Selecting highly affine and well-expressed TCRs for gene therapy of melanoma.
A recent phase 1 trial has demonstrated that the generation of tumor-reactive T lymphocytes by transfer of specific T-cell receptor (TCR) genes into autologous lymphocytes is feasible. However, compared with results obtained by infusion of tumor-infiltrating lymphocytes, the response rate observed in this first TCR gene therapy trial is low. One strategy that is likely to enhance the success rate of TCR gene therapy is the use of tumor-reactive TCRs with a higher capacity for tumor cell recognition. We therefore sought to develop standardized procedures for the selection of well-expressed, high-affinity, and safe human TCRs. Here we show that TCR surface expression can be improved by modification of TCR alpha and beta sequences and that such improvement has a marked effect on the in vivo function of TCR gene-modified T cells. From a panel of human, melanoma-reactive TCRs we subsequently selected the TCR with the highest affinity. Furthermore, a generally applicable assay was used to assess the lack of alloreactivity of this TCR against a large series of common human leukocyte antigen alleles. The procedures described in this study should be of general value for the selection of well- and stably expressed, high-affinity, and safe human TCRs for subsequent clinical testing.
Jorritsma
Annelies
A
Department of Immunology, the Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands.
Gomez-Eerland
Raquel
R
Dokter
Maarten
M
van de Kasteele
Willeke
W
Zoet
Yvonne M
YM
Doxiadis
Ilias I N
II
Rufer
Nathalie
N
Romero
Pedro
P
Morgan
Richard A
RA
Schumacher
Ton N M
TN
Haanen
John B A G
JB
D000818:Animals; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016219:Immunotherapy, Adoptive; D019169:Jurkat Cells; D020014:K562 Cells; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
D011948:Receptors, Antigen, T-Cell