Clinical Program in Pediatric Sarcomas

麦考尔实验室的一个主要目标是开发儿童癌症的免疫疗法。考虑到儿童癌症的标准治疗几乎总是可以诱导完全缓解，即使是不治之症，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，我们通过在完成标准多药化疗后立即给予免疫治疗，将基于免疫的治疗纳入现有的治疗方案。我们假设免疫疗法对微小残留肿瘤比对大体积肿瘤更有效，这是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实验室先前的工作直接证明，免疫反应在根除微小残留肿瘤疾病方面比原发性大肿瘤更有效（Merchant, Cancer immune 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关于如何在细胞毒性化疗后最好地提供基于免疫的治疗的独特见解，绝大多数儿童癌症患者接受细胞毒性化疗作为标准治疗的一部分。由于我们的转化研究项目针对的是儿童肉瘤，因此我们在这一领域保持活跃的临床项目至关重要，这为开展儿童癌症临床试验提供了必要的转诊网络，并为开展与人类疾病相关的研究提供了必要的生物标本。我们第二代强化免疫治疗研究的结果发表在《临床癌症研究》（Mackall et al， A Pilot study of consolidation immunotherapy in Patients with高风险小儿肉瘤，2008）。该项目在2009财年的第一个重要成就是，在2008年启动的一项免疫治疗试验中，儿童肉瘤患者的人数持续增加。该试验通过将基于树突状细胞的肿瘤疫苗施用于通过标准化疗导致淋巴细胞减少的高危儿童肉瘤患者，直接转化了我们的基础研究。此外，患者接受去除抑制性T细胞的自体淋巴细胞作为增强免疫反应的手段。累计18例患者，6例患者完成免疫治疗。该试验结合了一种辅助抗原，keyhold帽贝血青素（KLH），以增强免疫反应。迄今为止的结果表明，对KLH有强烈的免疫反应，但对肿瘤裂解物的反应有限。基于此，我们已获得Cytheris， Inc.的承诺，为该试验提供重组人白细胞介素-7 (IL-7)，我们已经修改了我们的CRADA，并提交了一份协议修正案，将IL-7添加到该治疗方案中。我们希望在这个方案中加入白细胞介素-7将增加对肿瘤裂解物疫苗的免疫反应。关于抑制性T细胞耗竭的结果尚待确定，但将影响本研究的未来修订。其他成就包括即将完成一项测试抗trail受体2单克隆抗体的临床试验，以及一项针对CTLA4单克隆抗体在儿童实体瘤中的作用的试验。此外，我们发表了一份手稿，详细介绍了儿童肉瘤长期幸存者中显著代谢功能障碍的发展（Hoffman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).