Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition

Bram Priem; Mandy M.T. van Leent; Abraham J.P. Teunissen; Alexandros Marios Sofias; Vera P. Mourits; Lisa Willemsen; Emma D. Klein; Roderick S. Oosterwijk; Anu E. Meerwaldt; Jazz Munitz; Geoffrey Prévot; Anna Vera Verschuur; Sheqouia A. Nauta; Esther M. van Leeuwen; Elizabeth L. Fisher; Karen A.M. de Jong; Yiming Zhao; Yohana C. Toner; Georgios Soultanidis; Claudia Calcagno; Paul H.H. Bomans; Heiner Friedrich; Nico Sommerdijk; Thomas Reiner; Raphaël Duivenvoorden; Eva Zupančič; Julie S. Di Martino; Ewelina Kluza; Mohammad Rashidian; Hidde L. Ploegh; Rick M. Dijkhuizen; Sjoerd Hak; Carlos Pérez-Medina; Jose Javier Bravo-Cordero; Menno P.J. de Winther; Leo A.B. Joosten; Andrea van Elsas; Zahi A. Fayad; Alexander Rialdi; Denis Torre; Ernesto Guccione; Jordi Ochando; Mihai G. Netea; Arjan W. Griffioen; Willem J.M. Mulder

doi:10.1016/j.cell.2020.09.059

Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition

Bram Priem, Mandy M.T. van Leent, Abraham J.P. Teunissen, Alexandros Marios Sofias, Vera P. Mourits, Lisa Willemsen, Emma D. Klein, Roderick S. Oosterwijk, Anu E. Meerwaldt, Jazz Munitz, Geoffrey Prévot, Anna Vera Verschuur, Sheqouia A. Nauta, Esther M. van Leeuwen, Elizabeth L. Fisher, Karen A.M. de Jong, Yiming Zhao, Yohana C. Toner, Georgios Soultanidis, Claudia CalcagnoPaul H.H. Bomans, Heiner Friedrich, Nico Sommerdijk, Thomas Reiner, Raphaël Duivenvoorden, Eva Zupančič, Julie S. Di Martino, Ewelina Kluza, Mohammad Rashidian, Hidde L. Ploegh, Rick M. Dijkhuizen, Sjoerd Hak, Carlos Pérez-Medina, Jose Javier Bravo-Cordero, Menno P.J. de Winther, Leo A.B. Joosten, Andrea van Elsas, Zahi A. Fayad, Alexander Rialdi, Denis Torre, Ernesto Guccione, Jordi Ochando, Mihai G. Netea, Arjan W. Griffioen, Willem J.M. Mulder

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134 Scopus citations

Abstract

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP₁₀-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP₁₀-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP₁₀-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

Original language	English
Pages (from-to)	786-801.e19
Journal	Cell
Volume	183
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2020.09.059
State	Published - 29 Oct 2020

Keywords

cancer
checkpoint inhibitors
immunotherapy
innate immunity
melanoma
myeloid cells
nanobiologics
nanomedicine
nanotechnology
trained immunity

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10.1016/j.cell.2020.09.059

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Priem, B., van Leent, M. M. T., Teunissen, A. J. P., Sofias, A. M., Mourits, V. P., Willemsen, L., Klein, E. D., Oosterwijk, R. S., Meerwaldt, A. E., Munitz, J., Prévot, G., Vera Verschuur, A., Nauta, S. A., van Leeuwen, E. M., Fisher, E. L., de Jong, K. A. M., Zhao, Y., Toner, Y. C., Soultanidis, G., ... Mulder, W. J. M. (2020). Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition. Cell, 183(3), 786-801.e19. https://doi.org/10.1016/j.cell.2020.09.059

@article{4155c20c95a7475eb548e9dbeaccd5cf,

title = "Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition",

abstract = "Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.",

keywords = "cancer, checkpoint inhibitors, immunotherapy, innate immunity, melanoma, myeloid cells, nanobiologics, nanomedicine, nanotechnology, trained immunity",

