The objectives of this research are to pursue treatment of cancer with biologically active radiolabeled MoAb such as Lym-1 and L-6 by examining the influence of basic factors, such as amount of administered MoAb; amount and schedule for administered radionuclide; radiation dose rate; alterations to tumor delivery by preceeding biologic response modifiers, e.g., unlabeled MoAb, interleukin, interferon or radiation; and site-specific attachments for toxins. Maximum tolerated dose and optimum biologic dose will be determined for each system. Treatment of mice and 14 patients with B cell malignancies using I-131 Lym-1, an IgG2a MoAb has provided evidence for the potential of this and similar MoAbs and also some of the factors and obstacles that must be manipulated. Methods to be used include: quantitative imaging that provides absolute amounts (and concentrations) of MoAb in tumor and organs for pharmacokinetics and radiation dosimetry in patients; tomographic imaging estimates of tumor volume; and in vitro tests for in vivo cytotoxicity. Statistical and protocol designs which provide the most information from a minimum number of patients will be used. Response-surface designs may provide more information that the more commonly used Phase I design when appropriate to the purpose. Chemical characterization of the residues of MoAb, such as Lym-1 and L-6 will be used for sitespecific attachment to specific residues of toxins so as to preserve biologic functions of importance to treatment of cancer, such as those that determine immunotargeting and those that stimulate cytotoxic systems in vivo. Strengths of this program project include: interactive, interdisciplinary investigative teams established in the 1970's; investigators who bridge the interface between basic and clinical sciences; use of methods already established and in some instances developed by the group; and existence of established resources and specialized laboratory investigators. While the investigators choose to pursue radionuclide-conjugated antibodies as the primary source of therapeutic effect, much of the information to be obtained is relevant to the use of other toxins and even antibodies without attached toxins.
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