Clinical Trials of Immunotherapies for Childhood Cancer

在2013财年，我们继续招募一项试验，在同种异体干细胞移植后使用活化NK细胞治疗高风险儿童癌症。这是建立在先前发表的一项针对高风险儿童肉瘤患者的同种异体干细胞移植的研究基础上的，该研究使用非清髓性同种异体外周血干细胞移植治疗具有匹配兄弟姐妹供体的超高风险儿童实体瘤患者。结果显示肿瘤复发率高，慢性GVHD。我们随后开发了一种方法来产生大量活化NK细胞的体外。此前有报道称，NK细胞能够介导无GVHD的同种异体干细胞移植后的移植物抗肿瘤效应。这是此类细胞首次用于人类，无论是儿童还是其他类型，因此非常新颖。到目前为止，我们已经在这项研究中治疗了10名患者，并观察到GVHD的发病率惊人地高。这些结果表明，与同种异体干细胞移植后自然重建的NK细胞不同，活化的NK细胞能够启动或潜在地增强低水平的同种异体反应性。我们随后修改了试验，纳入了GVHD的预防治疗，并准备发表结果。在2013财年，我们继续招募了唯一一项针对儿科黑色素瘤患者的抗ctla4儿科I期研究。我们在这项研究中看到了疾病的稳定，但没有看到客观的抗肿瘤反应。我们还证明，儿童使用这种药物会产生自身免疫毒性，其性质和严重程度与在成人中观察到的相似。2013财年，我们完成了肿瘤疫苗免疫重建联合试验（NCI 07-c-0206）患者的治疗，并在美国临床肿瘤学会（American Society of clinical Oncology）公布了临床结果。本研究关于免疫重建的生物学终点在项目I中进行了讨论，但我们也观察到转移性尤文氏肉瘤患者在完成一线治疗后的入组率为80%。这些结果是有意治疗的，并且明显优于我们之前在国家癌症研究所对免疫重建/树突状细胞疫苗的研究。我们计划招募未来的队列，试图确定该方案的哪些组成部分导致了有利的结果，以获得更多的方案经验，并优化该疗法，以便向其他机构推广。我们招募了2名患者，在HLA-A2+滑膜肉瘤患者中使用靶向NY-ESO-1+的基因工程T细胞受体进行试验。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，代表了与Adaptimmune LLC的合作。第二名入组患者在这种治疗后出现了显著的完全缓解。继续协议注册将在2014财年进行。在2013财年，我们还启动了一项基于抗cd19嵌合抗原受体治疗难治性B细胞急性淋巴细胞白血病的临床试验。到目前为止，已有10名患者接受了这项研究的治疗，8名患者的随访时间足够长，可以评估其反应。通过意向治疗分析，我们观察到急性淋巴细胞白血病患者的总体完全缓解率为62.5%，CR率为71%。毒性一直是细胞因子释放综合征，如先前报道，这是很容易管理的支持护理。该研究的早期结果已在美国癌症研究协会的新闻稿中得到强调，并在2013年ASCO的口头会议上进行了介绍。报名正在进行中。在2013财年，我们还发表了一篇论文，证明骨髓源性抑制细胞在儿童实体瘤患者中的扩展。这是这个人群中循环MDSC的第一个描述。值得注意的是，MDSC的独特之处在于它们具有先前描述的单核细胞和中性粒细胞MDSC的特征，并且还表达与纤维细胞相关的细胞表面标记。进一步的研究表明这些细胞具有血管生成和免疫抑制作用。它们也表达IL7R和TSLPR，并被TSLP扩增，但不被IL7扩增。总之，我们发现了一种新的细胞，称为免疫抑制纤维细胞，并建议使用新的命名法：F1和F2纤维细胞分别描述免疫刺激和免疫抑制纤维细胞。虽然纤维细胞在慢性炎症状态中被描述过，但它们在人类癌症中还没有被描述过。我们假设这种细胞包含了另一种机制，通过这种机制癌症逃避免疫并介导血管生成。2013年8月入选《BLOOD》全会论文。

In FY13, we continued enrollment of a trial of activated NK cells administered following allogeneic stem cell transplantation for high risk pediatric cancer. This built upon a previous published study of allogeneic stem cell transplantation for patients with high-risk pediatric sarcomas, that used a non-myeloablative allogeneic peripheral blood stem cell transplant for patients with matched sibling donors to treat patients with ultra-high risk pediatric solid tumors. Results showed a high rate of tumor recurrence and chronic GVHD. We subsequently developed an approach to generate large numbers of activated NK cells ex vivo. NK cells have previously been reported to be capable of mediating graft-versus-tumor effects after allogeneic stem cell transplantation without GVHD. This represents the first time such cells have been used in humans, pediatric or otherwise, and thus is highly novel. Thus far, we have treated 10 patients on this study and have observed a surprisingly high incidence of GVHD. These results suggest that activated NK cells, unlike NK cells which naturally reconstitute following allogeneic stem cell transplant, are capable of initiating or potentially augmenting low level alloreactivity. We have subsequently amended the trial to incorporate GVHD preventative therapy and are preparing the results for publication. In FY13 we continued enrollment to the only Phase I study of anti-CTLA4 in pediatrics, targeting patients with pediatric melanoma. We have seen disease stabilization on this study, but not objective antitumor responses. We also have demonstrated