Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses

Govindarajan Thangavelu; Chao Wang; Michael Loschi; Asim Saha; Mark J. Osborn; Scott N. Furlan; Kazutoshi Aoyama; Cameron S Mcdonald-Hyman; Ethan Aguilar; Amanda S. Janesick; Roshantha A. Chandraratna; Yosef Refaeli; Angela Panoskaltsis-Mortari; Kelli P. MacDonald; Geoffrey R. Hill; Robert Zeiser; Ivan Maillard; Jonathan S. Serody; William J. Murphy; David H. Munn; Bruce Blumberg; Chrysothemis Brown; Vijay Kuchroo; Leslie S. Kean; Keli L. Hippen; Randolph J. Noelle; Bruce R. Blazar

doi:10.1182/blood.2020005628

Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses

Govindarajan Thangavelu, Chao Wang, Michael Loschi, Asim Saha, Mark J. Osborn, Scott N. Furlan, Kazutoshi Aoyama, Cameron S Mcdonald-Hyman, Ethan Aguilar, Amanda S. Janesick, Roshantha A. Chandraratna, Yosef Refaeli, Angela Panoskaltsis-Mortari, Kelli P. MacDonald, Geoffrey R. Hill, Robert Zeiser, Ivan Maillard, Jonathan S. Serody, William J. Murphy, David H. MunnBruce Blumberg, Chrysothemis Brown, Vijay Kuchroo, Leslie S. Kean, Keli L. Hippen, Randolph J. Noelle, Bruce R. Blazar

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.

Original language	English (US)
Pages (from-to)	1090-1103
Number of pages	14
Journal	Blood
Volume	137
Issue number	8
DOIs	https://doi.org/10.1182/blood.2020005628
State	Published - Feb 25 2021

Bibliographical note

Funding Information:
The authors thank Elizabeth Nowak for input. This work was funded by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI034495, and NIH/National Heart, Lung, and Blood Institute grants R01 HL56067 (B.R.B.) and R01 AI091627 (I.M.); Deutsche Forschungsgemeinschaft grants 872/4-1 and SFB1160 TP B09, Deutsche Krebshilfe grant 70113473, Jose-Carreras Leukemia Foundation grant DJCLS 01R/2019 (R.Z); a fellowship from the Canadian Institutes of Health Research (CIHR) (G.T.); and funding from the Leukemia and Lymphoma Society, the Children's Cancer Research Fund, and the KidsFirst Fund (B.R.B.). Conflict-of-interest disclosure: B.R.B. has received remuneration as an advisor to Kamon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics and research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences Inc, and Abbvie Inc. B.R.B. is a cofounder of Tmunity. The remaining authors declare no competing financial interests. Roshantha A. Chandraratna died on 8 January 2019.

Funding Information:
This work was funded by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI034495, and NIH/National Heart, Lung, and Blood Institute grants R01 HL56067 (B.R.B.) and R01 AI091627 (I.M.); Deutsche Forschungsgemeinschaft grants 872/4-1 and SFB1160 TP B09, Deutsche Krebshilfe grant 70113473, Jose-Carreras Leukemia Foundation grant DJCLS 01R/2019 (R.Z); a fellowship from the Canadian Institutes of Health Research (CIHR) (G.T.); and funding from the Leukemia and Lymphoma Society, the Children's Cancer Research Fund, and the KidsFirst Fund (B.R.B.).

Publisher Copyright:
© 2021 American Society of Hematology

Keywords

Animals
Bone Marrow Transplantation/adverse effects
Cyclopropanes/therapeutic use
Drug Repositioning
Female
Graft vs Host Disease/drug therapy
Graft vs Leukemia Effect/drug effects
Humans
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Retinoid X Receptors/agonists
T-Lymphocytes, Regulatory/drug effects

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1182/blood.2020005628

Find It

Find It at U of M Libraries

Cite this

Thangavelu, G., Wang, C., Loschi, M., Saha, A., Osborn, M. J., Furlan, S. N., Aoyama, K., Mcdonald-Hyman, C. S., Aguilar, E., Janesick, A. S., Chandraratna, R. A., Refaeli, Y., Panoskaltsis-Mortari, A., MacDonald, K. P., Hill, G. R., Zeiser, R., Maillard, I., Serody, J. S., Murphy, W. J., ... Blazar, B. R. (2021). Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses. Blood, 137(8), 1090-1103. https://doi.org/10.1182/blood.2020005628

