Rationale for anti-GITR cancer immunotherapy

Knee, Deborah; Hewes, Becker; Brogdon, Jennifer L.

doi:10.1016/j.ejca.2016.06.028

Cited by 185 publications

(169 citation statements)

References 78 publications

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“…These conditions are ameliorated upon administration of exogenous IL-10 (210) or TNF-α blockade (196). In accordance, anti-GITR (211, 212) treatment of infected mice has similar effects in the composition of these infiltrates, and animals exhibit increased TNF-α production, increased heart parasitism and worse survival rate (213). The production of TGF-β, was discarded as the cause of the lack of cytokine production observed in effector CD8 + T cells isolated from inflammatory infiltrates in T. cruzi infected heart tissue, but it regulates the expansion of these cells and therefore has a protective role against cardiopathy (214, 215).…”

Section: Adaptive Immunitymentioning

confidence: 80%

The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease

2018

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Trypanosoma cruzi interacts with the different arms of the innate and adaptive host's immune response in a very complex and flowery manner. The history of host-parasite co-evolution has provided this protozoan with means of resisting, escaping or subverting the mechanisms of immunity and establishing a chronic infection. Despite many decades of research on the subject, the infection remains incurable, and the factors that steer chronic Chagas disease from an asymptomatic state to clinical onset are still unclear. As the relationship between T. cruzi and the host immune system is intricate, so is the amount and diversity of scientific knowledge on the matter. Many of the mechanisms of immunity are fairly well understood, but unveiling the factors that lead each of these to success or failure, within the coordinated response as a whole, requires further research. The intention behind this Review is to compile the available information on the different aspects of the immune response, with an emphasis on those phenomena that have been studied and confirmed in the human host. For ease of comprehension, it has been subdivided in sections that cover the main humoral and cell-mediated components involved therein. However, we also intend to underline that these elements are not independent, but function intimately and concertedly. Here, we summarize years of investigation carried out to unravel the puzzling interplay between the host and the parasite.

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Section: Adaptive Immunitymentioning

confidence: 80%

The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease

2018

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“…In a recent article review of GITR in the context of immune oncology [4], a number of clinical trials are currently evaluating GITR agonists for the treatment of a wide range of tumor indications. The data presented here are important and relevant because they suggest that GITR agonism may be most successful in indications with primed CD8 T cells which express higher levels of GITR, including tumors with high mutational load and in the presence of foreign antigens, such as virus-driven tumors.…”

Section: Discussionmentioning

confidence: 99%

“…GITR is upregulated on T cells when activated via their T-cell receptor. GITRL is found on many types of antigen presenting cells including DCs and macrophages and GITRL can be upregulated by cytokine or TLR stimulation [3, 4]. Agonism of GITR in vitro or in vivo with its cognate ligand, agonist antibodies, or multimeric fusion proteins has been shown to increase T-cell proliferation and cytokine release [5–7].…”

Section: Introductionmentioning

confidence: 99%

GITR ligand fusion protein agonist enhances the tumor antigen–specific CD8 T-cell response and leads to long-lasting memory

Durham¹,

Holoweckyj²,

MacGill³

et al. 2017

j. immunotherapy cancer

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BackgroundThe expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations.MethodsWe explored two separate murine tumor models, CT26 and TC-1, for responsiveness to GITR Ligand Fusion Protein(GITRL-FP) monotherapy. In TC-1, GITRL-FP was also combined with concurrent administration of an E7-SLP vaccine. We evaluated tumor growth inhibition by tumor volume measurements as well as changes in CD8 T cell populations and function including cytokine production using flow cytometry. Additionally, we interrogated how these therapies resulted in tumor antigen-specific responses using MHC-I dextramer staining and antigen-specific restimulations.ResultsIn this study, we demonstrate that a GITR ligand fusion protein (GITRL-FP) is an effective modulator of antigen-specific CD8 T cells. In a CT26 mouse tumor model, GITRL-FP promoted expansion of antigen-specific T cells, depletion of regulatory T cells (Tregs), and generation of long-lasting CD8 T cell memory. This memory expansion was dependent on the dose of GITRL-FP and resulted in complete tumor clearance and protection from tumor rechallenge. In contrast, in TC-1 tumor–bearing mice, GITRL-FP monotherapy could not prime an antigen-specific CD8 T cell response and was unable to deplete Tregs. However, when combined with a vaccine targeting E7, treatment with GITRL-FP resulted in an augmentation of the vaccine-induced antigen-specific CD8 T cells, the depletion of Tregs, and a potent antitumor immune response. In both model systems, GITR levels on antigen-specific CD8 T cells were higher than on all other CD8 T cells, and GITRL-FP interacted directly with primed antigen-specific CD8 T cells.ConclusionsWhen taken together, our results demonstrate that the delivery of GITRL-FP as a therapeutic can promote anti-tumor responses in the presence of tumor-specific CD8 T cells. These findings support further study into combination partners for GITRL-FP that may augment CD8 T-cell priming as well as provide hypotheses that can be tested in human clinical trials exploring GITR agonists including GITRL-FP.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-017-0247-0) contains supplementary material, which is available to authorized users.

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“…Currently there are several agents targeting GITR in ongoing clinical trials (Knee, Hewes et al, 2016) (Table 1). The first agonist anti-GITR mAb, (TRX518) against malignant melanoma showed little toxicity, but also little efficacy.…”

Section: Gitrmentioning

confidence: 99%

Stimulating T Cells Against Cancer With Agonist Immunostimulatory Monoclonal Antibodies

Han

Vesely

2019

International Review of Cell and Molecular Biology

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Elimination of cancer cells through anti-tumor immunity has been a long-sought after goal since Sir F. Macfarlane Burnet postulated the theory of immune surveillance against tumors in the 1950s. Finally, the use of immunotherapeutics against established cancer is becoming a reality in the past 5 years. Most notable are the monoclonal antibodies directed against inhibitory T cell receptors cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1). The next generation of monoclonal antibodies targeting T cells are designed to stimulate co-stimulatory receptors on T cells. Here we review the recent progress on these immunostimulatory agonist antibodies against the costimulatory receptors CD137, GITR, OX40, and CD27.

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Rationale for anti-GITR cancer immunotherapy

Cited by 185 publications

References 78 publications

The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease

The Unsolved Jigsaw Puzzle of the Immune Response in Chagas Disease

GITR ligand fusion protein agonist enhances the tumor antigen–specific CD8 T-cell response and leads to long-lasting memory

Stimulating T Cells Against Cancer With Agonist Immunostimulatory Monoclonal Antibodies

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