A primary goal of the Mackall laboratory is the development of immune based therapies for childhood cancer. Given the fact that standard therapies for childhood cancers can nearly always induce complete remission, even in incurable disease, our work has focused on delivering immune based therapy as a consolidative treatment. In other words, we attempt to incorporate immune based therapies into the existing therapeutic armamentarium, by administering immunotherapy immediately following completion of standard multiagent chemotherapy. This is based upon the premise that minimal residual cancer will be easier to eradicate than bulky tumors due to the more favorable immune cell:tumor cell ratio and due to the absence of an organized immunosuppressive microenvironment. Indeed, previous work from the Mackall laboratory directly demonstrated that immune responses are more effective at eradicating minimal residual neoplastic disease that primary bulky tumor (Merchant, Cancer Immun and Immunoth, 2006). Moreover, our expertise in the biology of T cell depletion provides us with unique insights regarding how best to deliver immune based therapy following cytotoxic chemotherapy, which the vast majority of childhood cancer patients receive as part of standard therapy. Because our translational research program has targeted childhood sarcomas, it is critical that we maintain an active clinical program in this arena, which provides the necessary referral network to conduct clinical trials in pediatric cancers and the necessary biologic specimens to conduct studies of relevance to human disease. The first important accomplishment of this project during FY2008 was the publication of the results of our first clinical trial that attempted to administer immune based therapy as consolidative therapy for pediatric sarcomas (Mackall, Clin Canc Res 2008; 14:4850). This work demonstrated that immune based therapy incorporating adoptive transfer and dendritic cell vaccination was well tolerated following a dose intensive multiagent regimen, that patients treated in this manner were immuncompetent to respond to vaccination and that overall survival of patients receiving immunotherapy was favorable given the high risk nature of the population under study. The work also demonstrated that the approach to vaccination in this study was not sufficient to induce tumor direct immune responses in the majority of patients. A second important accomplishment during FY2008 was the enrollment of 6 patients on a new trial of immune based therapy that built upon the lessons learned in the trial discussed above. We have incorporate a more potent dendritic cell for vaccination and have changed the immunogen from tumor specific peptide to tumor lysate. We have also incorporated a helper antigen, keyhold limpet hemocyanin, to augment immune responses. Results are preliminary but look promising. Other accomplishments include the publication of a report from a late effects study we conducted that carefully investigated survivorship issues in long term survivors or pediatric sarcoma (Hoffman, Pediatric Blood and Cancer, 2008; 50:341). We have published several earlier reports detailing results of this clinical trial and in FY 2008 we published the data demonstrating a high rate of metabolic syndrome in this population. This is critical to recognize since we have already published evidence that these patients have early cardiac disease and dyslipidemia, both of which can contribute to premature mortality. The observation that metabolic syndrome is also seen in this population confirms similar results in other cancer survivors that received dose intensive chemotherapy. We also collaborated on a project demonstrating a high rate of venous thrombosis in pediatric populations with solid tumors, which provides new insight into the importance of recognizing this potentially lethal complication of pediatric sarcoma (Paz-Priel, J Clin Onc 2007; 20:1519). Finally, we published an invited editorial questioning the continued focus of single arm studies on high dose therapy for Ewings sarcoma (Synder, Ped Blood and Cancer, 2007;49:115). Given that the role for high dose therapy remains entirely unclear based upon conflicting results from single arm studies and the fact that a trans-Atlantic randomized study of this modality is currently underway, the purpose of this manuscript was to discourage our community from conducting more single arm trials of the same modality and rather to consider enrolling patients and initiating other investigational therapies for patients with high risk Ewings sarcoma, including immune based therapies.