Thangavelu, G, Wang, C, Loschi, M, Saha, A , Osborn, MJ, Furlan, SN, Aoyama, K, Mcdonald-Hyman, CS, Aguilar, E, Janesick, AS, Chandraratna, RA, Refaeli, Y, Panoskaltsis-Mortari, A, MacDonald, KP, Hill, GR, Zeiser, R, Maillard, I, Serody, JS, Murphy, WJ, Munn, DH, Blumberg, B, Brown, C, Kuchroo, V, Kean, LS, Hippen, KL, Noelle, RJ & Blazar, BR 2021, 'Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses', Blood, vol. 137, no. 8, pp. 1090-1103. https://doi.org/10.1182/blood.2020005628

@article{e18ff6a64425450f82bbde2e33a9f7ac,

title = "Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses",

abstract = "The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.",

keywords = "Animals, Bone Marrow Transplantation/adverse effects, Cyclopropanes/therapeutic use, Drug Repositioning, Female, Graft vs Host Disease/drug therapy, Graft vs Leukemia Effect/drug effects, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Retinoid X Receptors/agonists, T-Lymphocytes, Regulatory/drug effects",

author = "Govindarajan Thangavelu and Chao Wang and Michael Loschi and Asim Saha and Osborn, {Mark J.} and Furlan, {Scott N.} and Kazutoshi Aoyama and Mcdonald-Hyman, {Cameron S} and Ethan Aguilar and Janesick, {Amanda S.} and Chandraratna, {Roshantha A.} and Yosef Refaeli and Angela Panoskaltsis-Mortari and MacDonald, {Kelli P.} and Hill, {Geoffrey R.} and Robert Zeiser and Ivan Maillard and Serody, {Jonathan S.} and Murphy, {William J.} and Munn, {David H.} and Bruce Blumberg and Chrysothemis Brown and Vijay Kuchroo and Kean, {Leslie S.} and Hippen, {Keli L.} and Noelle, {Randolph J.} and Blazar, {Bruce R.}",

note = "Funding Information: The authors thank Elizabeth Nowak for input. This work was funded by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI034495, and NIH/National Heart, Lung, and Blood Institute grants R01 HL56067 (B.R.B.) and R01 AI091627 (I.M.); Deutsche Forschungsgemeinschaft grants 872/4-1 and SFB1160 TP B09, Deutsche Krebshilfe grant 70113473, Jose-Carreras Leukemia Foundation grant DJCLS 01R/2019 (R.Z); a fellowship from the Canadian Institutes of Health Research (CIHR) (G.T.); and funding from the Leukemia and Lymphoma Society, the Children's Cancer Research Fund, and the KidsFirst Fund (B.R.B.). Conflict-of-interest disclosure: B.R.B. has received remuneration as an advisor to Kamon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics and research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences Inc, and Abbvie Inc. B.R.B. is a cofounder of Tmunity. The remaining authors declare no competing financial interests. Roshantha A. Chandraratna died on 8 January 2019. Funding Information: This work was funded by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI034495, and NIH/National Heart, Lung, and Blood Institute grants R01 HL56067 (B.R.B.) and R01 AI091627 (I.M.); Deutsche Forschungsgemeinschaft grants 872/4-1 and SFB1160 TP B09, Deutsche Krebshilfe grant 70113473, Jose-Carreras Leukemia Foundation grant DJCLS 01R/2019 (R.Z); a fellowship from the Canadian Institutes of Health Research (CIHR) (G.T.); and funding from the Leukemia and Lymphoma Society, the Children's Cancer Research Fund, and the KidsFirst Fund (B.R.B.). Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

year = "2021",

month = feb,

day = "25",

doi = "10.1182/blood.2020005628",

language = "English (US)",

volume = "137",

pages = "1090--1103",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "8",

}

TY - JOUR

T1 - Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses

AU - Thangavelu, Govindarajan

AU - Wang, Chao

AU - Loschi, Michael

AU - Saha, Asim

AU - Osborn, Mark J.

AU - Furlan, Scott N.

AU - Aoyama, Kazutoshi

AU - Mcdonald-Hyman, Cameron S

AU - Aguilar, Ethan

AU - Janesick, Amanda S.

