Interleukin-2 (IL-2) has been shown to enhance natural cell-mediated cytotoxicity and other cellular immune functions in vitro and in vivo. The gene for the human lymphokine has been cloned, and recombinant IL-2 is now available for clinical trials. In the proposed investigation, recombinant IL-2 will be administered by intravenous injection to patients with advanced refractory malignancies in order to determine its effect on cellular immunity, its toxicity, and its potential as an antineoplastic agent. The aberrant amino acid sequence of the Interleukin-2 to be used in clinical trials and other properties of the molecule have raised the possibility that IL-2 may be immunogenic, and serum from recipient patients will be monitored for the development of anti-IL-2 antibodies with a sensitive ELISA. Moreover, a series of experiments using an adsorbed affinity-purified neutralizing rabbit anti-IL-2 antiserum is proposed to determine the biological significance of such antibodies in humans. The association between IL-2 and the acute phase response will be documented and correlated with the dose of IL-2 administered. The mechanism by which high doses of IL-2 cause fever in humans and the role of IL-2 in the induction of IL-1 and prostaglandin E2 synthesis will be investigated. The relationship between the induction of the acute phase response and changes in cellular immune function will be studied and correlated with IL-2 dose and tumor response, if any, is observed. This proposal represents a comprehensive investigation of the in vivo effects of this potent biological response modifier which will delineate its potential role in the management of patients with immunodeficiency and neoplastic diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039489-02
Application #
3178524
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1985-06-01
Project End
1988-05-31
Budget Start
1986-06-01
Budget End
1987-05-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
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Mier, J W; Vachino, G; Klempner, M S et al. (1990) Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects. Blood 76:1933-40
Aronson, F R; Libby, P; Brandon, E P et al. (1988) IL-2 rapidly induces natural killer cell adhesion to human endothelial cells. A potential mechanism for endothelial injury. J Immunol 141:158-63
Mier, J W; Aronson, F R; Numerof, R P et al. (1988) Toxicity of immunotherapy with interleukin-2 and lymphokine-activated killer cells. Pathol Immunopathol Res 7:459-76
Mier, J W; Vachino, G; van der Meer, J W et al. (1988) Induction of circulating tumor necrosis factor (TNF alpha) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients. J Clin Immunol 8:426-36
Numerof, R P; Aronson, F R; Mier, J W (1988) IL-2 stimulates the production of IL-1 alpha and IL-1 beta by human peripheral blood mononuclear cells. J Immunol 141:4250-7
Atkins, M B; Mier, J W; Parkinson, D R et al. (1988) Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N Engl J Med 318:1557-63
Mier, J W; Dinarello, C A; Atkins, M B et al. (1987) Regulation of hepatic acute phase protein synthesis by products of interleukin 2 (IL 2)-stimulated human peripheral blood mononuclear cells. J Immunol 139:1268-72
Allegretta, M; Atkins, M B; Dempsey, R A et al. (1986) The development of anti-interleukin-2 antibodies in patients treated with recombinant human interleukin-2 (IL-2). J Clin Immunol 6:481-90
Atkins, M B; Gould, J A; Allegretta, M et al. (1986) Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J Clin Oncol 4:1380-91

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