Requirements for effective antitumor responses of TCR transduced T cells

Moniek A de Witte, Annelies Jorritsma, Andrew Kaiser, Marly D van den Boom, Maarten Dokter, Gavin M Bendle, John B A G Haanen, Ton N M Schumacher

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

Adoptive transfer of TCR gene-modified T cells has been proposed as an attractive approach to target tumors for which it is difficult or impossible to induce strong tumor-specific T cell responses by vaccination. Whereas the feasibility of generating tumor Ag-specific T cells by gene transfer has been demonstrated, the factors that determine the in vivo effectiveness of TCR-modified T cells are largely unknown. We have analyzed the value of a number of clinically feasible strategies to enhance the antitumor potential of TCR modified T cells. These experiments reveal three factors that contribute greatly to the in vivo potency of TCR-modified T cells. First, irradiation-induced host conditioning is superior to vaccine-induced activation of genetically modified T cells. Second, increasing TCR expression through genetic optimization of TCR sequences has a profound effect on in vivo antitumor activity. Third, a high precursor frequency of TCR modified T cells within the graft is essential. Tumors that ultimately progress in animals treated with this optimized regimen for TCR-based adoptive cell transfer invariably display a reduced expression of the target Ag. This suggests TCR gene therapy can achieve a sufficiently strong selective pressure to warrant the simultaneous targeting of multiple Ags. The strategies outlined in this study should be of value to enhance the antitumor activity of TCR-modified T cells in clinical trials.
Original languageEnglish
Pages (from-to)5128-36
Number of pages9
JournalJournal of Immunology
Volume181
Issue number7
Publication statusPublished - 1 Oct 2008

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