Human‐engineered Treg‐like cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo

Objectives Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune‐mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be...

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Veröffentlicht in:Clinical & translational immunology 2020, Vol.9 (11), p.e1214-n/a
Hauptverfasser: Sato, Yohei, Passerini, Laura, Piening, Brian D, Uyeda, Molly Javier, Goodwin, Marianne, Gregori, Silvia, Snyder, Michael P, Bertaina, Alice, Roncarolo, Maria‐Grazia, Bacchetta, Rosa
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container_end_page n/a
container_issue 11
container_start_page e1214
container_title Clinical & translational immunology
container_volume 9
creator Sato, Yohei
Passerini, Laura
Piening, Brian D
Uyeda, Molly Javier
Goodwin, Marianne
Gregori, Silvia
Snyder, Michael P
Bertaina, Alice
Roncarolo, Maria‐Grazia
Bacchetta, Rosa
description Objectives Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune‐mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg‐like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression. Methods The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA‐seq and TCR‐seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft‐versus‐host disease (xeno‐GvHD) and FOXP3‐deficient IPEX‐like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)‐ mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens. Results We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T‐cell transduction in the absence of FOXP3, including upregulation of Treg‐related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno‐GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper‐proliferation of CD4+ memory T cells in the FOXP3‐deficient IPEX‐like hu‐mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen‐primed T cells or tumor clearance in the PB hu‐mice. Conclusion These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs. In this study, we present novel molecular and preclinical in vivo data that support CD4LVFOXP3 clinical progression. These data support the clinical readiness of CD4LVFOXP3 to treat immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.
doi_str_mv 10.1002/cti2.1214
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Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg‐like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression. Methods The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA‐seq and TCR‐seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft‐versus‐host disease (xeno‐GvHD) and FOXP3‐deficient IPEX‐like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)‐ mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens. Results We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T‐cell transduction in the absence of FOXP3, including upregulation of Treg‐related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno‐GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper‐proliferation of CD4+ memory T cells in the FOXP3‐deficient IPEX‐like hu‐mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen‐primed T cells or tumor clearance in the PB hu‐mice. Conclusion These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs. In this study, we present novel molecular and preclinical in vivo data that support CD4LVFOXP3 clinical progression. These data support the clinical readiness of CD4LVFOXP3 to treat immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.</description><identifier>ISSN: 2050-0068</identifier><identifier>EISSN: 2050-0068</identifier><identifier>DOI: 10.1002/cti2.1214</identifier><identifier>PMID: 33304583</identifier><language>eng</language><publisher>Australia: John Wiley &amp; Sons, Inc</publisher><subject>Adaptive immunity ; Animal models ; Antigen (tumor-associated) ; Antigens ; CD4 antigen ; Cell proliferation ; CRISPR/Cas9 ; Cytokines ; Disease ; Effector cells ; Flow cytometry ; FOXP3 ; Foxp3 protein ; Gene expression ; gene therapy ; Genetic engineering ; Genotype &amp; phenotype ; Graft-versus-host reaction ; Immune clearance ; Immunological memory ; Immunoregulation ; Immunosurveillance ; IPEX syndrome ; lentiviral vector ; Lymphocytes ; Lymphocytes T ; Medical innovations ; Medical prognosis ; Memory cells ; Original ; Patients ; Peripheral blood ; regulatory T cells ; Ribonucleic acid ; RNA ; T cell receptors ; Transcription ; Xenografts</subject><ispartof>Clinical &amp; translational immunology, 2020, Vol.9 (11), p.e1214-n/a</ispartof><rights>2020 The Authors. published by John Wiley &amp; Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.</rights><rights>2020 The Authors. Clinical &amp; Translational Immunology published by John Wiley &amp; Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.</rights><rights>2020. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). 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Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg‐like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression. Methods The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA‐seq and TCR‐seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft‐versus‐host disease (xeno‐GvHD) and FOXP3‐deficient IPEX‐like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)‐ mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens. Results We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T‐cell transduction in the absence of FOXP3, including upregulation of Treg‐related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno‐GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper‐proliferation of CD4+ memory T cells in the FOXP3‐deficient IPEX‐like hu‐mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen‐primed T cells or tumor clearance in the PB hu‐mice. Conclusion These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs. In this study, we present novel molecular and preclinical in vivo data that support CD4LVFOXP3 clinical progression. 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translational immunology</jtitle><addtitle>Clin Transl Immunology</addtitle><date>2020</date><risdate>2020</risdate><volume>9</volume><issue>11</issue><spage>e1214</spage><epage>n/a</epage><pages>e1214-n/a</pages><issn>2050-0068</issn><eissn>2050-0068</eissn><abstract>Objectives Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune‐mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X‐linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg‐like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression. Methods The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA‐seq and TCR‐seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft‐versus‐host disease (xeno‐GvHD) and FOXP3‐deficient IPEX‐like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)‐ mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens. Results We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T‐cell transduction in the absence of FOXP3, including upregulation of Treg‐related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno‐GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper‐proliferation of CD4+ memory T cells in the FOXP3‐deficient IPEX‐like hu‐mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen‐primed T cells or tumor clearance in the PB hu‐mice. Conclusion These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs. In this study, we present novel molecular and preclinical in vivo data that support CD4LVFOXP3 clinical progression. These data support the clinical readiness of CD4LVFOXP3 to treat immune‐mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.</abstract><cop>Australia</cop><pub>John Wiley &amp; Sons, Inc</pub><pmid>33304583</pmid><doi>10.1002/cti2.1214</doi><tpages>23</tpages><orcidid>https://orcid.org/0000-0002-8042-0069</orcidid><oa>free_for_read</oa></addata></record>
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subjects Adaptive immunity
Animal models
Antigen (tumor-associated)
Antigens
CD4 antigen
Cell proliferation
CRISPR/Cas9
Cytokines
Disease
Effector cells
Flow cytometry
FOXP3
Foxp3 protein
Gene expression
gene therapy
Genetic engineering
Genotype & phenotype
Graft-versus-host reaction
Immune clearance
Immunological memory
Immunoregulation
Immunosurveillance
IPEX syndrome
lentiviral vector
Lymphocytes
Lymphocytes T
Medical innovations
Medical prognosis
Memory cells
Original
Patients
Peripheral blood
regulatory T cells
Ribonucleic acid
RNA
T cell receptors
Transcription
Xenografts
title Human‐engineered Treg‐like cells suppress FOXP3‐deficient T cells but preserve adaptive immune responses in vivo
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