Journal
CELL
Volume 183, Issue 3, Pages 786-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.09.059
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Funding
- National Institutes of Health (NIH) [R01 CA220234, R01 HL144072, P01 HL131478]
- NWO/ZonMW [Vici 91818622]
- NIH [R01 HL143814, P01HL131478, R01 AI139623]
- AMC PhD Scholarship
- Dutch Cancer Society (AngioSWITCH) [KWF-11651]
- Spinoza grant from the Netherlands Organisation for Scientific Research
- Central Norway Regional Health Authorities
- NCI Career Transition Award [K22CA196750]
- NCI Cancer Center Support Grant [P30-CA19652]
- American Cancer Society postdoctoral fellowship [1K22CA226040-01]
- Netherlands Heart Foundation National Headache Foundation [CVON 2011/B019, CVON 2017-20]
- Competitiveness Operational Programme grant of the Romanian Ministry of European Funds [P_37_762, MySMIS 103587]
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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.
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