications

References 20 publications

A Vaccinia Virus Armed with Interleukin-10 Is a Promising Therapeutic Agent for Treatment of Murine Pancreatic Cancer

A Vaccinia Virus Armed with Interleukin-10 Is a Promising Therapeutic Agent for Treatment of Murine Pancreatic Cancer

Interleukin-21 restores immunoglobulin production ex vivo in patients with common variable immunodeficiency and selective IgA deficiency

Modeling and Hemofiltration Treatment of Acute Inflammation

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