B7-h3-specific engager T cells for the immunotherapy of pediatric solid tumors

  • Christopher DeRenzo
  • David Torres
  • Victoria Tobin
  • Phuong Nguyen
  • Xiao-Tong Song
  • Stephen Gottschalk
Open Access
Poster presentation
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Keywords

Osteosarcoma Neuroblastoma High Grade Glioma Effector Function Internal Ribosomal Entry Site 

Background

B7-H3 positive tumors, including osteosarcoma, neuroblastoma, and high grade glioma, cause significant morbidity and mortality despite aggressive multimodality treatments. Current B7-H3-targeted immune-therapies take advantage of the monoclonal antibody 8H9, which is actively being evaluated in Phase I clinical trials. Engager T cells, which secrete bispecific engager molecules consisting of single chain variable fragments specific for CD3 and a tumor antigen, are a new class of antigen-specific T cells, with the unique ability to redirect bystander T cells to tumors, amplifying anti-tumor effects. The goal of this project was to develop B7-H3-specific Engager T cells, and pre-clinically evaluate their effector function in vitro and in vivo.

Methods

B7-H3-Engager T cells were generated by transducing T cells with a retroviral vector encoding a B7-H3-specific T cell engager and mOrange separated by an internal ribosomal entry site. B7-H3-Engager T cell effector function was then evaluated in vitro and in a metastatic osteosarcoma xenograft model.

Results

Post transduction 70-84% of T cells were positive for transgene expression. In coculture assay B7-H3-Engager T cells recognized B7-H3-positive osteosarcoma (LM7), neuroblastoma (CHLA255), and glioma (U373) cell lines, as judged by IFN-γ secretion, in contrast to B7-H3-negative tumor cells (HTB-119) (Figure 1). None of the targets were recognized by T cells secreting engager molecules specific for an irrelevant antigen (CD19-Engager T cells). Antigen-dependent recognition was confirmed in standard cytotoxicity assays (Figure 2). To assess anti-tumor activity of B7-H3-Engager T cells in vivo we used a metastatic osteosarcoma xenograft model that allows for serial bioluminescence imaging of LM7 cells that are genetically modified to express the fire fly luciferase gene (LM7-ffLuc). NSG mice were intravenously injected with LM7-ffLuc cells, followed by intravenous doses of B7-H3-Engager or control (CD19-Engager) T cells on days 28 and 35 post LM7-ffLuc injection. In contrast to control T cells, B7-H3-Engager T cells had potent anti-osteosarcoma activity (Figure 3) resulting in a survival advantage of treated mice.

Conclusions

We successfully generated B7-H3-Engager T cells and demonstrate that these cells recognize and kill B7-H3-positive tumor cells in an antigen-dependent manner, and have potent anti-osteosarcoma activity in vivo. Thus, B7-H3-Engager T cells may present a promising alternative to current T cell immunotherapy approaches for pediatric solid tumors.

Copyright information

© DeRenzo et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Christopher DeRenzo
    • 1
  • David Torres
    • 1
  • Victoria Tobin
    • 1
  • Phuong Nguyen
    • 1
  • Xiao-Tong Song
    • 1
  • Stephen Gottschalk
    • 2
  1. 1.Baylor College of MedicineHoustonUSA
  2. 2.Baylor College of Medicine, Center for Cell and Gene TherapyDepartment of PediatricsHoustonUSA

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