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

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. [Display omitted] •We have developed a trained immunity-inducing nanobiologic therapeutic named MTP-HDL•MTP-HDL favorably accumulates in hematopoietic organs of mice and non-human primates•MTP-HDL nanotherapy induces trained immunity through bone marrow progenitors in vivo•MTP-HDL nanotherapy inhibits tumor growth and potentiates immune checkpoint inhibition A bone marrow targeted nanobiologic platform that is designed to elicit trained immunity responses has the ability to reduce tumor growth and augment immune checkpoint blockade.