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Ref Type Journal Article
PMID (27265873)
Authors Ma Q, Garber HR, Lu S, He H, Tallis E, Ding X, Sergeeva A, Wood MS, Dotti G, Salvado B, Ruisaard K, Clise-Dwyer K, John LS, Rezvani K, Alatrash G, Shpall EJ, Molldrem JJ
Title A novel TCR-like CAR with specificity for PR1/HLA-A2 effectively targets myeloid leukemia in vitro when expressed in human adult peripheral blood and cord blood T cells.
Journal Cytotherapy
Vol 18
Issue 8
Date 2016 08
URL
Abstract Text The PR1 peptide, derived from the leukemia-associated antigens proteinase 3 and neutrophil elastase, is overexpressed on HLA-A2 in acute myeloid leukemia (AML). We developed a T-cell receptor (TCR)-like monoclonal antibody (8F4) that binds the PR1/HLA-A2 complex on the surface of AML cells, efficiently killing them in vitro and eliminating them in preclinical models. Humanized 8F4 (h8F4) with high affinity for the PR1/HLA-A2 epitope was used to construct an h8F4- chimeric antigen receptor (CAR) that was transduced into T cells to mediate anti-leukemia activity.Human T cells were transduced to express the PR1/HLA-A2-specific CAR (h8F4-CAR-T cells) containing the scFv of h8F4 fused to the intracellular signaling endo-domain of CD3 zeta chain through the transmembrane and intracellular costimulatory domain of CD28.Adult human normal peripheral blood (PB) T cells were efficiently transduced with the h8F4-CAR construct and predominantly displayed an effector memory phenotype with a minor population (12%) of central memory cells in vitro. Umbilical cord blood (UCB) T cells could also be efficiently transduced with the h8F4-CAR. The PB and UCB-derived h8F4-CAR-T cells specifically recognized the PR1/HLA-A2 complex and were capable of killing leukemia cell lines and primary AML blasts in an HLA-A2-dependent manner.Human adult PB and UCB-derived T cells expressing a CAR derived from the TCR-like 8F4 antibody rapidly and efficiently kill AML in vitro. Our data could lead to a new treatment paradigm for AML in which targeting leukemia stem cells could transfer long-term immunity to protect against relapse.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
H8F4 CAR-T cells H8F4 CAR-T cells 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
H8F4 CAR-T cells H8F4 CAR-T cells are T-cells engineered to expressed a chimeric antigen receptor (CAR) directed against PR1/HLA-A2, which potentially results in decreased tumor growth (PMID: 27265873).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown leukemia not applicable H8F4 CAR-T cells Preclinical - Cell culture Actionable In a preclinical study, h8F4 CAR-T cells induced lysis of leukemia cell lines expressing PR1/HLA-A2 in culture (PMID: 27265873). 27265873