author = "Bram Priem and {van Leent}, {Mandy M.T.} and Teunissen, {Abraham J.P.} and Sofias, {Alexandros Marios} and Mourits, {Vera P.} and Lisa Willemsen and Klein, {Emma D.} and Oosterwijk, {Roderick S.} and Meerwaldt, {Anu E.} and Jazz Munitz and Geoffrey Pr{\'e}vot and {Vera Verschuur}, Anna and Nauta, {Sheqouia A.} and {van Leeuwen}, {Esther M.} and Fisher, {Elizabeth L.} and {de Jong}, {Karen A.M.} and Yiming Zhao and Toner, {Yohana C.} and Georgios Soultanidis and Claudia Calcagno and Bomans, {Paul H.H.} and Heiner Friedrich and Nico Sommerdijk and Thomas Reiner and Rapha{\"e}l Duivenvoorden and Eva Zupan{\v c}i{\v c} and {Di Martino}, {Julie S.} and Ewelina Kluza and Mohammad Rashidian and Ploegh, {Hidde L.} and Dijkhuizen, {Rick M.} and Sjoerd Hak and Carlos P{\'e}rez-Medina and Bravo-Cordero, {Jose Javier} and {de Winther}, {Menno P.J.} and Joosten, {Leo A.B.} and {van Elsas}, Andrea and Fayad, {Zahi A.} and Alexander Rialdi and Denis Torre and Ernesto Guccione and Jordi Ochando and Netea, {Mihai G.} and Griffioen, {Arjan W.} and Mulder, {Willem J.M.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = oct,

day = "29",

doi = "10.1016/j.cell.2020.09.059",

language = "English",

volume = "183",

pages = "786--801.e19",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "3",

}

Priem, B, van Leent, MMT , Teunissen, AJP, Sofias, AM, Mourits, VP, Willemsen, L, Klein, ED, Oosterwijk, RS, Meerwaldt, AE, Munitz, J, Prévot, G, Vera Verschuur, A, Nauta, SA, van Leeuwen, EM, Fisher, EL, de Jong, KAM, Zhao, Y, Toner, YC, Soultanidis, G, Calcagno, C, Bomans, PHH, Friedrich, H, Sommerdijk, N, Reiner, T, Duivenvoorden, R, Zupančič, E, Di Martino, JS, Kluza, E, Rashidian, M, Ploegh, HL, Dijkhuizen, RM, Hak, S, Pérez-Medina, C, Bravo-Cordero, JJ, de Winther, MPJ, Joosten, LAB, van Elsas, A, Fayad, ZA, Rialdi, A, Torre, D, Guccione, E , Ochando, J, Netea, MG, Griffioen, AW & Mulder, WJM 2020, 'Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition', Cell, vol. 183, no. 3, pp. 786-801.e19. https://doi.org/10.1016/j.cell.2020.09.059

TY - JOUR

T1 - Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition

AU - Priem, Bram

AU - van Leent, Mandy M.T.

AU - Teunissen, Abraham J.P.

AU - Sofias, Alexandros Marios

AU - Mourits, Vera P.

AU - Willemsen, Lisa

AU - Klein, Emma D.

AU - Oosterwijk, Roderick S.

AU - Meerwaldt, Anu E.

AU - Munitz, Jazz

AU - Prévot, Geoffrey

AU - Vera Verschuur, Anna

AU - Nauta, Sheqouia A.

AU - van Leeuwen, Esther M.

AU - Fisher, Elizabeth L.

AU - de Jong, Karen A.M.

AU - Zhao, Yiming

AU - Toner, Yohana C.

AU - Soultanidis, Georgios

AU - Calcagno, Claudia

AU - Bomans, Paul H.H.

AU - Friedrich, Heiner

AU - Sommerdijk, Nico

AU - Reiner, Thomas

AU - Duivenvoorden, Raphaël

AU - Zupančič, Eva

AU - Di Martino, Julie S.

AU - Kluza, Ewelina

AU - Rashidian, Mohammad

AU - Ploegh, Hidde L.

AU - Dijkhuizen, Rick M.

AU - Hak, Sjoerd

AU - Pérez-Medina, Carlos

AU - Bravo-Cordero, Jose Javier

AU - de Winther, Menno P.J.

AU - Joosten, Leo A.B.

AU - van Elsas, Andrea

AU - Fayad, Zahi A.

AU - Rialdi, Alexander

AU - Torre, Denis

AU - Guccione, Ernesto

AU - Ochando, Jordi

AU - Netea, Mihai G.

AU - Griffioen, Arjan W.

AU - Mulder, Willem J.M.

PY - 2020/10/29

Y1 - 2020/10/29

N2 - Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

AB - Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

KW - cancer

KW - checkpoint inhibitors

KW - immunotherapy

KW - innate immunity

KW - melanoma

KW - myeloid cells

KW - nanobiologics

KW - nanomedicine

KW - nanotechnology

KW - trained immunity

UR - http://www.scopus.com/inward/record.url?scp=85094983590&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.09.059

DO - 10.1016/j.cell.2020.09.059

M3 - Article

C2 - 33125893

AN - SCOPUS:85094983590

SN - 0092-8674

VL - 183

SP - 786-801.e19

JO - Cell

JF - Cell

IS - 3

ER -

Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition

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Keywords

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