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Clin Cancer Res. 2016 Jun 1;22(11):2734-43. doi: 10.1158/1078-0432.CCR-15-2361. Epub 2015 Dec 14.

Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation.

Author information

1
Institute of Immunology, Charité, Campus Buch, Berlin, Germany. matthias.leisegang@mdc-berlin.de.
2
Department of Pathology, The University of Chicago, Illinois.
3
Department of Medicine, The University of Chicago, Illinois.
4
Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago, Illinois.
5
Molecular Cell Biology and Gene Therapy, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Institute of Biology, Humboldt University Berlin, Berlin, Germany.
6
Institute of Immunology, Charité, Campus Buch, Berlin, Germany. Department of Pathology, The University of Chicago, Illinois.

Abstract

PURPOSE:

Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic nonsynonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T-cell receptor (TCR) that is specific for a single AAS.

EXPERIMENTAL DESIGN:

By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy.

RESULTS:

When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intratumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T-cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar.

CONCLUSIONS:

Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer, but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape. Clin Cancer Res; 22(11); 2734-43. ©2015 AACRSee related commentary by Liu, p. 2602.

PMID:
26667491
PMCID:
PMC4891260
DOI:
10.1158/1078-0432.CCR-15-2361
[Indexed for MEDLINE]
Free PMC Article

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