Nanoparticle T cell engagers for the treatment of acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is the most common type of leukemia and has a 5-year survival rate of 25%. The standard-of-care for AML has not changed in the past few decades. Promising immunotherapy options are being developed for the treatment of AML; yet, these regimens require highly laborious and sophisticated techniques. We create nanoTCEs using liposomes conjugated to monoclonal antibodies to enable specific binding. We also recreate the bone marrow niche using our 3D culture system and use immunocompromised mice to enable use of human AML and T cells with nanoTCEs. We show that CD33 is ubiquitously present on AML cells. The CD33 nanoTCEs bind preferentially to AML cells compared to Isotype. We show that nanoTCEs effectively activate T cells and induce AML killing in vitro and in vivo . Our findings suggest that our nanoTCE technology is a novel and promising immuno-therapy for the treatment of AML and provides a basis for supplemental investigations for the validation of using nanoTCEs in larger animals and patients.

The Potential Role of 3D In Vitro Acute Myeloid Leukemia Culture Models in Understanding Drug Resistance in Leukemia Stem Cells

“…However, their efficacy and safety profiles are not well-investigated. A group of investigators utilized 3D tissue-engineered bone marrow (3DTEBM) as a platform to test the efficacy of a novel nanoparticle T cell engager (nano-TCE) in killing AML cells in vitro [ 43 ]. Thus, the use of 3D models in the era of targeted immunotherapy can serve as a preliminary platform to assess the efficacy and safety of emerging therapeutic agents specific to AML.…”

Glycans as Targets for Drug Delivery in Cancer

“…By actively supporting the establishment of an immunosuppressive microenvironment, GBPs have emerged as promising targets of more efficient immunotherapies. Several studies have developed NPs functionalized with a mAb targeting Siglec-3 (CD33), which is abundantly expressed on the surface of acute myeloid leukaemia cells [ 124 , 125 , 126 , 127 ]. Furthermore, novel bi-specific liposomal-based NP T cell engagers (nanoTCEs) are conjugated with two mAbs targeting two distinct epitopes, one being a cancer antigen, and the other the Siglec-3 [ 124 ].…”

“…Several studies have developed NPs functionalized with a mAb targeting Siglec-3 (CD33), which is abundantly expressed on the surface of acute myeloid leukaemia cells [ 124 , 125 , 126 , 127 ]. Furthermore, novel bi-specific liposomal-based NP T cell engagers (nanoTCEs) are conjugated with two mAbs targeting two distinct epitopes, one being a cancer antigen, and the other the Siglec-3 [ 124 ]. This formulation has shown to be efficient in the targeting and killing of AML cells, both in vitro and in vivo.…”