Requirements for effective antitumor responses of TCR transduced T cells.
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.
de Witte
Moniek A
MA
Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.
Jorritsma
Annelies
A
Kaiser
Andrew
A
van den Boom
Marly D
MD
Dokter
Maarten
M
Bendle
Gavin M
GM
Haanen
John B A G
JB
Schumacher
Ton N M
TN
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000528:radiation effects / Q000637:transplantation*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D005720:Gamma Rays; D005822:Genetic Vectors / Q000528:radiation effects; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage* / Q000235:genetics* / Q000528:radiation effects / Q000627:therapeutic use; D012190:Retroviridae / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic; D019172:Transplantation Conditioning; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014916:Whole-Body Irradiation
D019496:Cancer Vaccines; D011948:Receptors, Antigen, T-Cell; D014765:Viral Vaccines; D010047:Ovalbumin