Construction and Functional Characterization of a Fully Human Anti-mesothelin Chimeric Antigen Receptor (CAR) Expressing T Cell

  • Leila Jafarzadeh Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Elham Masoumi Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Department of Immunology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
  • Khadijeh Alishah Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
  • Hamid Reza Mirzaei Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Arezoo Jamali Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institute, Langen, Germany AND Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
  • Keyvan Fallah-Mehrjardi Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Hosein Rostamian Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Mohammad Khakpoor-Koosheh Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Reza Meshkani Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Farshid Noorbakhsh Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  • Jamshid Hadjati Department of Medical Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Keywords:
Adoptive immunotherapy, Chimeric antigen receptor, Mesothelin

Abstract

Chimeric antigen receptor (CAR) T cell therapy is considered as an encouraging approach for
the treatment of hematological malignancies. However, its efficacy in solid tumors has not been satisfying, mainly in the immunosuppressive network of the tumor microenvironment and paucity of appropriate target antigens. Mesothelin (MSLN) is a tumor-associated antigen (TAA) expressed in numerous types of solid tumors such as gastrointestinal, ovarian, and pancreatic tumors. Owing to high expression in tumor cells and low expression in normal tissues, MSLN-targeted therapies like monoclonal antibodies have been previously developed.
In the present study, a CAR T cell harboring the second-generation of a fully human anti-MSLN-CAR construct containing CD3ζ and 4-1BB signaling domains was produced and it was functionally evaluated against an MSLN-expressing cell line.
The findings showed potent, specific proliferation, cytotoxic activity, and interleukin (IL)-2, Tumor necrosis factor-(TNF) α, and Interferon-(IFN) γ production in an antigen-dependent manner. Cytotoxic activity was shown in effector-to-target ratio from 1:1 to 20:1, but the most adequate efficacy was observed in the ratio of 10:1. Non-specific activity against MSLN negative cell line was not observed.
Our data demonstrated that primary human T cells expressing fully human MSLN-CAR construct are effective against MSLN-expressing cell lines in vitro, suggesting this MSLN-CAR construct as a potential therapeutic tool in a clinical setting.

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Published
2020-06-23
How to Cite
1.
Jafarzadeh L, Masoumi E, Alishah K, Mirzaei HR, Jamali A, Fallah-Mehrjardi K, Rostamian H, Khakpoor-Koosheh M, Meshkani R, Noorbakhsh F, Hadjati J. Construction and Functional Characterization of a Fully Human Anti-mesothelin Chimeric Antigen Receptor (CAR) Expressing T Cell. Iran J Allergy Asthma Immunol. 19(3):264-275.
Section
Original Article(s)