Clinical Program in Pediatric Sarcomas

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A primary goal of the Mackall laboratory is 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. We therefore incorporate immune based therapies into the existing therapeutic armamentarium, by administering immunotherapy immediately following completion of standard multiagent chemotherapy. We hypothesize that immunotherapy will be more effective against minimal residual cancer than against bulky tumors due to a more favorable immune cell:tumor cell ratio and the absence of an organized immunosuppressive microenvironment. 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). Furthermore, 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. Results of our second generation study of consolidative immunotherapy was published in Clinical Cancer Research (Mackall et al, A Pilot Study of Consolidative Immunotherapy in Patients with High-Risk Pediatric Sarcomas, 2008). The first important accomplishment of this project during FY2009 was continued accrual of patients with pediatric sarcomas on a trial of immune based therapy initiated in 2008. The trial directly translates our basic research by administering dendritic cell based tumor vaccines to patients with high-risk pediatric sarcomas rendered lymphopenic by standard chemotherapy. In addition, patients receive autologous lymphocytes depleted of suppressive T cells as a means to enhance immune responses. A total of 18 patients have been accrued and 6 patients have completed immunotherapy. This trial incorporates a helper antigen, keyhold limpet hemocyanin (KLH), to augment immune responses. Results thus far demonstrate vigorous immune responses to KLH but limited responses to the tumor lysate. Based upon this, we have obtained commitment from Cytheris, Inc. to provide recombinant human interleukin-7 (IL-7) for this trial, we have amended our CRADA with this entity and we have submitted a protocol amendment to add IL-7 to this therapeutic regimen. We are hopeful that adding interleukin-7 to this regimen will increase the immune response to the tumor lysate vaccine. Results regarding depletion of suppressive T cells are pending but will influence future amendments on this study. Other accomplishments include near completion of accrual to a clinical trial of testing monoclonal antibodies to anti-TRAIL receptor 2 and continued accrual to a trial testing the effects of a monoclonal antibody targeting CTLA4 in pediatric solid tumors. Furthermore, we published a manuscript detailing the development of significant metabolic dysfunction in long term survivors of pediatric sarcoma (Hoffman et al, Pediatric Blood and Cancer, 2008).