Depleting regulatory T cells with arginine-rich, cell-penetrating, peptide-conjugated morpholino oligomer targeting FOXP3 inhibits regulatory T-cell function

BackgroundPatients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib.MethodsWe immunized women (n = 12) with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD) and a portion of the intracellular domain (ICD) of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day) was administered concurrently. Peripheral blood antibody and T cell responses were measured.ResultsThis regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%).ConclusionsdHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway.Trial registryClinicalTrials.gov NCT00952692

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“…These vectors will be entering clinical trials shortly [26]. We have also reported strategies for depleting Treg [27]. …”

Section: Discussionmentioning

confidence: 99%

Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion

et al. 2012

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“…showed that an arginine-rich cell-penetrating phoshorodiamitade morpholino oligomer (PPMO), by targeting FOXP3, inhibited Treg cell function and induced effector T cell response (73), suggesting that PPMO antisense-based strategy might be used as a potential tool to improve immunotherapy.…”

Section: Environment and Treg Cellsmentioning

confidence: 99%

Role of Metabolism in the Immunobiology of Regulatory T Cells

Galgani

Rosa

Cava

et al. 2016

The Journal of Immunology

101

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Intracellular metabolism is central to cell activity and function. CD4+CD25+ regulatory T cells (Tregs) that express the transcription factor FOXP3 play a pivotal role in the maintenance of immune tolerance to self. Recent studies showed that the metabolism and function of Tregs are influenced significantly by local environmental conditions and the availability of certain metabolites. It also was reported that defined metabolic programs associate with Treg differentiation, expression of FOXP3, and phenotype stabilization. This article reviews how metabolism modulates FOXP3 expression and Treg function, what environmental factors are involved, and how metabolic manipulation could alter Treg frequency and function in physiopathologic conditions.

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“…Consequently, a P60 treatment combined with a tumor associated epitope immunization, protected mice against tumor implantation by reducing the Treg immunosuppressive potential [79]. Another arginine-rich, antisense peptide-conjugated phosphorodiamidate morpholino, structurally similar to RNA, can be taken up, in vitro, by activated T cells and trigger a downregulation of Foxp3 expression in the T cells [80]. Foxp3 has also been targeted in vaccination technology that uses Foxp3 RNA-transfected DC and elicits a robust Foxp3-specific cytotoxic T cell response.…”

Section: ) Targeting Foxp3 In Cancer Immunotherapymentioning

confidence: 99%

Foxp3 expression in T regulatory cells and other cell lineages

Devaud

Darcy

Kershaw

2014

Cancer Immunol Immunother

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Forkhead box P3 (Foxp3) is an important transcription factor that belongs to the forkhead/winged-helix family of transcriptional regulators. Foxp3 has been extensively studied over the past 13 years as a master regulator of transcription in a specific T-cell type, CD4(+) regulatory T cells (Treg), both in humans and in mice. Compelling data characterize Foxp3 as critically important and necessary for the development and the differentiation of Treg. It has been considered initially as the only specific marker for Treg. However, recent work has proposed that Foxp3 can be expressed by other types of lymphoid cells or myeloid cells and also by some non-hematopoietic cells such as epithelial cells. It remains controversial about the expression of Foxp3 in cells other than Treg, but understanding the potential expression and function of this master regulator in different cell subsets could have a wide range of implications for immune tolerance and several pathologies including autoimmune disorders and immune responses to cancer.

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Depleting regulatory T cells with arginine-rich, cell-penetrating, peptide-conjugated morpholino oligomer targeting FOXP3 inhibits regulatory T-cell function

Cited by 11 publications

References 39 publications

Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion

Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion

Role of Metabolism in the Immunobiology of Regulatory T Cells

Foxp3 expression in T regulatory cells and other cell lineages

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