TY - JOUR
T1 - A dual-receptor T-cell platform with Ab-TCR and costimulatory receptor achieves specificity and potency against AML
AU - Dao, Tao
AU - Xiong, Guangyan
AU - Mun, Sung Soo
AU - Meyerberg, Jeremy
AU - Korontsvit, Tatyana
AU - Xiang, Jingyi
AU - Cui, Ziyou
AU - Chang, Aaron Y.
AU - Jarvis, Casey
AU - Cai, Winson
AU - Luo, Hanzhi
AU - Pierson, Aspen
AU - Daniyan, Anthony
AU - Yoo, Sarah
AU - Takao, Sumiko
AU - Kharas, Michael
AU - Kentsis, Alex
AU - Liu, Cheng
AU - Scheinberg, David A.
N1 - © 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
PY - 2024/2/8
Y1 - 2024/2/8
N2 - Chimeric antigen receptor T-cell (CAR T) therapy has produced remarkable clinical responses in B-cell neoplasms. However, many challenges limit this class of agents for the treatment of other cancer types, in particular the lack of tumor-selective antigens for solid tumors and other hematological malignancies, such as acute myeloid leukemia (AML), which may be addressed without significant risk of severe toxicities while providing sufficient abundance for efficient tumor suppression. One approach to overcome this hurdle is dual targeting by an antibody–T-cell receptor (AbTCR) and a chimeric costimulatory signaling receptor (CSR) to 2 different antigens, in which both antigens are found together on the cancer cells but not together on normal cells. To explore this proof of concept in AML, we engineered a new T-cell format targeting Wilms tumor 1 protein (WT1) and CD33; both are highly expressed on most AML cells. Using an AbTCR comprising a newly developed TCR-mimic monoclonal antibody against the WT1 RMFPNAPYL (RMF) epitope/HLA-A2 complex, ESK2, and a secondary CSR comprising a single-chain variable fragment directed to CD33 linked to a truncated CD28 costimulatory fragment, this unique platform confers specific T-cell cytotoxicity to the AML cells while sparing healthy hematopoietic cells, including CD33
+ myelomonocytic normal cells. These data suggest that this new platform, named AbTCR-CSR, through the combination of a AbTCR CAR and CSR could be an effective strategy to reduce toxicity and improve specificity and clinical outcomes in adoptive T-cell therapy in AML.
AB - Chimeric antigen receptor T-cell (CAR T) therapy has produced remarkable clinical responses in B-cell neoplasms. However, many challenges limit this class of agents for the treatment of other cancer types, in particular the lack of tumor-selective antigens for solid tumors and other hematological malignancies, such as acute myeloid leukemia (AML), which may be addressed without significant risk of severe toxicities while providing sufficient abundance for efficient tumor suppression. One approach to overcome this hurdle is dual targeting by an antibody–T-cell receptor (AbTCR) and a chimeric costimulatory signaling receptor (CSR) to 2 different antigens, in which both antigens are found together on the cancer cells but not together on normal cells. To explore this proof of concept in AML, we engineered a new T-cell format targeting Wilms tumor 1 protein (WT1) and CD33; both are highly expressed on most AML cells. Using an AbTCR comprising a newly developed TCR-mimic monoclonal antibody against the WT1 RMFPNAPYL (RMF) epitope/HLA-A2 complex, ESK2, and a secondary CSR comprising a single-chain variable fragment directed to CD33 linked to a truncated CD28 costimulatory fragment, this unique platform confers specific T-cell cytotoxicity to the AML cells while sparing healthy hematopoietic cells, including CD33
+ myelomonocytic normal cells. These data suggest that this new platform, named AbTCR-CSR, through the combination of a AbTCR CAR and CSR could be an effective strategy to reduce toxicity and improve specificity and clinical outcomes in adoptive T-cell therapy in AML.
KW - Humans
KW - Immunotherapy, Adoptive
KW - Leukemia, Myeloid, Acute/pathology
KW - Receptors, Antigen, T-Cell
KW - Single-Chain Antibodies
KW - T-Lymphocytes
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:001184059500001&DestLinkType=FullRecord&DestApp=WOS_CPL
UR - http://www.scopus.com/inward/record.url?scp=85182647971&partnerID=8YFLogxK
U2 - 10.1182/blood.2023021054
DO - 10.1182/blood.2023021054
M3 - Article
C2 - 38048594
SN - 0006-4971
VL - 143
SP - 507
EP - 521
JO - Blood
JF - Blood
IS - 6
ER -