Abstract

This proposal will investigate the toxicity and clinical efficacy of autologous IL-2-activated lymphocytes (LAK cells) in patients with advanced malignant disease in a Phase-II clinical trial. The tumoricidal activity of the LAK cell recipients' circulating blood mononuclear cells against natural killer-resistant tumor cell lines, serum levels of IL-2 and IL-2 antibodies and other parameters will be serially monitored. The ability of LAK cells to infiltrate tumors will be determined using 111 Indium-labelled cells and body scans. Serum levels of IL-1, gamma interferon, and tumor necrosis factor will be measured. The in vitro effects of these pyrogenic cytokines on acute phase protein synthesis i cultured hepatoma cells and neuropeptide synthesis in cultured hypothalamus cells will be determined. The effects of these cytokines as well as supernatants from IL-2-activated mononuclear cells and sera from LAK cell recipients on cultured endothelial cells will be investigated. Desialated glycoproteins that appear on the surface of lymphocytes as a consequence of activation by IL-2 will be characterized in two dimensional Western blots using peanut agglutinin and with monoclonal antibodies produced by hybridomas generated from mice immunized with affinity-purified LAK cell proteins. The immunogenicity of these activation antigens in patients receiving LAK cell infusions will be determined with the FACS-IV. This investigation will determine the therapeutic potential and the mechanisms of toxicity of LAK cell treatment as well as provide information on the activation of tumoricidal lymphocytes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043950-02
Application #
3186450
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1987-02-01
Project End
1990-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111

  Publications

Vannier, E; Kaser, A; Atkins, M B et al. (1999) Elevated circulating levels of soluble interleukin-1 receptor type II during interleukin-2 immunotherapy. Eur Cytokine Netw 10:37-42
Tilg, H; Dinarello, C A; Mier, J W (1997) IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. Immunol Today 18:428-32
Stoddart Jr, J H; Jasuja, R R; Sikorski, M A et al. (1996) Protease-resistant L-selectin mutants. Down-modulation by cross-linking but not cellular activation. J Immunol 157:5653-9
Sikorski, M A; Staunton, D E; Mier, J W (1996) L-selectin crosslinking induces integrin-dependent adhesion: evidence for a signaling pathway involving PTK but not PKC. Cell Adhes Commun 4:355-67
Tilg, H; Atkins, M B; Dinarello, C A et al. (1995) Induction of circulating interleukin 10 by interleukin 1 and interleukin 2, but not interleukin 6 immunotherapy. Cytokine 7:734-9
Tilg, H; Shapiro, L; Vannier, E et al. (1994) Induction of circulating antagonists to IL-1 and TNF by IL-2 administration and their effects on IL-2 induced cytokine production in vitro. J Immunol 152:3189-98
Tilg, H; Trehu, E; Atkins, M B et al. (1994) Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83:113-8
Tilg, H; Trehu, E; Shapiro, L et al. (1994) Induction of circulating soluble tumour necrosis factor receptor and interleukin 1 receptor antagonist following interleukin 1 alpha infusion in humans. Cytokine 6:215-9
Trehu, E G; Isner, J M; Mier, J W et al. (1993) Possible myocardial toxicity associated with interleukin-4 therapy. J Immunother Emphasis Tumor Immunol 14:348-51
Tilg, H; Pape, D; Trehu, E et al. (1993) A method for the detection of erythrocyte-bound interleukin-8 in humans during interleukin-1 immunotherapy. J Immunol Methods 163:253-8

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