The goal of Project 1 is to develop """"""""combined modality radioimmunotherapy"""""""" (CMRIT) as an integral part of a multimodality treatment plan, with curative intent for patients with non-Hodgkin's lymphoma (NHL). Lym-1 preferentially targets an HLA-DRIO epitope present on most malignant B-cells, providing a remarkable opportunity to enhance the therapeutic index by specifically targeting a radionuclide to NHL. The majority of 72 NHL patients treated with one of 3 new drugs developed at UC Davis: 131l-Lym-1, 67Cu-2lT-BAT-Lym-1, and 90Y- 2IT-BAD-Lym-1, responded. A time dependent proportional hazards model conclusively showed that response to 1311-Lym-1 therapy was associated with improved survival in a multivariate analysis that adjusted for risk factors. Several patients are alive more than 5 years after RIT. CMRIT with the advanced radiopharamceuticals 90Y-DOTA-peptide- Lym-1 and Taxol will be evaluated as a therapeutic strategy for NHL. In a Raji-tumored nude mouse model, CMRIT with 90Y-DOTA-peptide-Lym-1 and Taxol, in doses clinically achievable in humans, provided therapeutic synergy without increased toxicity, when administered at the optimal time and sequence. Other advances designed for the new Phase clinical protocols in Project 1 are: patient-specific dosing, peripheral blood stem cell support to ameliorate myelotoxicity and allow higher doses of 90Y, a biodegradable Unker, """"""""DOTA-peptide"""""""" to decrease normal organ doses and increase the therapeutic index, and low doses of Cyclosporin A to prevent development of human anti-mouse antibody. Preclinical studies will examine the potential for therapeutic synergy of RIT and agents that promote apoptosis and/or inhibit DNA repair, specifically, anti-CD22 monoclonal antibodies and nucleoside analogues. Preclinical and Phase l clinical studies proposed in Project 1 will continue the progress achieved over the past several years. Cohesive interaction of our interdisciplinary group will allow successful completion of these plans. The Phase l CMRIT trials designed for this Proposal will facilitate subsequent Phase 11 and 111 trials at other institutions. New strategies developed in preclinical studies will continue to allow translation of novel advances from the laboratory to the clinic, for the ultimate benefits of patients with NHL.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA047829-14
Application #
6493945
Study Section
Subcommittee E - Prevention &Control (NCI)
Project Start
2001-09-30
Project End
2003-03-31
Budget Start
Budget End
Support Year
14
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Schellinger, Joan G; Kudupudi, Avinash; Natarajan, Arutselvan et al. (2012) A general chemical synthesis platform for crosslinking multivalent single chain variable fragments. Org Biomol Chem 10:1521-6
Saludes, Jonel P; Natarajan, Arutselvan; DeNardo, Sally J et al. (2010) The remarkable stability of chimeric, sialic acid-derived alpha/delta-peptides in human blood plasma. Chem Biol Drug Des 75:455-60
Kumaresan, Pappanaicken R; Luo, Juntao; Lam, Kit S (2009) On-demand cleavable linkers for radioimmunotherapy. Methods Mol Biol 539:191-211
DeNardo, G L; Mirick, G R; Hok, S et al. (2009) Molecular specific and cell selective cytotoxicity induced by a novel synthetic HLA-DR antibody mimic for lymphoma and leukemia. Int J Oncol 34:511-6
Balhorn, Rod; Hok, Saphon; DeNardo, Sally et al. (2009) Hexa-arginine enhanced uptake and residualization of selective high affinity ligands by Raji lymphoma cells. Mol Cancer 8:25
Sulchek, Todd; Friddle, Raymond; Ratto, Timothy et al. (2009) Single-molecule approach to understanding multivalent binding kinetics. Ann N Y Acad Sci 1161:74-82
DeNardo, Gerald L; Natarajan, Arutselvan; Hok, Saphon et al. (2008) Nanomolecular HLA-DR10 antibody mimics: A potent system for molecular targeted therapy and imaging. Cancer Biother Radiopharm 23:783-96
Natarajan, Arutselvan; Xiong, Cheng-Yi; Gruettner, Cordula et al. (2008) Development of multivalent radioimmunonanoparticles for cancer imaging and therapy. Cancer Biother Radiopharm 23:82-91
Lehmann, Joerg; Natarajan, Arutselvan; Denardo, Gerald L et al. (2008) Short communication: nanoparticle thermotherapy and external beam radiation therapy for human prostate cancer cells. Cancer Biother Radiopharm 23:265-71
Kumaresan, Pappanaicken R; Luo, Juntao; Song, Aimin et al. (2008) Evaluation of ketone-oxime method for developing therapeutic on-demand cleavable immunoconjugates. Bioconjug Chem 19:1313-8

Showing the most recent 10 out of 187 publications