Requirements for Effective Antitumor Responses of TCR Transduced T Cells

• Published in: The Journal of immunology (1950) 2008-10, Vol.181 (7), p.5128-5136
• Main Authors: de Witte, Moniek A, Jorritsma, Annelies, Kaiser, Andrew, van den Boom, Marly D, Dokter, Maarten, Bendle, Gavin M, Haanen, John B. A. G, Schumacher, Ton N. M
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Cancer Vaccines - administration & dosage; Cancer Vaccines - genetics; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - radiation effects; CD8-Positive T-Lymphocytes - transplantation; Cell Line, Tumor; Gamma Rays; Genetic Vectors - radiation effects; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Transgenic; Ovalbumin - genetics; Receptors, Antigen, T-Cell - administration & dosage; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - radiation effects; Receptors, Antigen, T-Cell - therapeutic use; Retroviridae - genetics; Retroviridae - immunology; Transduction, Genetic; Transplantation Conditioning; Viral Vaccines - administration & dosage; Viral Vaccines - genetics; Viral Vaccines - immunology; Whole-Body Irradiation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.7.5128

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.