Transforming Growth Factor-β Receptor Blockade Augments the Effectiveness of Adoptive T-Cell Therapy of Established Solid Cancers

Wallace, Africa F.; Kapoor, Veena; Sun, Jing; Mrass, Paulus; Weninger, Wolfgang; Heitjan, Daniel F.; June, Carl H.; Kaiser, Larry R.; Ling, Leona; Albelda, Steven Μ.

doi:10.1158/1078-0432.ccr-08-0356

Cited by 74 publications

(57 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is likely that TGF-b inhibitors will have their most important therapeutic activity in cancer through effects on the TME, particularly, but not only, in neutralizing or reversing immune suppression. Indeed, the combination of TGF-b inhibition together with existing immunotherapies, such as cancer vaccines (Jia et al 2005;Nemunaitis and Murray 2006;Kim et al 2008), adoptive Tcell transfer Wallace et al 2008), chimeric antigen receptor T-cell therapy (Gill and June 2015;Wu et al 2015), and immune checkpoint blockade (Topalian et al 2012;Lipson et al 2013), will likely provide the major basis of their therapeutic usage. Here again, the major players appear to be TGF-b1 and -b2.…”

Section: Potential Oncology Applications For Tgf-b Blockadementioning

confidence: 99%

“…The fraction of glioblastoma or metastatic melanoma patients achieving long-term durable responses after galunisertib or fresolimumab therapy (Morris et al 2014;Brandes et al 2016), may become significant if combined with other drugs. Bearing in mind the safety of TGF-b signaling inhibitors at the doses used, the outlook for use of Proof-of-principle usage of TGF-b blockade for enhancement of immunotherapy has been shown preclinically using LY2109761 in adoptive T-cell therapy (Wallace et al 2008), and using the normally unstable TbRI SMI, SB505124, encapsulated in a slow-release biodegradable polymeric nanoparticle for the stimulation of interleukin 2 (IL-2) therapy of melanoma (Park et al 2012). A novel approach has been taken by generating mRNA encoding a "fusokine," that is, a fusion protein of the immune stimulant, interferon-b, with the ectodomain of TbRII, which acts as a TGF-b "sink."…”

Section: Tgf-b Signaling Blockade In Immunotherapymentioning

confidence: 99%

See 1 more Smart Citation

Targeting TGF-β Signaling for Therapeutic Gain

Akhurst

2017

Cold Spring Harb Perspect Biol

172

139

View full text Add to dashboard Cite

Transforming growth factor bs (TGF-bs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-b type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-b ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-b signaling for therapeutic benefit. This review will cover the basics of TGF-b signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-b blockade strategies, and give an update on preclinical and clinical trials for TGF-b blockade in a variety of solid tumor types.

show abstract

Section: Potential Oncology Applications For Tgf-b Blockadementioning

confidence: 99%

Section: Tgf-b Signaling Blockade In Immunotherapymentioning

confidence: 99%

Targeting TGF-β Signaling for Therapeutic Gain

Akhurst

2017

Cold Spring Harb Perspect Biol

172

139

View full text Add to dashboard Cite

show abstract

“…Evidence from preclinical studies indicates that alteration of the tumor microenvironment using TGF-b signaling inhibitor or IDO-blocking agent 1-methyl tryptophan (1-MT) results in the restoration of T-cell response (15)(16)(17)(18). In our preliminary experiments, we have tested whether BLI coupled with pGBeLT reporter is sensitive to TCRdependent T-cell function during adoptive therapy combined with either TGF-b receptor I kinase (TbR-I) inhibitor or 1-MT in living subjects.…”

Section: Imaging Of Adoptively Transferred T-cell Function In Micementioning

confidence: 99%

“…Because IDO can be induced by IFN-g, IDO-negative cancer cells may be initiated to express IDO when exposed to an inflammatory context in the tumor microenvironment, and thereby hinder CD8 þ T-cell-mediated tumor regression before it can be effective (4,5,12). Recently, strong evidence has indicated that modification of the tumor microenvironment, such as the blockade of the TGF-b signaling pathway (15,16), inhibition of IDO (17,18), or depletion of Tregs (19,20) is able to augment the cytotoxicity of CD8 þ T cells.…”

