Clinical Trials of Immunotherapies for Childhood Cancer

在2013财年，我们继续招募了一项在同种异体干细胞移植治疗高危儿科癌症后给予活化NK细胞的试验。这是建立在先前发表的对高危儿科肉瘤患者进行异基因干细胞移植的研究基础上的，该研究使用非清髓性异基因外周血干细胞移植治疗具有匹配同胞供体的患者，以治疗超高风险儿科实体瘤患者。结果显示肿瘤复发率和慢性GVHD。我们随后开发了一种方法来产生大量的激活的NK细胞离体。NK细胞先前已被报道能够在无GVHD的异基因干细胞移植后介导移植物抗肿瘤效应。这是此类细胞首次用于人类、儿科或其他领域，因此具有高度新颖性。到目前为止，我们在这项研究中已经治疗了10名患者，并观察到GVHD的发生率惊人地高。这些结果表明，活化的NK细胞，不像自然重建后异基因干细胞移植的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预防治疗，并准备发表结果。在2013财年，我们继续招募儿童抗CTLA 4的唯一I期研究，目标是儿童黑色素瘤患者。我们在这项研究中看到了疾病稳定，但没有客观的抗肿瘤反应。我们还证明了儿童使用这种药物会出现自身免疫毒性，其性质和严重程度与成人相似。在2013财年，我们完成了对接受联合肿瘤疫苗免疫重建试验（NCI 07-c-0206）治疗的患者的治疗，并在美国临床肿瘤学会（American Society of Clinical Oncology）上展示了临床结果。本研究中关于免疫重建的生物学终点在项目I中讨论，但我们还观察到在完成一线治疗后入组的转移性尤文肉瘤患者的发生率为80%。这些结果是意向性治疗，并且显著优于我们先前在国家癌症研究所进行的免疫重建/树突状细胞疫苗研究中观察到的结果。我们计划招募未来的队列，以尝试确定该方案的哪些组成部分负责有利的结果，以产生更多的经验与他的方案，并优化这种疗法出口到其他机构。我们招募了2名患者参加在患有滑膜肉瘤的HLA-A2+患者中使用靶向NY-ESO-1+的基因工程T细胞受体的试验。该试验旨在重现在向肉瘤和黑色素瘤患者给予类似T细胞与高剂量IL 2的试验中看到的有希望的结果，并代表与Adaptimmune LLC的合作。入组的第二例患者在该治疗后持续出现显著的完全缓解。将在FY 14期间继续进行方案入组。在2013财年，我们还启动了一项针对难治性B细胞急性淋巴细胞白血病患者的基于抗CD 19嵌合抗原受体的治疗的临床试验。到目前为止，已有10例患者在本研究中接受了治疗，8例患者接受了足够长时间的随访，以评估缓解情况。使用意向治疗分析，我们观察到总体完全缓解率为62.5%，急性淋巴细胞白血病患者的CR率为71%。毒性是细胞因子释放综合征，如先前报道的，其已经通过支持性护理容易地管理。这项研究的早期结果在美国癌症研究协会的新闻稿中得到了强调，并在ASCO 2013的口头会议上提出。入组正在进行中。在2013财年，我们还发表了一篇手稿，证明了小儿实体瘤患者中髓源性抑制细胞的扩增。这是该人群中首次描述的循环MDSC。值得注意的是，MDSC是独特的，因为它们具有先前描述的单核细胞和嗜中性MDSC的特征，并且还表达与纤维细胞相关的细胞表面标志物。进一步的研究表明，这些细胞是血管生成和免疫抑制。它们还表达IL 7 R和TSLPR，并通过TSLP而不是IL 7扩增。总之，我们确定了一种新的细胞，称为免疫抑制纤维细胞，并建议利用一个新的命名法：F1与F2纤维细胞分别描述免疫刺激与免疫抑制纤维细胞。虽然纤维细胞已被描述为慢性炎症状态，但它们以前没有在人类癌症中被描述过。我们推测，这种细胞还包括另一种机制，通过这种机制，癌症逃避免疫和介导血管生成。这项工作被选为2013年8月血液全体会议论文。

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.