Effective anti-tumor adoptive immunotherapy: utilization of exogenous IL-2-independent cytotoxic T lymphocyte clones.
To attain one of the final goals for cancer immunotherapy, cytotoxic T lymphocyte (CTL) clones were selected on the basis of exogenous IL-2 independence after limiting dilution culture from mixed lymphocyte tumor cell culture cells of FBL-3 tumor-immune spleens. About 10% of the clones could be propagated up to >5 times by weekly passages in the presence of splenic feeder and stimulating tumor cells. Two of the representative FBL-3-specific CTL clones that were able to undergo the fifth passage were expanded in large numbers for adoptive transfer by two rounds of a weekly passage with medium containing IL-2. FBL-3-specific CTL clones thus obtained showed a strong ability to eliminate the established tumors when transferred into tumor-bearing nude mice. In addition, the cells were recovered from the mouse spleen even 8 months after the transfer. The most striking differences between the CTL clones used in this experiment and those maintained conventionally in the presence of IL-2 were the abilities to produce IL-2 by themselves and the high expression level of the integrin molecule, VLA-4, that disappeared when cultured completely in the continuous presence of IL-2 in vitro during 12 weeks. In addition, concomitant with the disappearance of exogenous IL-2 independence and VLA-4 expression, the CTL clones lost their capacity to eradicate the tumor in vivo. Thus, the higher capacity of CTL clones to produce IL-2 on their own seemed to be correlated with the in vivo efficacy for tumor eradication and the long-term maintenance of their physiological profiles typical of memory T cells.
Iwashiro
Michihiro
M
Department of Oral and Maxillofacial Surgery, and Institute of Immunology, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan. keiyo@doc.medic.mie-u.ac.jp
Jinyan
Wang
W
Toda
Masaaki
M
Linan
Wang
W
Kato
Takuma
T
Kuribayashi
Kagemasa
K
D019264:Adoptive Transfer; D000818:Animals; D002455:Cell Division; D002999:Clone Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D016219:Immunotherapy, Adoptive / Q000379:methods*; D039041:Integrin alpha4beta1 / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D013997:Time Factors
D039041:Integrin alpha4beta1; D007376:Interleukin-2; D012333:RNA, Messenger; D007371:Interferon-gamma