Clinical Program in Pediatric Sarcomas

Mackall实验室的主要目标是开发基于免疫的治疗方法， 儿童癌症。鉴于儿童癌症的标准疗法几乎可以 总是诱导完全缓解，即使是在不治之症，我们的工作重点是 提供基于免疫的治疗作为巩固治疗。因此，我们将免疫 通过给予免疫疗法， 完成标准多药化疗后立即进行。我们假设 免疫疗法对微小残留癌比对巨大肿瘤更有效 由于更有利的免疫细胞：肿瘤细胞比例和缺乏有组织的 免疫抑制微环境Mackall实验室以前的工作直接 表明免疫反应在消除最小残留方面更有效， 肿瘤性疾病，即原发性大体积肿瘤（Merchant，Cancer Immun and Immunoth，2006）。 此外，我们在T细胞耗竭生物学方面的专业知识为我们提供了独特的见解， 关于如何在细胞毒性化疗后最好地提供基于免疫的治疗， 绝大多数儿童癌症患者接受标准治疗。因为我们的 转化研究计划针对儿童肉瘤，这是至关重要的，我们 在这一竞技场中保持积极的临床计划，提供必要的转诊 在儿科癌症和必要的生物标本中进行临床试验的网络 进行与人类疾病相关的研究。我们的第二代研究结果 巩固性免疫疗法发表在Clinical Cancer Research（Mackall等人，A Pilot 高风险儿童肉瘤患者的巩固免疫治疗研究，2008）。的 该项目在2009财年的第一个重要成就是患者持续增加 在2008年开始的免疫疗法试验中，审判 直接将我们的基础研究转化为基于树突状细胞的肿瘤疫苗， 患有高危儿童肉瘤的患者通过标准化疗呈现淋巴细胞减少。在 此外，患者接受去除抑制性T细胞的自体淋巴细胞作为手段， 来增强免疫反应累计18名患者，6名患者 完成免疫治疗。本试验纳入了辅助抗原，钥孔血蓝蛋白 (KLH)增强免疫反应。迄今为止的结果表明， KLH，但对肿瘤裂解物的反应有限。在此基础上，我们获得了承诺 来自Cytheris，Inc.为了提供用于本试验的重组人白细胞介素-7（IL-7），我们 与该实体一起修订了我们的CRADA，我们已提交了一份方案修订案，将IL-7添加到 这个治疗方案我们希望在这个方案中加入白细胞介素-7， 增加对肿瘤裂解物疫苗的免疫应答。关于消耗的结果 抑制性T细胞尚未确定，但将影响本研究的未来修订。其他 取得的成就包括即将完成对检测单克隆抗体的临床试验的增加， 抗肿瘤坏死因子相关凋亡诱导配体受体2的抗体，并继续增加到一项试验中， 靶向CTLA 4的单克隆抗体在儿科实体瘤中的应用。此外，我们还发布了一份 详细描述了长期严重代谢功能障碍的发展的手稿 儿科肉瘤的幸存者（霍夫曼等人，儿科血液和癌症，2008）。

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).