Designed Ankyrin Repeat Protein (DARPin) to target chimeric antigen receptor (CAR)-redirected T cells towards CD4 + T ce
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ORIGINAL INVESTIGATION
Designed Ankyrin Repeat Protein (DARPin) to target chimeric antigen receptor (CAR)‑redirected T cells towards CD4+ T cells to reduce the latent HIV+ cell reservoir Lea Patasic1 · Janna Seifried1,7 · Valerie Bezler5 · Marcell Kaljanac5 · Irene C. Schneider2 · Heike Schmitz1 · Christiane Tondera1 · Jessica Hartmann2 · Andreas Hombach3 · Christian J. Buchholz2 · Hinrich Abken3,5 · Renate König1,4,6 · Klaus Cichutek1,2,4 Received: 16 September 2019 / Accepted: 19 August 2020 © The Author(s) 2020
Abstract Chimeric Antigen Receptor (CAR)-redirected T cells show great efficacy in the patient-specific therapy of hematologic malignancies. Here, we demonstrate that a DARPin with specificity for CD4 specifically redirects and triggers the activation of CAR engineered T cells resulting in the depletion of C D4+ target cells aiming for elimination of the human immunodeficiency virus (HIV) reservoir. Keywords DARPin · CAR T cells · HIV reservoir · T cell therapy
Introduction Engineered T cell therapy utilizing chimeric antigen receptors (CARs) is one of the most promising technologies for the treatment of hematologic malignancies [1, 2]. CARs recognize antigen by binding to cell surface proteins independent of MHC (major histocompatibility complex) presentation and with high specificity, avoiding T cell escape mechanisms based on HLA (human leukocyte antigen) loss
Edited by: Matthias J. Reddehase Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00430-020-00692-0) contains supplementary material, which is available to authorized users.
utilized by many viruses and tumors. Patient’s T cells are isolated and genetically armed ex vivo with CARs encompassing a binding domain for surface antigens expressed on the targeted cells. Upon antigen binding, an immunological synapse is formed resulting in CAR-mediated recruitment of downstream kinases and finally the release of cytotoxic granules containing perforin and granzyme B, leading to the elimination of the targeted cells. The first clinical trials for CAR T cells were performed with the objective of targeting HIV-infected T cells [3], using a CD4 molecule fused to the Fc receptor γ chain (FcRγ) to redirect T cells to viral gp120 on the cell surface of HIV-infected cells. These first-generation CARs, however, failed to reduce the viral burden in patients for prolonged periods, probably in large
* Janna Seifried [email protected]
4
German Center for Infection Research (DZIF), Langen, Germany
* Klaus Cichutek [email protected]
5
Regensburg Center for Interventional Immunology (RCI), Department of Genetic Immunotherapy, University Hospital Regensburg, Regensburg, Germany
1
Host‑Pathogen Interactions, Paul-Ehrlich-Institut, Langen, Germany
6
2
Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany
Immunity and Pathogenesis Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
7
3
Center for Molecular Medicine Cologne,
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