Minimally cultured tumor-infiltrating lymphocytes display optimal characteristics for adoptive cell therapy.
Adoptive cell therapy (ACT) with tumor-reactive lymphocytes in patients with refractory melanoma can result in tumor regression and prolonged survival. Generating tumor-reactive lymphocyte cultures is technically difficult and resource intensive; these limitations have restricted the widespread application of ACT. Tumor-infiltrating lymphocytes (TIL) from melanoma contain tumor antigen-reactive cells. The "standard" method for producing TIL cultures for clinical administration requires extended in vitro expansion in interleukin-2, then identification of tumor-reactive cells by immunologic assays. We show here that limitations in reagents and methods during screening underrepresent the actual reactivity of TIL cultures. Furthermore, the extended culture times necessitated by the screening assays resulted in telomere shortening and reduced expression of CD27 and CD28 in the TIL cultures, properties that our prior studies showed are correlated with in vivo persistence and clinical response. We have thus developed an alternative "young" TIL method that demonstrated superior in vitro attributes compared with standard TIL. This approach uses the entire resected tumor to rapidly expand TIL for administration without in vitro testing for tumor recognition. Our observations suggest that younger TIL can have an undetermined but high level of antigen reactivity, and other advantageous attributes such as long telomeres and high levels of CD27 and CD28. We suggest that minimally cultured, unselected lymphocytes represent an alternative strategy for generating TIL cultures suitable for use in ACT that, if effective in vivo, may facilitate the widespread application of this approach to a broader population of patients with melanoma.
Tran
Khoi Q
KQ
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1201, USA.
Zhou
Juhua
J
Durflinger
Katherine H
KH
Langhan
Michelle M
MM
Shelton
Thomas E
TE
Wunderlich
John R
JR
Robbins
Paul F
PF
Rosenberg
Steven A
SA
Dudley
Mark E
ME
D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000637:transplantation*; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D016615:Telomere / Q000502:physiology
D016207:Cytokines
J Immunol Methods. 1990 Apr 17;128(2):189-201
1691237
J Immunother. 2005 May-Jun;28(3):258-67
15838383
J Immunother (1991). 1992 Jul;12(1):1-12
1637779
J Immunol. 2005 Nov 15;175(10):7046-52
16272366
J Immunol. 2006 Nov 1;177(9):6527-39
17056585
Cancer. 2007 Feb 1;109(3):455-64
17200963
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16168-73
12427970
J Immunol. 2006 Jun 15;176(12):7726-35
16751420
Blood. 2005 Jan 1;105(1):241-50
15345595
Science. 2006 Oct 6;314(5796):126-9
16946036
CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66
17237035
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9571-6
15980149
Int J Cancer. 2007 Jan 15;120(2):337-43
17066423
J Clin Invest. 2005 Jun;115(6):1616-26
15931392
Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4
10685652
Science. 2002 Oct 25;298(5594):850-4
12242449
J Clin Oncol. 2005 Apr 1;23(10):2346-57
15800326
N Engl J Med. 1988 Dec 22;319(25):1676-80
3264384
Blood. 1998 Sep 1;92(5):1549-55
9716582
J Immunother. 2007 Jan;30(1):123-9
17198091
J Immunother. 2003 Jul-Aug;26(4):332-42
12843795
J Natl Cancer Inst. 1994 Aug 3;86(15):1159-66
8028037
Science. 2003 Apr 11;300(5617):339-42
12690202
J Immunother. 2002 May-Jun;25(3):243-51
12000866
J Clin Oncol. 2006 Nov 1;24(31):5060-9
17075125
Blood. 2007 Aug 15;110(4):1123-31
17468341
J Clin Oncol. 2008 Nov 10;26(32):5233-9
18809613
Immunol Rev. 1997 Jun;157:195-216
9255631
Science. 2003 Apr 11;300(5617):337-9
12690201
Blood. 2005 Mar 1;105(5):1898-904
15542583