PMID- 9610908
OWN - NLM
STAT- MEDLINE
DCOM- 19980717
LR  - 20191102
IS  - 1524-9557 (Print)
IS  - 1524-9557 (Linking)
VI  - 21
IP  - 3
DP  - 1998 May
TI  - Adenovirus-mediated interleukin-2 production by tumors induces growth of 
      cytotoxic tumor-infiltrating lymphocytes against human renal cell carcinoma.
PG  - 170-80
AB  - Combination therapy with interleukin-2 (IL-2) and tumor-infiltrating lymphocytes 
      (TILs) demonstrates significant clinical activity in patients with metastatic 
      renal cell carcinoma (RCC). To investigate whether local delivery of IL-2 via 
      gene transfer is capable of improving the potency and efficacy of in vitro 
      propagated TILs as compared with standard growth conditions [400 BRMP U (BU)/ml], 
      a replication-deficient adenovirus expressing the human IL-2 gene under control 
      of the cytomegalovirus (CMV) promoter (Ad-IL-2) has been constructed in our 
      laboratory. RCC-TIL cultures were initiated by directly infecting RCC tumor 
      suspension with Ad-IL-2 at a multiplicity of infection of 10:1. Subsequently the 
      TIL cultures were restimulated with nonirradiated autologous RCC infected with 
      Ad-IL-2 (RCC-Ad-IL-2) every 10 days (TIL/tumor = 50:1). Cell growth, phenotype, 
      cytotoxicity, and cytokine messenger RNA (mRNA) expression were analyzed and 
      compared with TIL growth stimulated with exogenous IL-2 (400 BU/ml). All five 
      TILs tested responded to RCC-Ad-IL-2 activation, and a completed clearance of 
      tumor cells was observed in cultures within 7-10 days. Lysis of nonirradiated 
      RCC-Ad-IL-2 cells by TILs also was observed in cultures 3-5 days after 
      restimulation. The IL-2 concentration in cell culture supernatants was maintained 
      between 10 BU and 35 BU/ml (2 and 7 ng/ml), respectively. When compared with 
      exogenous IL-2, RCC-Ad-IL-2 induced less growth expansion of TILs whereas a 
      reduced CD56+ (23 +/- 14% vs. 44 +/- 13%; p < 0.05) but increased CD3+CD4+ cell 
      population (32 +/- 11% vs. 15 +/- 6%; p < 0.05) with enhanced T cell-receptor use 
      (59 +/- 10% vs. 42 +/- 7%; p < 0.005) was determined. An augmented human 
      leukocyte antigen (HLA)-restricted and tumor-specific cytotoxicity was detected 
      in RCC-Ad-IL-2-expanded TILs (day 35, 15.3 +/- 4.2 LU vs. 4.6 +/- 1.8 LU; p < 
      0.005). These properties were mediated by the CD8+ and CD4+ T-cell populations, 
      as demonstrated by antibody-blocking assays. A unique cytokine profile also was 
      detected in RCC-Ad-IL-2-induced TILs, which demonstrated an upregulation of both 
      GM-CSF and IL-6 mRNA as compared with TILs expanded in the presence of exogenous 
      IL-2. These data suggest that RCC-Ad-IL-2 is a potent immune stimulant that can 
      be used in vitro as an immunogen to propagate cytotoxic RCC-TILs for adoptive 
      immunotherapy or potentially in vivo by direct injection as a live tumor vaccine.
FAU - Mulders, P
AU  - Mulders P
AD  - Department of Urology, The Jonsson Comprehensive Cancer Center, UCLA School of 
      Medicine, Los Angeles, California 90024, USA.
FAU - Tso, C L
AU  - Tso CL
FAU - Pang, S
AU  - Pang S
FAU - Kaboo, R
AU  - Kaboo R
FAU - McBride, W H
AU  - McBride WH
FAU - Hinkel, A
AU  - Hinkel A
FAU - Gitlitz, B
AU  - Gitlitz B
FAU - Dannull, J
AU  - Dannull J
FAU - Figlin, R
AU  - Figlin R
FAU - Belldegrun, A
AU  - Belldegrun A
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Immunother
JT  - Journal of immunotherapy (Hagerstown, Md. : 1997)
JID - 9706083
RN  - 0 (Interleukin-2)
SB  - IM
MH  - Adenoviridae/*genetics
MH  - Carcinoma, Renal Cell/*immunology
MH  - Cells, Cultured
MH  - Cytotoxicity, Immunologic
MH  - Flow Cytometry
MH  - Gene Expression
MH  - Genetic Vectors
MH  - Humans
MH  - Immunotherapy, Adoptive
MH  - Interleukin-2/*genetics
MH  - Kidney Neoplasms/*immunology/metabolism/therapy
MH  - Lymphocytes, Tumor-Infiltrating/*immunology
MH  - Phenotype
MH  - Polymerase Chain Reaction
MH  - *Transfection
MH  - Tumor Cells, Cultured
EDAT- 1998/06/04 00:00
MHDA- 1998/06/04 00:01
CRDT- 1998/06/04 00:00
PHST- 1998/06/04 00:00 [pubmed]
PHST- 1998/06/04 00:01 [medline]
PHST- 1998/06/04 00:00 [entrez]
AID - 10.1097/00002371-199805000-00002 [doi]
PST - ppublish
SO  - J Immunother. 1998 May;21(3):170-80. doi: 10.1097/00002371-199805000-00002.