Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition. Cell. 2020 Oct 29;183(3):786-801.e19.
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.
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.
doi: 10.1016/j.cell.2020.09.059. PMID: 33125893; PMCID: PMC8074872.
