Magnitude of Off-Target Allo-HLA Reactivity by Third-Party Donor-Derived Virus-Specific T Cells Is Dictated by HLA-Restriction.

Wesley Huisman,Lois Hageman,J H Frederik Falkenburg,Didier A T Leboux,Inge Jedema,Lieve E Van Der Maarel,Derk Amsen

doi:10.3389/fimmu.2021.630440

Wesley Huisman, Lois Hageman + Show 5 more

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https://doi.org/10.3389/fimmu.2021.630440

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Abstract

T-cell products derived from third-party donors are clinically applied, but harbor the risk of off-target toxicity via induction of allo-HLA cross-reactivity directed against mismatched alleles. We used third-party donor-derived virus-specific T cells as model to investigate whether virus-specificity, HLA restriction and/or HLA background can predict the risk of allo-HLA cross-reactivity. Virus-specific CD8pos T cells were isolated from HLA-A*01:01/B*08:01 or HLA-A*02:01/B*07:02 positive donors. Allo-HLA cross-reactivity was tested using an EBV-LCL panel covering 116 allogeneic HLA molecules and confirmed using K562 cells retrovirally transduced with single HLA-class-I alleles of interest. HLA-B*08:01-restricted T cells showed the highest frequency and diversity of allo-HLA cross-reactivity, regardless of virus-specificity, which was skewed toward multiple recurrent allogeneic HLA-B molecules. Thymic selection for other HLA-B alleles significantly influenced the level of allo-HLA cross-reactivity mediated by HLA-B*08:01-restricted T cells. These results suggest that the degree and specificity of allo-HLA cross-reactivity by T cells follow rules. The risk of off-target toxicity after infusion of incompletely matched third-party donor-derived virus-specific T cells may be reduced by selection of T cells with a specific HLA restriction and background.

Highlights

Adoptive transfer of autologous or human leukocyte antigen (HLA)-matched patient-specific T-cell products, including antigen-specific T cells, Chimeric Antigen Receptor (CAR) T cells and T-cell receptor (TCR) modified T cells are clinically applied and show feasibility and safety [1,2,3,4,5]
To study the influence of HLA restriction and antigen specificity on the level of allo-HLA cross-reactivity mediated by virus-specific T cells, bulk virus-specific T-cell populations targeting single epitopes were isolated from total Peripheral blood mononuclear cells (PBMCs) of HLA-A∗01:01/HLA-B∗08:01pos or HLA-A ∗02:01/HLA-B∗07:02pos healthy donors
We demonstrated that 50% (83/164) of virusspecific T-cell populations contained T cells that cross-reacted against HLA-mismatched Epstein-Barr virus (EBV)-LCLs, in line with previous findings [11]

Summary

Introduction

Adoptive transfer of autologous or human leukocyte antigen (HLA)-matched patient-specific T-cell products, including antigen-specific T cells, Chimeric Antigen Receptor (CAR) T cells and T-cell receptor (TCR) modified T cells are clinically applied and show feasibility and safety [1,2,3,4,5]. In our study we focused on virus-specific T-cell products derived from healthy third-party donors that can be used for the treatment of uncontrolled viral reactivations and/or viral disease in patients without easy access to autologous or donorderived virus-specific T cells. Adoptive transfer of partially HLA-matched virus-specific T cells from healthy third-party donors is a potential strategy to temporarily provide anti-viral immunity to these patients. These third party donorderived virus-specific T cells have not been tolerized by thymic negative selection to the non-matched HLA molecules that are present within the patient [8, 9], thereby implying the risk of offtarget toxicity due to allo-HLA cross-reactivity directed against the mismatched HLA alleles [10]

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