Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition
Priem, Bram; van Leent, Mandy M.T.; Teunissen, Abraham J.P.; Sofias, Alexandros Marios; Mourits, Vera P.; Willemsen, Lisa; Klein, Emma D.; Oosterwijk, Roderick S.; Meerwaldt, Anu E.; Munitz, Jazz; Prévot, Geoffrey; Vera Verschuur, Anna; Nauta, Sheqouia A.; van Leeuwen, Esther M.; Fisher, Elizabeth L.; de Jong, Karen A.M.; Zhao, Yiming; Toner, Yohana C.; Soultanidis, Georgios; Calcagno, Claudia; Bomans, Paul H.H.; Friedrich, Heiner; Sommerdijk, Nico; Reiner, Thomas; Duivenvoorden, Raphaël; Zupančič, Eva; Di Martino, Julie S.; Kluza, Ewelina; Rashidian, Mohammad; Ploegh, Hidde L.; Dijkhuizen, Rick M.; Hak, Sjoerd; Pérez-Medina, Carlos; Bravo-Cordero, Jose Javier; de Winther, Menno P.J.; Joosten, Leo A.B.; van Elsas, Andrea; Fayad, Zahi A.; Rialdi, Alexander; Torre, Denis; Guccione, Ernesto; Ochando, Jordi; Netea, Mihai G.; Griffioen, Arjan W.; Mulder, Willem J.M.
(2020) Cell, volume 183, issue 3, pp. 786 - 801.e19
(Article)
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
... read more
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.
show less
Download/Full Text
The full text of this publication is not available.
Keywords: cancer, checkpoint inhibitors, immunotherapy, innate immunity, melanoma, myeloid cells, nanobiologics, nanomedicine, nanotechnology, trained immunity, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 0092-8674
Publisher: Cell Press
Note: Funding Information: The authors thank the Icahn School of Medicine and the Amsterdam UMC. They would also like to extend their gratitude to the following Mount Sinai core facilities: flow cytometry core, microscopy core, CCMS, and BMEII's preclinical imaging core as well as the animal facility at the VU Amsterdam. We thank Kaley Joyes for editing the manuscript. This work was supported by National Institutes of Health (NIH) grants R01 CA220234, R01 HL144072, P01 HL131478, and NWO/ZonMW Vici 91818622 (all to W.J.M.M.); NIH grants R01 HL143814, P01HL131478 (Z.A.F.), and R01 AI139623 (J.O.). B.P. was supported by the AMC PhD Scholarship. A.W.G. was supported by a grant from the Dutch Cancer Society (AngioSWITCH, KWF-11651); M.G.N. was supported by a Spinoza grant from the Netherlands Organisation for Scientific Research; S.H. and A.M.S. are supported by grants from the Central Norway Regional Health Authorities; J.J.B.C. is supported by an NCI Career Transition Award (K22CA196750) and NCI Cancer Center Support Grant P30-CA19652; M.R. is supported by American Cancer Society postdoctoral fellowship (1K22CA226040-01); M.P.J.d.W. is supported by the The Netherlands Heart Foundation National Headache Foundation (CVON 2011/ B019 and CVON 2017-20); and L.A.B.J. was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587). W.J.M.M. developed and supervised the study. B.P. M.M.T.v.L. A.W.G. M.G.N. and W.J.M.M. designed experiments. W.J.M.M. M.G.N. and A.J.P.T. designed the nanobiologics, and E.D.K. K.A.M.J. Y.Z. G.P. T.R. and C.P.M. produced, (radio)labeled, and analyzed nanobiologics. V.P.M. L.A.B.J. and M.G.N. designed, executed, and analyzed in vitro trained immunity experiments. B.P. M.M.T.v.L. A.M.S. E.D.K. R.S.O. A.E.M. J.M. A.V.V. E.M.L. E.L.F. Y.Z. Y.C.T. E.Z. J.S.D.M. A.v.E. C.P.M. J.J.B.C. and A.W.G. coordinated and performed in vivo and ex vivo mouse studies. In vivo imaging experiments were performed, analyzed, and interpreted by B.P. M.M.T.v.L. E.D.K. R.S.O. A.E.M. E.L.F. Y.C.T. A.M.S. J.S.D.M. J.J.B.C. S.H. R.M.D. M.R. J.M. G.S. C.C. S.A.N. H.L.P. and Z.A.F. Flow cytometry was performed and analyzed by B.P. M.M.T.v.L. Y.C.T. and J.O. RNA sequencing and ATAC sequencing were performed and analyzed by L.W. E.K. A.R. D.T. M.P.J.d.W. and E.G. CryoTEM was performed and interpreted by P.H.H.B. H.F. and N.S. B.P. M.M.T.v.L. A.W.G. and W.J.M.M. wrote the manuscript and produced the figures. All authors contributed to writing the manuscript and approved the final draft. B.P. Z.A.F. M.G.N. A.W.G. and W.J.M.M. provided funding. W.J.M.M. L.A.B.J. J.O. Z.A.F. and M.G.N. are scientific co-founders of and have equity in Trained Therapeutix Discovery. W.J.M.M. and Z.A.F. have consulting agreements with Trained Therapeutix Discovery. Funding Information: This work was supported by National Institutes of Health ( NIH ) grants R01 CA220234 , R01 HL144072 , P01 HL131478 , and NWO /ZonMW Vici 91818622 (all to W.J.M.M.); NIH grants R01 HL143814 , P01HL131478 (Z.A.F.), and R01 AI139623 (J.O.). B.P. was supported by the AMC PhD Scholarship. A.W.G. was supported by a grant from the Dutch Cancer Society (AngioSWITCH, KWF-11651 ); M.G.N. was supported by a Spinoza grant from the Netherlands Organisation for Scientific Research ; S.H. and A.M.S. are supported by grants from the Central Norway Regional Health Authorities ; J.J.B.C. is supported by an NCI Career Transition Award ( K22CA196750 ) and NCI Cancer Center Support Grant P30-CA19652 ; M.R. is supported by American Cancer Society postdoctoral fellowship ( 1K22CA226040-01 ); M.P.J.d.W. is supported by the The Netherlands Heart Foundation National Headache Foundation ( CVON 2011/ B019 and CVON 2017-20 ); and L.A.B.J. was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587 ). Publisher Copyright: © 2020 Elsevier Inc.
(Peer reviewed)