Abstract

The objective of this study is the development and evaluation of anti-tumor immunotoxins (IT's) for intraperitoneal therapy of advanced intraperitoneal malignancy. Immunotoxins (monoclonal antibody-ricin A chain conjugates) directed against carcinoembronic antigen and human transferrin receptor will be used. The anti- tumor effects of these IT's will be evaluated in human tumor xenografts established as intraperitoneal tumors in nude mice. Alternate methods of immunotoxin construction will be evaluation, to optimize anti-tumor efficacy in these models. Further enhancement of anti-tumor effect of the IT's will be sought, by the in vivo use of modified forms of the IT potentiator monensin (monensin linoleate, monensin in emulsion, and liposomal monensin.) Augmentation of IT anti-tumor effect by combination with radioimmunotherapy (90 Yttrium antibody or 90 Yttrium-IT) will also be examined. A limited clinical trial of i.p. IT's in refractory intraperitoneal malignancy will be performed. This trial will investigate toxicity and efficacy of i.p. IT's, and the biodistribution of 111 Indium-IT's after i.p. infusion will be determined by external scanning and tissue biopsy. These studies should yield important information regarding development of IT's as clinical anti-cancer agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039748-05
Application #
3179147
Study Section
Experimental Immunology Study Section (EI)
Project Start
1985-09-30
Project End
1990-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655

  Publications

Griffin, T; Rybak, M E; Recht, L et al. (1993) Potentiation of antitumor immunotoxins by liposomal monensin. J Natl Cancer Inst 85:292-8
Ito, T; Griffin, T W; Collins, J A et al. (1992) Intratumoral and whole-body distributions of C110 anti-carcinoembryonic antigen radioimmunotoxin after intraperitoneal and intravenous injection: a quantitative autoradiographic study. Cancer Res 52:1961-7
Griffin, T W; Stocl, M; Collins, J et al. (1992) Combined antitumor therapy with the chemotherapeutic drug doxorubicin and an anti-transferrin receptor immunotoxin: in vitro and in vivo studies. J Immunother (1991) 11:12-8
Maher, V E; Drukman, S J; Kinders, R J et al. (1992) Human antibody response to the intravenous and intraperitoneal administration of the F(ab')2 fragment of the OC125 murine monoclonal antibody. J Immunother (1991) 11:56-66
Aas, M; Mardirossian, G; Griffin, T W et al. (1992) Long-term biodistribution in tumored mice of murine and chimeric B72.3-IgG antibody radiolabeled with 114mIn via both DTPA and a macrocyclic chelator. J Nucl Biol Med 36:33-40
Levin, L V; Griffin, T W (1991) Specific adhesion of carcinoembryonic antigen-bearing colorectal cancer cells to immobilized carcinoembryonic antigen. Cancer Lett 60:143-52
Ito, T; Qiu, H; Collins, J A et al. (1991) Preclinical assessments of 90Y-labeled C110 anti-carcinoembryonic antigen immunotoxin: a therapeutic immunoconjugate for human colon cancer. Cancer Res 51:255-60
Griffin, T; Raso, V (1991) Monensin in lipid emulsion for the potentiation of ricin A chain immunotoxins. Cancer Res 51:4316-22
Griffin, T W; Brill, A B; Stevens, S et al. (1991) Initial clinical study of indium-111-labeled clone 110 anticarcinoembryonic antigen antibody in patients with colorectal cancer. J Clin Oncol 9:631-40
Recht, L; Torres, C O; Smith, T W et al. (1990) Transferrin receptor in normal and neoplastic brain tissue: implications for brain-tumor immunotherapy. J Neurosurg 72:941-5

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