AU - Chandraratna, Roshantha A.

AU - Refaeli, Yosef

AU - Panoskaltsis-Mortari, Angela

AU - MacDonald, Kelli P.

AU - Hill, Geoffrey R.

AU - Zeiser, Robert

AU - Maillard, Ivan

AU - Serody, Jonathan S.

AU - Murphy, William J.

AU - Munn, David H.

AU - Blumberg, Bruce

AU - Brown, Chrysothemis

AU - Kuchroo, Vijay

AU - Kean, Leslie S.

AU - Hippen, Keli L.

AU - Noelle, Randolph J.

AU - Blazar, Bruce R.

N1 - Funding Information: The authors thank Elizabeth Nowak for input. This work was funded by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI034495, and NIH/National Heart, Lung, and Blood Institute grants R01 HL56067 (B.R.B.) and R01 AI091627 (I.M.); Deutsche Forschungsgemeinschaft grants 872/4-1 and SFB1160 TP B09, Deutsche Krebshilfe grant 70113473, Jose-Carreras Leukemia Foundation grant DJCLS 01R/2019 (R.Z); a fellowship from the Canadian Institutes of Health Research (CIHR) (G.T.); and funding from the Leukemia and Lymphoma Society, the Children's Cancer Research Fund, and the KidsFirst Fund (B.R.B.). Conflict-of-interest disclosure: B.R.B. has received remuneration as an advisor to Kamon Pharmaceuticals, Inc, Five Prime Therapeutics Inc, Regeneron Pharmaceuticals, Magenta Therapeutics, and BlueRock Therapeutics and research support from Fate Therapeutics, RXi Pharmaceuticals, Alpine Immune Sciences Inc, and Abbvie Inc. B.R.B. is a cofounder of Tmunity. The remaining authors declare no competing financial interests. Roshantha A. Chandraratna died on 8 January 2019. Funding Information: This work was funded by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases grants P01 AI056299 and R01 AI034495, and NIH/National Heart, Lung, and Blood Institute grants R01 HL56067 (B.R.B.) and R01 AI091627 (I.M.); Deutsche Forschungsgemeinschaft grants 872/4-1 and SFB1160 TP B09, Deutsche Krebshilfe grant 70113473, Jose-Carreras Leukemia Foundation grant DJCLS 01R/2019 (R.Z); a fellowship from the Canadian Institutes of Health Research (CIHR) (G.T.); and funding from the Leukemia and Lymphoma Society, the Children's Cancer Research Fund, and the KidsFirst Fund (B.R.B.). Publisher Copyright: © 2021 American Society of Hematology

PY - 2021/2/25

Y1 - 2021/2/25

N2 - The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.

AB - The nuclear receptor (NR) subclass, retinoid X receptors (RXRs), exert immunomodulatory functions that control inflammation and metabolism via homodimers and heterodimers, with several other NRs, including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers, but not heterodimers. In this study, in vivo IRX4204 compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T-cell proliferation, reducing T-helper 1 differentiation, and promoting regulatory T-cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating proinflammatory pathways. In vitro, inducible Treg differentiation from naive CD4+ T cells was enhanced by IRX4204. In vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage-tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrated that IRX4204 supports Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T-cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be a novel approach to preventing acute GVHD in the clinic.

KW - Animals

KW - Bone Marrow Transplantation/adverse effects

KW - Cyclopropanes/therapeutic use

KW - Drug Repositioning

KW - Female

KW - Graft vs Host Disease/drug therapy

KW - Graft vs Leukemia Effect/drug effects

KW - Humans

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Retinoid X Receptors/agonists

KW - T-Lymphocytes, Regulatory/drug effects

UR - http://www.scopus.com/inward/record.url?scp=85101370442&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85101370442&partnerID=8YFLogxK

U2 - 10.1182/blood.2020005628

DO - 10.1182/blood.2020005628

M3 - Article

C2 - 32976550

AN - SCOPUS:85101370442

SN - 0006-4971

VL - 137

SP - 1090

EP - 1103

JO - Blood

JF - Blood

IS - 8

ER -

Repurposing a novel anti-cancer RXR agonist to attenuate murine acute GVHD and maintain graft-versus-leukemia responses

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this