Volume 3 Supplement 2

30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)

Open Access

Costimulation to enhance the antitumor activity of CD19 eng T cells

  • Mireya Velasquez1,
  • David Torres2,
  • Aarohi Thakkar1,
  • Sunitha Kakarla1,
  • Carolyn Arber Barth1,
  • Xiao-Tong Song2 and
  • Stephen Gottschalk1
Journal for ImmunoTherapy of Cancer20153(Suppl 2):P58

https://doi.org/10.1186/2051-1426-3-S2-P58

Published: 4 November 2015

Background

Immunotherapy with T cells or bispecific T cell engagers is one promising approach to improve outcomes for patients with CD19-positive hematological malignancies. We had previously shown that T cells expressing bispecific T cell engagers that recognize CD19 and CD3 (CD19-ENG T cells) are activated in an antigen dependent manner, recruit resident T cells to tumors, and have anti-tumor activity in preclinical models. In this project we now wanted to evaluate if provision of co-stimulation enhances the effector function of CD19-ENG T cells by expressing CD80 and 41BBL on their cell surface (CD19 ENG/costim T cells).

Methods

CD19-ENG T cells were generated by transducing T cells with a retroviral vector encoding a CD19-specific T cell engager, and CD19-ENG/Costim T cells were generated by double transducing T cells with the previous construct and a 2nd retroviral vector encoding the costimulatory molecules 41BBL and CD80. The effector function of the generated T cells was evaluated in vitro and in a xenograft model.

Results

CD19-ENG and CD19-ENG/Costim T cells recognized CD19+ lymphoma (Daudi, Raji) and acute leukemia (BV173) cells as judged by IFN-g secretion. Both ENG T cell populations produced IL-2 in the presence of CD19-positive targets expressing CD80 and CD86 (Daudi and Raji). However, CD19-ENG/Costim T cells produced higher levels of IL-2 in comparison to CD19-ENG T cells after stimulation with BV173 (CD19+CD80-CD86-). ENG and ENG/Costim T cells specific for an irrelevant antigen (EphA2) did not produce cytokines, confirming antigen dependence. Specificity was confirmed in cytotoxicity assays. In vivo anti-tumor activity of CD19-ENGand CD19-ENG/Costim T cells was assessed in a BV173/NSG xenograft model. First we determined the minimal required CD19-ENG T cell dose to observe anti-tumor effects. Three injections of 1x107 CD19-ENG T cells cured 5/5 mice, one injection 2/5 mice, and one dose of 1x106 CD19-ENG T cells had no anti-tumor effects. In contrast one dose of 1x106 or 1x107 CD19-ENG/Costim T cells cured 5/5 mice. ENG T cells or ENG/Costim T cells recognizing EphA2 had no anti-tumor effects.

Conclusions

Provision of co-stimulation increases the effector function of CD19-ENG T cells resulting in enhanced anti-tumor activity in vivo. Genetically modifying T cells to express engagers and additional molecules to enhance their effector function may present a promising alternative to current CD19-targeted immunotherapies.

Authors’ Affiliations

(1)
Baylor College of Medicine, Center for Cell and Gene Therapy
(2)
Baylor College of Medicine

Copyright

© Velasquez 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.

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