that children experience autoimmune toxicity with this agent, which is similar in nature and severity to that observed in adults. In FY13, we completed treatment of patients treated on our combined tumor vaccine, immune reconstitution trial (NCI 07-c-0206) and presented clinical results at the American Society of Clinical Oncology. The biologic endpoints on this study regarding immune reconstitution are discussed in Project I, but we also observed a 80% rate for patients with metastatic Ewing sarcoma enrolled after completion of frontline therapy. These results are intent-to-treat and are significantly better than observed on our previous study of immune reconstitution/dendritic cell vaccine at the National Cancer Institute. We plan enrollment of future cohorts to attempt to identify what components of this regimen are responsible for the favorable outcomes, to generate more experience with his regimen and to optimize this therapy for export to other institutions. We enrolled 2 patients on a trial using a genetically engineered T cell receptor targeting NY-ESO-1+ in HLA-A2+ patients with 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 Adaptimmune LLC. The second patient enrolled had a dramatic complete response that is sustained after this therapy. Continue protocol enrollment will occur during FY14. In FY13, we also initiated a clinical trial of anti-CD19 chimeric antigen receptor based therapy for patients with refractory B cell acute lymphoblastic leukemia. Thus far, 10 patients have been treated on this study and 8 patients have been followed long enough to evaluate for response. Using an intent-to-treat analysis, we observe a 62.5% complete response rate overall, with a 71% CR rate for patients with acute lymphoblastic leukemia. Toxicity has been cytokine release syndrome as previously reported which has been readily managed with supportive care. Early results of this study have been highlighted in a press release at the American Association for Cancer Research and was presented in an oral session at ASCO 2013. Enrollment is ongoing. In FY13 we also published a manuscript demonstrating expansion of myeloid derived suppressor cells in patients with pediatric solid tumors. This is the first description of circulating MDSC is this population. Notably, the MDSC were unique in that they possessed feature of previously described monocytic and neutrophilic MDSC and also expressed cell surface markers associated with fibrocytes. Further studies demonstrated these cells to be angiogenic and to be immunosuppressive. They also express IL7R and TSLPR and are expanded by TSLP, but not IL7. In conclusion, we identified a new cell, termed an immunosuppressive fibrocyte and suggested utilization of a new nomenclature: F1 vs F2 fibrocytes to describe immunostimulatory vs immunosuppressive fibrocytes respectively. Although fibrocytes have been described in chronic inflammatory states, they have not previously been described in human cancer. We postulate that this cell comprises yet another mechanism through which cancer evade immunity and mediate angiogenesis. This work was selected as the Plenary Paper in BLOOD in August 2013.