Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains.
We previously demonstrated the feasibility of generating therapeutic numbers of cytotoxic T lymphocyte (CTL) clones expressing a CD20-specific scFvFc:CD3zeta chimeric T cell receptor (cTCR), making them specifically cytotoxic for CD20+ B lymphoma cells. However, the process of generating and expanding he CTL clones was laborious, the CTL clones expressed the cTCR at low surface density, and they exhibited suboptimal proliferation and cytotoxicity. To improve the performance of the CTLs in vitro and in vivo, we engineered "second-generation'' plasmid constructs containing a translational enhancer (SP163) and CD28 and CD137 costimulatory domains in cis with the CD3zeta intracellular signaling domain of the cTCR gene. Furthermore, we verified the superiority of generating genetically modified polyclonal T cells expressing the second-generation cTCR rather than T cell clones. Our results demonstrate that SP163 enhances the surface expression of the cTCR; that the second-generation cTCR improves CTL activation, proliferation, and cytotoxicity; and that polyclonal T cells proliferate rapidly in vitro and mediate potent CD20-specific cytotoxicity. This study provides the preclinical basis for a clinical trial of adoptive T cell immunotherapy for patients with relapsed CD20+ mantle cell lymphoma and indolent lymphomas.
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Jinjuan
J
Wang
Michael
M
Jensen
Yukang
Y
Lin
Xingwei
X
Sui
Eric
E
Chen
Catherine G
CG
Lindgren
Brian
B
Till
Andrew
A
Raubitschek
Stephen J
SJ
Forman
Xiaojun
X
Qian
Scott
S
James
Philip
P
Greenberg
Stanley
S
Riddell
Oliver W
OW
Press
D018106:CD28 Antigens / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D006801:Humans; D016219:Immunotherapy, Adoptive; D019169:Jurkat Cells; D008223:Lymphoma / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics* / Q000378:metabolism
D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9