Our previous studies in murine models have elucidated the propensity for skewing of regenerated T cell populations in thymic-deficient hosts suggesting that such skewing could be exploited in the context of clinical approaches to induce responses to nominal antigen during a period of immune reconstitution. We have developed a clinical trial to test this hypothesis wherein T cell populations are collected prior to intensive chemotherapy in patients with Ewing?s sarcoma and alveolar rhabdomyosarcoma. Upon completion of cytotoxic therapy, immune reconstitution/immunotherapy is undertaken which consists of reinfused T cells, tumor-specific peptide pulsed antigen presenting cells and interleukin-2. The goals of this clinical trial are twofold. First, we plan to investigate whether this strategy can improve immune reconstitution in this cohort of patients compared to similarly treated historical controls. Endpoints for this objective include flow cytometric analysis of regenerating peripheral blood lymphocyte subpopulations. Second, we are investigating whether peptides derived from the breakpoint region of tumor specific fusion proteins can be used as immunogens to generate measurable and/or clinical significant anti-tumor responses. Endpoints for this analysis include evidence of biologically measurable responses (i.e. cytokine production, proliferation and/or cytolysis) to peptide pulsed autologous targets. Thus far, patients have been enrolled on two clinical trials. In the first trial, both immune reconstitution and tumor vaccine endpoints are addressed. Thus far, nine patients have received T cell infusions and concurrent tumor vaccination. Seven have been evaluated for immune reconstitution endpoints. Five of the seven show significant increases in CD4+ T cell counts within 6 weeks following autologous T cell infusion and IL-2. In two cases, this has resulted in supranormal CD4+ T cell counts upon completion of the third cycle of immunorestorative therapy. Two patients showed no significant responses to T cell infusions: one which did not receive IL-2 due to underlying Sweet?s syndrome and one with widespread recurrent tumor. With regard to biologic responses to the peptide pulsed vaccine, six patients have been evaluated for immune responses. Three patients have evidence of biologic responses to the peptide pulsed vaccine. Therefore, preliminary results in this patient population suggest that a combined immune reconstitution/tumor vaccine approach may prove feasible for inducing anti-tumor immune responses in the setting of minimal residual neoplastic disease. Ongoing studies are also underway in a second clinical trial to determine whether immune responses to the breakpoint region of the tumor specific fusion proteins can be induced in a population with recurrent tumor in whom autologous T cells are not available for immune reconstitution. The results of these trials were presented to the International Society of Pediatric Oncology at their annual meeting in Montreal, Canada. AIDS RELATED 50% - cancer immunotherapy, Ewing's sarcoma family of tumors (ESFT), rhabdomyosarcoma, vaccines, - Human Subjects & Human Subjects: Minor under 18 Years Old & Human Tissues, Fluids, Cells, etc.
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