St. Jude Reference #SJ-22-0021
Description
The lack of targetable antigens is a key limitation for developing successful T cell-based immunotherapies. Members of the unfolded protein response (UPR) represent ideal immunotherapy targets because they are overexpressed on cancer cells and correlate with metastatic potential. Current choices for single chimeric antigen receptors that recognize more than one antigen are few; and those that do exist use two single chain variable fragments (scFv) with one linker, with the size of both scFvs increasing the potential for steric hindrance.
Researchers at St. Jude generated a bispecific chimeric antigen receptor which uses a combination of a peptide and single chain variable fragment as a dual specificity antigen binding domain targeting GRP78 (glucose related protein 78) and CD123, two antigens widely present on the cell surface of many pediatric solid and brain tumors, including AML. They designed 4 different constructs with 4 unique linkers between the two binding domains to be used as a cellular therapy for the treatment of GRP78+/CD123+ acute myeloid leukemias (AML), aiming to bolster antitumor activity and to prevent immune escape.
A single infusion of the GRP78.CD123 bispecific-CAR T cells had potent anti-AML activity, resulting in a significant survival advantage. This CAR can be expressed in several immune cells (for example but not limited to γδ T cells, iNKT cells, NK cells, or macrophages). Further, this peptide- scFv antigen binding domains can be broadly applied to other bispecific CAR T cell designs.
Keywords
Immunotherapy, acute myeloid leukemia (AML), CD123, Glucose-regulated-protein 78 (GRP78), bispecific, dual targer chimeric antigen receptor, CAR, γδ T cells, iNKT cells, NK cells, macrophages, hematological malignancies, solid tumors.
Granted patents or published applications
Application published June 20, 2023 as WO 2023/137069
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