Oncotarget

Research Papers:

Human HLA-A*02:01/CHM1+ allo-restricted T cell receptor transgenic CD8+ T Cells specifically inhibit Ewing sarcoma growth in vitro and in vivo

Franziska Blaeschke, Uwe Thiel _, Andreas Kirschner, Melanie Thiede, Rebeca Alba Rubio, David Schirmer, Thomas Kirchner, Günther H.S. Richter, Sabine Mall, Richard Klar, Stanley Riddell, Dirk H. Busch, Angela Krackhardt, Thomas G.P. Grunewald and Stefan Burdach

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Oncotarget. 2016; 7:43267-43280. https://doi.org/10.18632/oncotarget.9218

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Abstract

Franziska Blaeschke1,10,*, Uwe Thiel1,*, Andreas Kirschner1, Melanie Thiede1, Rebeca Alba Rubio2, David Schirmer1, Thomas Kirchner2,3,4, Günther H.S. Richter1, Sabine Mall5, Richard Klar5, Stanley Riddell6, Dirk H. Busch7,8, Angela Krackhardt5, Thomas G.P. Grunewald2,3,4, Stefan Burdach1,9

1Laboratory for Functional Genomics and Transplantation Biology, Department of Pediatrics and Children‘s Cancer Research Center, Klinikum rechts der Isar, Technische Universitaet Muenchen, Munich, Germany

2Laboratory for Pediatric Sarcoma Biology, Institute of Pathology of the LMU Munich, Munich, Germany

3German Cancer Consortium (DKTK), Heidelberg, Germany

4German Cancer Research Center, Heidelberg, Germany

5Medizinische Klinik III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

6Department of Medicine, University of Washington, Seattle, WA, USA

7Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitaet Muenchen, München, Germany

8Focus Group “Clinical Cell Processing and Purification”, Institute for Advanced Study, Technische Universität München, Munich, Germany

9Munich Comprehensive Cancer Center (CCC), Klinikum rechts der Isar, Technische Universität München, Munich, Germany

10Present address: Laboratory for Immunotherapy, Dr. von Hauner Children’s Hospital, LMU München, Munich, Germany

*These authors share first authorship

Correspondence to:

Uwe Thiel, email: uwe.thiel@tum.de

Keywords: Ewing sarcoma, immunotherapy, T cell receptor transgenic T cells, adoptive transfer, allogeneic stem cell transplantation

Received: January 14, 2016     Accepted: April 24, 2016     Published: May 07, 2016

ABSTRACT

The endochondral bone protein Chondromodulin-I (CHM1) provides oncogene addiction in Ewing sarcoma (ES). We pre-clinically tested the targetability of CHM1 by TCR transgenic, allo-restricted, peptide specific T cells to treat ES. We previously generated allo-restricted wildtype CD8+ T cells directed against the ES specific antigen CHM1319 causing specific responses against ES. However, utilization of these cells in current therapy protocols is hampered due to high complexity in production, relatively low cell numbers, and rapid T cell exhaustion.

In order to provide off-the-shelf products in the future, we successfully generated HLA-A*02:01-restricted T cell receptor (TCR) transgenic T cells directed against CHM1319 by retroviral transduction.

After short-term expansion a 100% purified CHM1319-TCR-transgenic T cell population expressed a CD62L+/CD45RO and CD62L+/CD45RA+ phenotype. These cells displayed specific in vitro IFNg and granzyme B release in co-culture with HLA-A*02:01+ ES cell lines expressing CHM1. When co-injected with ES cells in Rag2-/-ɣc-/- mice, CHM1-specific TCR-transgenic T cells significantly inhibited the formation of lung and liver metastases in contrast to control mice. Lungs and livers of representative mice displayed CD8+ T cell infiltration in the presence (control group treated with unspecific T cells) and in the absence (study group) of metastatic disease, respectively. Furthermore, mice receiving unspecific T cells showed signs of graft-versus-host-disease in contrast to all mice, receiving CHM1319-TCR-transgenic T cells.

CHM1319 specific TCR-transgenic T cells were successfully generated causing anti-ES responses in vitro and in vivo. In the future, CHM1319-TCR-transgenic T cells may control minimal residual disease rendering donor lymphocyte infusions more efficacious and less toxic.


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