We have completed entry of patients onto the most recent high risk sarcoma study and have demonstrated the feasibility of escalating the dose-intensity of doxorubicin by more than 50% compared to our most dose-intensive previous regimen, with the use of the cardioprotector ADR-529. We also demonstrated the feasibility of repetitive high-dose alkylating agent therapy followed by peripheral blood stem cell rescue as consolidation therapy. Toxicity to this regimen was severe, with febrile neutropenia occurring in virtually all patients and with more than 40% of febrile episodes having documented infections. An additional toxicity seen was the develpment of palmar-plantar erythrodysesthesia syndrome in the majority of patients. With the completion of this study, the POB has elected to pursue an immunotherapy approach in an attempt to improve the outcome of metastatic and recurrent sarcoma patients. Using a peptide vaccination strategy developed by Berzofski and colleaguues, we have demonstrated the ability to generated specific CTL that recognize tumor tumors bearing the t(2;13) or the t(11;22) translocations seen in alveolar rhabdomyosarcoma (ARMS) and Ewing's tumors (EFT) respectively. Furthermore, these CTLs have been shown to significantly limit tumor growth in established tumors in a murine model. We have coupled this approach with an attempt to reconstitute T cell function post-chemotherapy based on studies in our Branch documented severe T cell depletion for up to 1 year following standard high dose chemotherapy for these patients. We have recently obtained IRB approval to conduct a limited-institution pilot study using standard chemotherapy followed by autologous T cell reconstitution and peptide vaccination using peptide-pulsed autlogous APC's for newly diagnosed metastatic patients with EFT and ARMS bearing the above mentioned trnaslocations. A similar approach without chemotherapy will also be used in recurrent patients. In osteosarcoma (OS), we are awaiting IND filing to begin a study using a long-acting somatostatin compound in an attmept to determine whether interrpution of the GH-IGF-I axis will have salutory effects in patients with recurrent OS based on laboratory and pilot clinical studies previously conducted in our Branch.
