Dual T cell receptor expressing CD8+ T cells with tumor- and self-specificity can inhibit tumor growth without causing severe autoimmunity.
The engineering of Ag-specific T cells by expression of TCR genes is a convenient method for adoptive T cell immunotherapy. A potential problem is the TCR gene transfer into self-reactive T cells that survived tolerance mechanisms. We have developed an experimental system with T cells that express two TCRs with defined Ag-specificities, one recognizing a tumor-specific Ag (LCMV-gp(33)), the other recognizing a self-Ag in the pancreas (OVA). By using tumor cells expressing high and low amounts of Ag and mice expressing high and low levels of self-Ag in the pancreas (RIP-OVA-Hi and RIP-OVA-Lo), we show that 1) tumor rejection requires high amount of tumor Ag, 2) severe autoimmunity requires high amount of self-Ag, and 3) if Ag expression on tumor cells is sufficient and low in the pancreas, successful adoptive T cell therapy can be obtained in the absence of severe autoimmunity. These results are shown with T cells from dual TCR transgenic mice or T cells that were redirected by TCR gene transfer. Our data demonstrate that the approach of adoptively transferring TCR redirected T cells can be effective without severe side effects, even when high numbers of T cells with self-reactivity were transferred.
Weinhold
Monika
M
Institute of Immunology, Charité, Hindenburgdamm 30, Berlin, Germany.
Sommermeyer
Daniel
D
Uckert
Wolfgang
W
Blankenstein
Thomas
T
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000502:physiology; D001324:Autoantigens / Q000502:physiology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002645:Chickens; D018984:Epitopes, T-Lymphocyte / Q000502:physiology; D006131:Growth Inhibitors / Q000502:physiology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics
D000951:Antigens, Neoplasm; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D011948:Receptors, Antigen, T-Cell