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。这方面的一个主要焦点是发展儿童癌症的巩固免疫疗法。由于儿童癌症的标准前期治疗通常会导致完全缓解或非常好的部分缓解（即使是不治之症），我们假设将基于免疫的治疗作为巩固治疗将改善结果。这是基于大量证据表明，免疫反应在针对低负担疾病时最有效，免疫反应可能因淋巴细胞减少而增强，淋巴细胞减少在几乎所有接受剂量强化标准治疗的儿科癌症患者中都存在。为此，我们寻求将基于免疫的疗法整合到现有的治疗方法中，在完成标准多药化疗后立即进行免疫治疗。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。我们第一代和第二代强化免疫治疗研究的结果之前发表过（2002年医学和儿科肿瘤学，2005年自然医学和2008年临床癌症研究）。在2011财年，我们完成了2008年启动的一项基于免疫疗法的儿童肉瘤患者试验的累积。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。患者也接受去除抑制性T细胞rhIL7和辅助抗原keyhold帽贝血青素（KLH）的自体淋巴细胞，以增强免疫反应。该方案非常新颖，代表了rhIL7在儿童中的首次使用，也是目前唯一在肿瘤疫苗试验中使用rhIL7的例子。共有44名患者入组，其中20名已开始免疫治疗。在剩余的24例中，我们预计10例将在2011财年开始免疫治疗，其中4例因肿瘤裂解液/淋巴细胞收集不足而不符合条件，10例因原发性治疗期间疾病进展而不能。迄今为止的结果显示，与未使用rhIL7的历史试验相比，对KLH有强烈的免疫反应，对肿瘤裂解物有显著的免疫反应，增强了免疫重建，以及有希望的无病率和总生存率。我们预计该试验的治疗将在2012财年完成，届时我们将开始发表这些结果。该项目的第二个主要成果是提交了一项针对高危儿童肉瘤患者的同种异体干细胞移植的初步研究结果。这项研究（NCI 02-c-0259）使用非清髓性异体外周血干细胞移植患者与匹配的兄弟姐妹供体。我们证明了该方法具有良好的耐受性，没有治疗相关的死亡率，并且还提出了新的观察结果，即患有非常高风险的儿童实体瘤的患者在同种异体干细胞移植后尽管复发，但化疗反应性增加，生存期延长。这些结果为化学敏感性和免疫环境之间迄今未被认识到的相互作用提供了新的证据，这在非移植环境中是潜在的可利用的。该报告已在《血液与骨髓移植生物学》上发表并正在修订中。2011财年的其他成就包括启动了一项异体干细胞移植试验，其中包括在干细胞移植后淋巴细胞减少期间给予活化NK细胞输注。这是高度新颖的，首次在儿科患者中使用活化的NK细胞，并使用一种新的人工抗原提呈细胞来扩增这些细胞。结果尚未公布，但试验是开放的，第一个患者已经积累。其他成就包括持续累积的唯一一项针对儿科黑色素瘤患者的抗ctla4儿科I期研究。我们已经在黑色素瘤患者身上看到了部分反应的证据，也看到了一些疾病稳定的证据。有趣的是，初步结果表明，与成人相比，儿童可能会经历更大的自身免疫毒性，如果得到证实，这一发现将为儿科免疫调节疗法提供新的见解。2011财年，我们还开展了首个使用基因工程T细胞受体靶向儿童肉瘤的试验。具体来说，我们将在患有NY-ESO-1+HLA-A2+滑膜肉瘤的儿童和成人患者中使用靶向NY-ESO-1的T细胞受体。该试验旨在重现在给肉瘤和黑色素瘤患者施用高剂量il - 2的类似T细胞的试验中看到的有希望的结果，代表了宾夕法尼亚大学和圣路易斯华盛顿大学的合作。由于滑膜肉瘤包括大量的儿科肉瘤，因此在儿科人群中开展这项试验是很重要的。

A primary goal of the Mackall laboratory is the development of immune based therapies for childhood cancer. A primary focus in this regard has been in developing consolidation immunotherapy for childhood cancer. Because standard upfront therapies for childhood cancer often induce complete remission or a very good partial remission (even in incurable disease), we hypothesize that delivering immune based therapy as a consolidative treatment will improve outcomes. This is based upon a large body of evidence demonstrating that immune responses are most effective when directed toward low burden disease and evidence that immune responses may be potentiated by lymphopenia, which exists in nearly all pediatric cancer patients following dose intensive standard therapy. To this end, we seek to integrate 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 first- and second-generation studies of consolidative immunotherapy were previously published (Medical and Pediatric Oncology 2002, Nature Medicine 2005 and Clin Canc Res 2008). During FY2011 we completed 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. Patients also receive autologous lymphocytes depleted of suppressive T cells, rhIL7, and a helper antigen, keyhold limpet hemocyanin (KLH), to augment immune responses. This regimen is highly novel representing the first use of rhIL7 in children and the only current example of rhIL7 being used in the context of a tumor vaccine trial. A total of 44 patients have been enrolled and 20 have initiated immunotherapy. Of the remaining 24, we expect that 10 will initiate immunotherapy within FY11, while 4 are ineligible due to insufficient collection of tumor lysate/lymphocytes and 10 are unable due to progressive disease during primary therapy. Results thus far demonstrate vigorous immune responses to KLH, and significant immune responses to tumor lysate, enhanced immune reconstitution compared to historical trials that did not utilize rhIL7, as well as promising rates of disease free and overall survival. We anticipate that treatment on this trial will be completed during FY12 and we will initiate publication of these results at that time. A second major achievement of this project was submission of our results of a pilot study of allogeneic stem cell transplantation for patients with high risk pediatric sarcomas for publication. This study (NCI 02-c-0259) used a non-myeloablative allogeneic peripheral blood stem cell transplant for patients with matched sibling donors. We demonstrated that the approach was well tolerated with no treatment related mortality and also made the novel observation that patients with very high risk pediatric solid tumors experience increased chemoresponsiveness and prolonged survival despite recurrence post-allogeneic stem cell transplant. These results provide novel evidence for heretofore unappreciated interactions between chemosensitivity and the immune milieu which is potentially exploitable in non-transplant settings. This report has been submitted and is in revision in the Biology of Blood and Marrow Transplantation. Other achievements during FY11 included initiation of an allogeneic stem cell transplantation trial which incorporates activated NK cell infusions administered during the period of lymphopoenia following stem cell transplant. This is highly novel using activated NK cells for the first time in pediatric patients and using a novel artificial antigen presenting cell for expansion of these cells. Results are not yet available but the trial is open and the first patient has been accrued. Other accomplishments include continued accrual to the only Phase I study of anti-CTLA4 in pediatrics, targeting patients with pediatric melanoma. We have seen evidence for a partial response in a patient with melanoma and some evidence for disease stabilization. Interestingly, preliminary results suggest that children may experience increased autoimmune toxicity compared to adults, a finding which if verified, provides new insights into immunomodulating therapies in pediatrics. During FY11, we also opened the first trial using a genetically engineered T cell receptor targeting children with sarcomas. Specificially, we will administer a T cell receptor targeting NY-ESO-1 in pediatric and adult patients with NY-ESO-1+HLA-A2+ synovial sarcoma. This trial seeks to reproduce promising results seen in a trial administering similar T cells with high dose IL2 to patients with sarcoma and melanoma and represents a collaboration with the University of Pennsylvania and Washington University in St. Louis. Because synovial sarcoma comprises a significant number of sarcomas seen in pediatrics, this trial is important to initiate in the pediatric population.