Adoptive cell therapy for patients with melanoma, using tumor-infiltrating lymphocytes genetically engineered to secrete interleukin-2.
Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) after lymphodepletion mediates regression in 50% of patients with metastatic melanoma. In vivo persistence and telomere length of the transferred cells correlate with antitumor response. In an attempt to prolong the in vivo survival of the transferred cells, TILs were genetically engineered to produce interleukin (IL)-2. In vitro, these transduced TILs secreted IL-2 while retaining tumor specificity and exhibited prolonged survival after IL-2 withdrawal. In a phase I/II clinical trial, seven evaluable patients received transduced TILs and one patient experienced a partial response associated with in vivo persistence of IL-2-transduced TILs in circulating lymphocytes. An additional five patients received transduced TILs in conjunction with IL-2 administration. Persistence of IL-2-transduced TILs was observed in three patients, including one partial responder. The transgene DNA as well as vector-derived IL2 mRNA could be detected for 4 months in responding patients. The low response rate in this trial was possibly due to a reduction in telomere length in cells as a result of prolonged in vitro culture. In this study, insertion of the IL-2 gene into antitumor TILs increased their ability to survive after IL-2 withdrawal in vitro but did not increase their in vivo persistence or clinical effectiveness.
Heemskerk
Bianca
B
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Liu
Ke
K
Dudley
Mark E
ME
Johnson
Laura A
LA
Kaiser
Andrew
A
Downey
Stephanie
S
Zheng
Zhili
Z
Shelton
Thomas E
TE
Matsuda
Kant
K
Robbins
Paul F
PF
Morgan
Richard A
RA
Rosenberg
Steven A
SA
D019264:Adoptive Transfer / Q000379:methods*; D000328:Adult; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000637:transplantation*; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000628:therapy*; D014161:Transduction, Genetic; D019076:Transgenes; D016896:Treatment Outcome
D007376:Interleukin-2