Section: Introductionmentioning

confidence: 99%

Immunomodulation of Curcumin on Adoptive Therapy with T Cell Functional Imaging in Mice

Chang

Chuang

Hsu

et al. 2012

Cancer Prevention Research

View full text Add to dashboard Cite

Adoptive T-cell therapy involves the ex vivo expansion and subsequent transfusion of tumor-specific T lymphocytes to eliminate tumors. Using immune modulators to block immunosuppressive factors in the tumor microenvironment has emerged as a promising strategy to enhance T-cell-mediated tumor regression. Curcumin, a major component of turmeric, has been shown to possess antitumor and immunomodulatory effects by regulating a diverse range of molecular targets. Thus, we hypothesize that these beneficial effects of curcumin may improve the therapeutic efficacy of adoptive therapy. Here, we have shown that curcumin enhances cytotoxicity of CD8 þ T cells toward tumors via alteration of the tumor microenvironment when combined with adoptive therapy. We found that T-cell accumulation and function were increased in combined treatment due to the blockade of different immunosuppressors, including TGFb, indoleamine 2,3-dioxygenase, and regulatory T cells. Furthermore, bioluminescent imaging with a granzyme B promoter-conjugated optical reporter also reflected improved cytotoxicity of antigen-specific CD8 þ T cells in tumor-bearing mice during treatment. These findings suggest that combination of multitargeting drugs, such as curcumin, with adoptive therapy may have potential for clinical application. In addition, using a granzyme B-specific imaging reporter to assess T-cell function may also be applied for the development and therapeutic evaluation of new immunotherapy in preclinical studies. Cancer Prev Res; 5(3); 444-52. Ó2011 AACR.

show abstract

“…This plays a vital role in cancer etiology through the interactions with tumor cells. TGF-β is a potent tumor suppressor that has a negative impact on surrounding host immune cells in the tumor microenvironment (Wallace et al, 2008;Kelly and Morris, 2010). Therefore, adoptive immune cell therapy must consider the immunosuppression of TGF-β in tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Construction of eukaryotic expression vector pTAR-GET- DNT?R? and its expression in breast cancer COS-7 cells

Zhao¹,

Hu²,

Li³

et al. 2015

cge

View full text Add to dashboard Cite

Objective: To synthesize the gene of human dominant-negative transforming growth factor beta receptor (DNTβRⅡ) by means of oligo chemic synthesis and PCR amplification, construct pTAR-GET-DNTβRⅡ eukaryotic expression vector and investigate whether its expression in breast cancer COS-7 cells. Methods:The DNTβRⅡ gene fragment was inserted into pTAR-GET to conduct a eukaryotic plasmid, then sequenced and identified by restrictive endonuclease digestion. The eukaryotic expression vector pTAR-GET-DNTβRⅡ was constructed and then transfected into COS-7 cells, to evaluate its expression by RT-PCR method. Results:The eukaryotic expression vector pTAR-GET-DNTβRⅡ was successfully constructed and could be instantaneously transfected and finally expressed in COS-7 cells. Conclusion:Full length gene of DNTβRⅡ can be synthesized by means of oligo chemic synthesis and PCR amplification. The construction of eukaryotic expression vector pTAR-GET-DNTβRⅡ and its successful expression in breast cancer COS-7 cells, may provide the basis for further study of breast cancer anti-tumor immunotherapy by adoptive immune cell therapy.

show abstract

Transforming Growth Factor-β Receptor Blockade Augments the Effectiveness of Adoptive T-Cell Therapy of Established Solid Cancers

Abstract: We found that systemic blockade of TGF-beta receptor activity augmented the antitumor activity of adoptively transferred T cells and may thus be a useful adjunct in future clinical trials.

Cited by 74 publications

References 55 publications

Targeting TGF-β Signaling for Therapeutic Gain

Targeting TGF-β Signaling for Therapeutic Gain

Immunomodulation of Curcumin on Adoptive Therapy with T Cell Functional Imaging in Mice

Construction of eukaryotic expression vector pTAR-GET- DNT?R? and its expression in breast cancer COS-7 cells

Contact Info

Product

Resources

About