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

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• 作者：Qing Ma¹ ; ^&dagger ; ; Haven R. Garber¹ ; ^&dagger ; ; Sijie Lu¹ ; Hong He¹ ; Eran Tallis¹ ; Xiaoling Ding¹ ; Anna Sergeeva¹ ; Michael S. Wood² ; Gianpietro Dotti² ; Barbara Salvado² ; Kathryn Ruisaard¹ ; Karen Clise-Dwyer¹ ; Lisa St John¹ ; Katayoun Rezvani¹ ; Gheath Alatrash¹ ; Elizabeth J. Shpall¹ ; Jeffrey J. Molldrem¹ ; ^{jmolldre@mdanderson.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：acute myeloid leukemia (AML) ; CAR-T cell ; h8F4 ; PR1 ; UCB
• 刊名：Cytotherapy
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：18
• 期：8
• 页码：985-994
• 全文大小：1535 K

文摘

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.

Methods

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.

Results

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.

Conclusions

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.