Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

Gray, Juliet; French, Ruth R.; James, Sonya; Al‐Shamkhani, Aymen; Johnson, Peter; Glennie, Martin J.

doi:10.1002/eji.200838208

Cited by 53 publications

(29 citation statements)

References 49 publications

(54 reference statements)

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“…In these tumors antigen-specific CD8 þ immunity is downmodulated and tumors progress at a fast pace with T-cell tolerance representing the major hurdle (21). Triple combination of ISmAbs makes sense since synergistic effects of the combined treatment consisting of anti-CD137 plus anti-B7-H1 (34, 35) mAbs or anti-CD137 plus anti-OX40 mAbs (36) have been reported in mouse models of transplantable tumors. As expected from the mechanism of action of these three antibodies, we observe an increase in T-cell infiltrates in tumor tissue composed of both activated CD4 þ and CD8 þ T lymphoblasts.…”

Section: Discussionmentioning

confidence: 99%

Combined Immunostimulatory Monoclonal Antibodies Extend Survival in an Aggressive Transgenic Hepatocellular Carcinoma Mouse Model

Morales-Kastresana

Sanmamed

Rodríguez

et al. 2013

Clinical Cancer Research

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Purpose: Immunostimulatory monoclonal antibodies (ISmAb) that unleash antitumor immune responses are showing efficacy in cancer clinical trials. Anti-B7-H1 (PD-L1) monoclonal antibodies (mAb) block a critical inhibitory pathway in T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation. A combination of these ISmAbs (anti-CD137 þ anti-OX40 þ anti-B7-H1) was tested using a transgenic mouse model of multifocal and rapidly progressing hepatocellular carcinoma, in which c-myc drives transformation and cytosolic ovalbumin (OVA) is expressed in tumor cells as a model antigen.Experimental Design: Flow-cytometry and immunohistochemistry were used to quantify tumorinfiltrating lymphocytes (TIL) elicited by treatment and assess their activation status and cytolytic potential. Tolerance induction and its prevention/reversal by treatment with the combination of ISmAbs were revealed by in vivo killing assays.Results: The triple combination of ISmAbs extended survival of mice bearing hepatocellular carcinomas in a CD8-dependent fashion and synergized with adoptive T-cell therapy using activated OVA-specific TCRtransgenic OT-1 and OT-2 lymphocytes. Mice undergoing therapy showed clear increases in tumor infiltration by activated and blastic CD8 þ and CD4 þ T lymphocytes containing perforin/granzyme B and expressing the ISmAb-targeted receptors on their surface. The triple combination of ISmAbs did not result in enhanced OVA-specific cytotoxic T lymphocyte (CTL) activity but other antigens expressed by cell lines derived from such hepatocellular carcinomas were recognized by endogenous TILs. Adoptively transferred OVA-specific OT-1 lymphocytes into tumor-bearing mice were rendered tolerant, unless given the triple mAb therapy. Conclusion: Extension of survival and dense T-cell infiltrates emphasize the translational potential of combinational immunotherapy strategies for hepatocellular carcinoma.

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Section: Discussionmentioning

confidence: 99%

Combined Immunostimulatory Monoclonal Antibodies Extend Survival in an Aggressive Transgenic Hepatocellular Carcinoma Mouse Model

Morales-Kastresana

Sanmamed

Rodríguez

et al. 2013

Clinical Cancer Research

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“…Many reports indicate that agonistic signaling through T cell costimulatory receptors can enhance immunity to cancer (5)(6)(7)(8)(9). Glucocorticoid-induced TNF receptor (GITR) family-related protein (10,11) is one such receptor that has received significant attention in recent years.…”

Section: Ostimulation Of T Cells Is Crucial For Generating Efficienmentioning

confidence: 99%

Therapeutic Glucocorticoid-Induced TNF Receptor-Mediated Amplification of CD4+ T Cell Responses Enhances Antiparasitic Immunity

Haque

Stanley

Amante

et al. 2010

The Journal of Immunology

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Chronic infectious diseases and cancers are often associated with suboptimal effector T cell responses. Enhancement of T cell costimulatory signals has been extensively studied for cancer immunotherapy but not so for the treatment of infectious disease. The few previous attempts at this strategy using infection models have lacked cellular specificity, with major immunoregulatory mechanisms or innate immune cells also being targeted. In this study, we examined the potential of promoting T cell responses via the glucocorticoid-induced TNF receptor (GITR) family-related protein in a murine model of visceral leishmaniasis. GITR stimulation during established infection markedly improved antiparasitic immunity. This required CD4+ T cells, TNF, and IFN-γ, but crucially, was independent of regulatory T (Treg) cells. GITR stimulation enhanced CD4+ T cell expansion without modulating Treg cell function or protecting conventional CD4+ T cells from Treg cell suppression. GITR stimulation substantially improved the efficacy of a first-line visceral leishmaniasis drug against both acute hepatic infection and chronic infection in the spleen, demonstrating its potential to improve clinical outcomes. This study identifies a novel strategy to therapeutically enhance CD4+ T cell-mediated antiparasitic immunity and, importantly, achieves this goal without impairment of Treg cell function.

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“…Subsequent studies by other groups and ourselves have confirmed and extended this finding that 'dual costimulation' is therapeutic in breast cancer [116], melanoma [117] and lymphoma models [118].…”

Section: Immunotherapies Overcome Tumor-induced Immunosuppressionmentioning

confidence: 70%

Cytokines and Metabolic Factors Regulate Tumoricidal T-Cell Function During Cancer Immunotherapy

et al. 2016

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Recent advances in cancer biology and genetics have fostered precision therapies targeting tumor-specific attributes. Immune-based therapies that elicit cytolytic T cells (CTL) specific for tumor antigens can provide therapeutic benefit to cancer patients, however, cure rates are typically low. This largely results from immunosuppressive mechanisms operating within the tumor microenvironment, many of which inflict metabolic stresses upon CTL. Conversely, immunotherapies can mitigate specific metabolic stressors. For instance, dual costimulation immunotherapy with CD134 (OX40) plus CD137 (4-1BB) agonists appears to mediate tumor control in part by engaging cytokine networks that enable infiltrating CTL to compete for limiting supplies of glucose. Future efforts combining modalities that endow CTL with complimentary metabolic advantages should improve therapeutic efficacies.

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Optimising anti‐tumour CD8 T‐cell responses using combinations of immunomodulatory antibodies

Cited by 53 publications

References 49 publications

Combined Immunostimulatory Monoclonal Antibodies Extend Survival in an Aggressive Transgenic Hepatocellular Carcinoma Mouse Model

Combined Immunostimulatory Monoclonal Antibodies Extend Survival in an Aggressive Transgenic Hepatocellular Carcinoma Mouse Model

Therapeutic Glucocorticoid-Induced TNF Receptor-Mediated Amplification of CD4+ T Cell Responses Enhances Antiparasitic Immunity

Cytokines and Metabolic Factors Regulate Tumoricidal T-Cell Function During Cancer Immunotherapy

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