Tumor associated antigens are appropriate targets for radioimmunoconjugate therapy with monoclonal antibodies. Gastrointestinal adenocarcinomas have been shown to be rich in glycoprotein antigens including the TAG-72 antigen. TAG-72 antigen is a unique tumor associated antigen which was originally defined by monoclonal antibody (MAb) B72.3. Second generation MAbs have been developed which also recognize the TAG-72 antigen. One of these antibodies (MAb CG49) also exhibits high levels of binding to upper gastrointestinal tract cancers and has a 10 fold greater affinity than MAb B72.3 for the TAG-72 antigen. Phase I trials with MAb CC49 as a radioimmunoconjugate have shown that hematopoietic toxicity precludes delivery of adequate dose to tumor and overcoming hematopoietic toxicity with autologous bone marrow rescue can circumvent this problem. In this proposal, we describe a series of studies designed to optimize the use of this antibody as a radioimmunoconjugate with more optimal radionuclides (177-Lutetium and 90-Yttrium) in the therapy of gastrointestinal tract cancers. The first two clinical trials proposed are standard phase trials with the exception that hematopoietic toxicity will be treated with maximum support including the use of autologous bone marrow rescue in phase I trial designs in order to document whether there is any other organ specific toxicity associated with this form of therapy. The third clinical trial will utilize the best of the two radioimmunoconjugates in combination with recombinant interferon gamma which will be used for its antigen modulating effect in order to achieve better dose to tumor. The final trial described is another phase II trial employing combination therapy with standard chemotherapy (5-FU and leucovorin) with the best selected radioimmunoconjugate in patients with metastatic colorectal carcinoma. In all of these trials, documentation of intersubject variations in pharmacokinetics, radiotoxicity to bone marrow, and estimates of dose to tumor in normal tissue will be performed and correlated with clinical outcome. A multidisciplinary team with established experience in this area has been assembled conduct of clinical trials and overall program coordination will be done by Dr. Margaret Tempero. She will be assisted in biostatistics by Dr. Anderson and in immunohistochemistry by Dr. Linder. Dr. David Golcher will be the Program Leader for the Laboratory of Radiochemistry, Pharmacology and Biodistribution and will supervise studies in biodistribution of pharmacokinetics and will coordinate with investigators Dr. Quadri for radiochemistry studies, Dr. Joshi for radiotoxicity studies of hematopoietic tissue, and Dr. Augustine, a radiopharmacist, who will be responsible for quality assurance. Dr. Peter Leichner will be the Program Leader for the Laboratory Program for Dosimetry. He will perform all the dosimetry estimates with the assistance of Dr. Dalrymple who will participate in nuclear scan interpretations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01CA058272-01
Application #
3549984
Study Section
Special Emphasis Panel (SRC (74))
Project Start
1993-09-30
Project End
1996-09-29
Budget Start
1993-09-30
Budget End
1994-09-29
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Tempero, M; Leichner, P; Baranowska-Kortylewicz, J et al. (2000) High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial. Clin Cancer Res 6:3095-102
Blanco, I; Kawatsu, R; Harrison, K et al. (1997) Antiidiotypic response against murine monoclonal antibodies reactive with tumor-associated antigen TAG-72. J Clin Immunol 17:96-106
Akabani, G; Hawkins, W G; Eckblade, M B et al. (1997) Patient-specific dosimetry using quantitative SPECT imaging and three-dimensional discrete Fourier transform convolution. J Nucl Med 38:308-14
Leichner, P K; Akabani, G; Colcher, D et al. (1997) Patient-specific dosimetry of indium-111- and yttrium-90-labeled monoclonal antibody CC49. J Nucl Med 38:512-6
Lotze, M T (1996) Cytokine gene therapy of cancer. Cancer J Sci Am 2:63-72