IL-12 + GM-CSF Microsphere Therapy Induces Eradication of Advanced Spontaneous Tumors in her-2/neu Transgenic Mice But Fails to Achieve Long-Term Cure Due to the Inability to Maintain Effector T-Cell Activity

Nair, Raji E.; Jong, Yong S.; Jones, Stacy; Sharma, Atima; Mathiowitz, Edith; Egilmez, Nejat K.

doi:10.1097/01.cji.0000175489.19314.d2

Cited by 38 publications

(41 citation statements)

References 30 publications

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“…It is anticipated that by re-activating the T lymphocytes, these cells will orchestrate a cascade of events that result in the killing of tumor locally and that with the release of tumor antigens from the dead and dying tumor cells there will be an induction of a systemic anti-tumor immunity. This expectation has been confirmed in two animal tumor models [141,142] and several clinical trials have shown that low doses of IL-12 injected locally into tumors show little or no toxicity (reviewed in [143]). An Investigational New Drug (IND) application for a local sustained delivery device for the introduction of IL-12 into tumor nodules has recently been approved by the FDA and a Phase I clinical trial that will address the safety and later the efficacy of this in situ tumor vaccination strategy is to be initiated shortly.…”

Section: Discussionmentioning

confidence: 83%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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Section: Discussionmentioning

confidence: 83%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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“…This same result has been achieved in murine models by the slow release into tissue of IL-12 encapsulated microspheres. 51 We anticipate that similar clinical effects would be induced by intratumoral injection of IL-12 cDNA or IL-12 protein encapsulated microspheres.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral injection of IL-12 plasmid DNA – results of a phase I/IB clinical trial

et al. 2007

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Effective eradication of established tumor and generation of a lasting systemic immune response are the goals of cancer immunotherapy. The objective of this phase IB study was to assess the safety and toxicity of treatment to metastatic tumor underlying the skin with the DNA encoding interleukin-12 (IL-12). This treatment strategy allowed the patient's own tumor to serve as a source of autologous antigen in the tumor microenvironment. We proposed that IL-12 protein produced by the transfected cells would result in the generation of both a local and systemic antitumor response. The tumor was treated with either three or six intratumoral injections of plasmid containing IL-12 DNA. This treatment strategy resulted in no significant local or systemic toxicity. The treatment did not result in an increase in serum IL-12 protein. The size of the treated lesion decreased significantly (greater than 30%) in five of the 12 patients. However, nontreated subcutaneous lesions or other disease did not decrease in size.

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“…However, the co-administration of both GM-CSF and IL-12 resulted in a synergistic increase in tumor-infiltrating effector cells, IFN-γ production and reduced tumor burden [70]. The combination of GM-CSF and IL-12 has also been applied in several other rodent models, including intracranial glioma [71], transgene-induced spontaneous mammary tumors [72] and metastatic lung and colon cancers [73]. In each of these studies, tumor eradication was dependent upon both T and NK cells and correlated with the infiltration of these cell types into the tumor.…”

Section: Granulocyte-macrophage Colony-stimulating Factor (Gm-csf)/il-12mentioning

confidence: 99%

Immunotherapy of cancer by IL-12-based cytokine combinations

Weiss

Subleski

Wigginton

et al. 2007

Expert Opinion on Biological Therapy

204

121

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Cancer is a multi-faceted disease comprising complex interactions between neoplastic and normal cells. Over the past decade, there has been considerable progress in defining the molecular, cellular and environmental contributions to the pathophysiology of tumor development. Despite these advances, the conventional treatment of patients still generally involves surgery, radiotherapy and/ or chemotherapy and the clinical outcome for many of these efforts remains unsatisfactory. Recent studies have highlighted the feasibility of using immunotherapeutic approaches that seek to enhance host immune responses to developing tumors. These strategies include immunomodulatory cytokines, with tumor necrosis factor (TNF) alpha, type I or type II Interferons (IFNs), Interleukins (IL)-2, IL-12, IL-15 and IL-18 being among the most potent inducers of anti-tumor activity in a variety of pre-clinical studies. More recently, some exciting new cytokines have been characterized, such as IL-21, IL-23, IL-27, and their immunomodulatory and anti-tumor effects in vitro and in vivo suggest that they may have considerable promise for future immunotherapy protocols. The promise of cytokine therapy does indeed derive from the identification of these novel cytokines, but even more fundamentally, the field is greatly benefiting from the ever-expanding amount of preclinical data that convincingly demonstrate synergistic and/or novel biological effects that may be achieved through the use of several combinations of cytokines with complementary immunestimulating capabilities. One cytokine in particular, IL-12, holds considerable promise by virtue of the fact that it plays a central role in regulating both innate and adaptive immune responses, can by itself induce potent anti-cancer effects, and synergizes with several other cytokines for increased immunoregulatory and anti-tumor activities. This review will discuss the anti-tumor activity of IL-12, with a special emphasis on its ability to synergize with other cytokines for enhancement of immune effector cell populations and regulation of host-tumor cell interactions and the overall tumor microenvironment.

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IL-12 + GM-CSF Microsphere Therapy Induces Eradication of Advanced Spontaneous Tumors in her-2/neu Transgenic Mice But Fails to Achieve Long-Term Cure Due to the Inability to Maintain Effector T-Cell Activity

Cited by 38 publications

References 30 publications

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Intratumoral injection of IL-12 plasmid DNA – results of a phase I/IB clinical trial

Immunotherapy of cancer by IL-12-based cytokine combinations

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