Volume 2 Supplement 3
Tumor-specific donor lymphocyte infusion therapy with allogeneic T cells utilizing novel retrovirus vector silencing endogenous TCR expression
© Ikeda et al.; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
Donor Lymphocyte infusion (DLI) is a therapy for the patients with relapsed hematological malignancy after allogeneic hematopoetic stem cell transplantation. However, the development of Graft-Versus-Host Disease (GVHD) is a serious adverse event and the efficacy is limited when one needs to control the GVHD. To inhibit the development of GVHD with increased tumor-specificity of transferred allogeneic lymphocytes, here we demonstrate the development of DLI with lymphocytes engineered to express tumor-specific T cell receptor (TCR) in combination with decreased GVHD-inducing potential utilizing the novel retrovirus vector (siTCR vector) that specifically silences endogenous TCR in gene-engineered T cells.
Human PBMC were transduced with a high affinity TCR specific to a cancer/testis antigen, NY-ESO-1, by the retrovirus vector with siRNA specific to the endogenous TCR. Resulting TCR gene-transduced T cells were examined for their reactivity to allogeneic LCL by 3H uptake proliferation assay. Immunodeficient NOG mice were inoculated with a NY-ESO-1-expressing human melanoma cell line NW-MEL-38, received TCR gene-transduced T cells, and monitored for tumor growth and the development of GVHD.
Human lymphocytes that were genetically engineered to express a high affinity NY-ESO-1-specific TCR with siTCR vector showed reduced expression of endogenous TCR associated with the dramatically diminished reactivity to allogeneic lymphocytes. When administrated into NOG mice, these TCR gene-transduced T cells induced tumor regression without the development of GVHD.
The results here suggest that the allogeneic T cells transduced with a tumor-specific TCR by siTCR vector showed diminished GVHD potential. These T cells will be applicable to the donor lymphocytes infusion therapy after allogeneic stem cell transplantation for the treatment of hematological malignancy, providing diminished GVHD and increased tumor eradication.
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.