Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia

The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies. This is attributed to a shortage of leukemia-specific cell-surface antigens that...

Full description

Saved in:

Bibliographic Details
Published in:	Frontiers in immunology Vol. 14; p. 1294555
Main Authors:	Branella, Gianna M, Lee, Jasmine Y, Okalova, Jennifer, Parwani, Kiran K, Alexander, Jordan S, Arthuzo, Raquel F, Fedanov, Andrew, Yu, Bing, McCarty, David, Brown, Harrison C, Chandrakasan, Shanmuganathan, Petrich, Brian G, Doering, Christopher B, Spencer, H Trent
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 2023
Subjects:	acute myeloid leukemia (AML) Animals chimeric antigen receptor (CAR) gamma delta (γδ) T cells Immunotherapy, Adoptive Leukemia, Myeloid, Acute ligand-based therapeutics Ligands Mice Proto-Oncogene Proteins c-kit - genetics Receptor Protein-Tyrosine Kinases secreted bispecific T cell engager Stem Cell Factor stem cell factor (SCF) c-kit (CD117) chimeric antigen receptor (CAR) ligand-based therapeutics acute myeloid leukemia (AML) stem cell factor (SCF) gamma delta (γδ) T cells secreted bispecific T cell engager
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies. This is attributed to a shortage of leukemia-specific cell-surface antigens that distinguish healthy from malignant myeloid populations, and the inability to manage myeloid depletion unlike B-cell aplasia. Therefore, the development of targeted therapeutics for myeloid malignancies, such as acute myeloid leukemia (AML), requires new approaches. Herein, we developed a ligand-based CAR and secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF). c-kit is highly expressed on AML blasts and correlates with resistance to chemotherapy and poor prognosis, making it an ideal candidate for which to develop targeted therapeutics. We utilize γδ T cells as a cytotoxic alternative to αβ T cells and a transient transfection system as both a safety precaution and switch to remove alloreactive modified cells that may hinder successful transplant. Additionally, the use of γδ T cells permits its use as an allogeneic, off-the-shelf therapeutic. To this end, we show mSCF CAR- and hSCF sBite-modified γδ T cells are proficient in killing c-kit AML cell lines and sca-1 murine bone marrow cells . , hSCF sBite-modified γδ T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of γδ T-cell homing to murine bone marrow. Together, these data demonstrate preclinical efficacy and support further investigation of SCF-based γδ T-cell therapeutics for the treatment of myeloid malignancies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2023.1294555