T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: Towards tumor-directed oligoclonal T cell therapy

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• 作者：Fatemeh Rahimi Jamnani ; Fatemeh Rahbarizadeh ; Mohammad Ali Shokrgozar ; Fereidoun Mahboudi ; Davoud Ahmadv ; Zahra Sharifzadeh ; Ladan Parhamifar ; S. Moein Moghimi
• 关键词：CAR ; chimeric antigen receptor ; CDR ; complementarity determining region ; HCAb ; heavy-chain antibodies ; IPTG ; isopropyl-尾-D-thio-galactoside ; MHC ; major histocompatibility complex ; TAG 72 ; tumor associated glycoprotein 72 ; TCR ; T cell receptor ; TMB ; 3 ; 3&prime ; 5 ; 5&prime ; -tetramethyl benzidine ; VHH ; variable domain of camel heavy-chain antibody ; VHH-CAR ; VHH-chimeric antigen receptor
• 刊名：Biochimica et Biophysica Acta (BBA)/General Subjects
• 出版年：January, 2014
• 年：2014
• 卷：1840
• 期：1
• 页码：378-386
• 全文大小：1219 K

文摘

Background

Adoptive cell therapy with engineered T cells expressing chimeric antigen receptors (CARs) originated from antibodies is a promising strategy in cancer immunotherapy. Several unsuccessful trials, however, highlight the need for alternative conventional binding domains and the better combination of costimulatory endodomains for CAR construction to improve the effector functions of the engineered T cells. Camelid single-domain antibodies (VHHs), which are the smallest single domain antibodies, can endow great targeting ability to CAR-engineered T cells.

Methods

We have developed a method to generate genetically engineered Jurkat T cells armed with a CAR comprising the anti-HER2 VHH as targeting moiety. From an immune camel library, five VHH clones were selected as a set of oligoclonal anti-HER2 VHHs that exhibited diverse binding abilities and joined them to CD28-CD3味 and CD28-OX40-CD3味 signaling endodomains. Jurkat T cells expression of VHH-CARs and cell functions were evaluated.

Results

The oligoclonal engineered T cells showed higher proliferation, cytokine secretion and cytotoxicity than each individual VHH-CAR-engineered Jurkat T cells.

Conclusions

The combination of superior targeting ability of oligoclonal VHHs with the third generation CAR can substantially improve the function of engineered T cells.

General significance

Antigen-specific directed oligoclonal T cells are alternatively promising, but safer systems, to combat tumor cells.