We propose a phase I clinical trial to study the toxicity profile and immunologic impact of rhIL-12 in patients with advanced breast cancer who have undergone high dose chemotherapy with stem cell rescue. Patients undergoing stem cell transplantation experience a prolonged period of cellular and humoral immune dysfunction. This state carries implications for both infection risk as well as disease recurrence. Recent studies suggest that the use of cytokine therapy post-transplant may result in earlier recovery of immune competence and inhibit tumor growth. IL-12 is a novel cytokine that is thought play a crucial role in cellular and humoral immunity. It induces gammaIFN production by T cells and has been found to augment NK and T cell mediated cytotoxic killing in vitro. Animal studies have suggested IL-12 exhibits potent antitumor activity. Initial phase I clinical studies have demonstrated that rhIL-12 exhibits its immunologic effects in a dose dependent manner. The toxicity of this agent in the post-transplant setting has been defined. We propose to conduct a dose escalation phase I study in which cohorts of 3-6 patients will be treated with increasing doses of SQ rhIL-12 until the maximum tolerated dose level is defined. In an ongoing study of immune reconstitution following high dose chemotherapy for advanced breast cancer, we have found that patients experience both quantitative and qualitative disturbances in cellular immunity during the first 6 months following transplant. We postulate that the use of rhIL-12 posttransplant may lead to more rapid immune reconstitution in this population and may carry benefits with regard to disease recurrence. We propose to serially examine measures of cellular and humoral immunity in patients treated with rhIL-12 in the post-transplant period including T cell subset analysis, mitogen induced T cell proliferation, measures of NK mediated cytotoxicity, and DTH responses.
