Clinical Trials of Immunotherapies for Childhood Cancer

儿童癌症免疫疗法的临床试验

• 批准号: 8763569
• 负责人: Crystal Mackall
• 金额: $ 77.09万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763569
• 关键词: Acute Lymphocytic Leukemia; Adult; Allogenic; American Association of Cancer Research; American Society of Clinical Oncology; Antigen Receptors; Antitumor Response; Autoimmune Process; B-Cell Acute Lymphoblastic Leukemia; Basic Science; CD19 gene; CTAG1 gene; CTLA4 gene; Cancer Vaccines; Cell surface; Cells; Child; Childhood; Childhood Solid Neoplasm; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Conduct Clinical Trials; Dendritic Cell Vaccine; Development; Disease; Dose; Enrollment; Ethics; Future; Genetic Engineering; Goals; Graft-Versus-Tumor Induction; HLA-A2 Antigen; Human; IL2 gene; IL7 gene; IL7R gene; Immune; Immunity; Immunosuppressive Agents; Immunotherapy; In complete remission; Incidence; Inflammatory; Institution; Laboratories; Learning; Malignant Childhood Neoplasm; Malignant Neoplasms; Manuscripts; Mediating; Metastatic Ewing' s Sarcoma; Myelogenous; National Cancer Institute; Natural Killer Cells; Nature; Nomenclature; Oral; Outcome; Paper; Patients; Pediatric Neoplasm; Pediatrics; Peripheral Blood Stem Cell; Population; Press Releases; Protocols documentation; Publications; Publishing; Recurrence; Refractory; Regimen; Reporting; Research; Sampling; Severities; Siblings; Source; Stem cell transplant; Supportive care; Suppressor-Effector T-Lymphocytes; Syndrome; T-Cell Receptor; T-Lymphocyte; TSLP gene; Time; Toxic effect; Translational Research; Transplant Recipients; United States National Institutes of Health; Work; angiogenesis; base; bench to bedside; chronic graft versus host disease; cohort; cytokine; experience; graft vs host disease; high risk; human subject; innovation; melanoma; novel; phase 1 study; programs; reconstitution; response; sarcoma; synovial sarcoma; tumor

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.

2013 财年，我们继续开展一项针对高危儿童癌症的同种异体干细胞移植后施用活化 NK 细胞的试验。该研究建立在之前发表的一项针对高危儿科肉瘤患者的同种异体干细胞移植研究的基础上，该研究对匹配的兄弟姐妹供体的患者使用非清髓性同种异体外周血干细胞移植来治疗超高危儿科实体瘤患者。结果显示肿瘤复发率和慢性 GVHD 率很高。我们随后开发了一种离体产生大量活化 NK 细胞的方法。此前有报道称，在无 GVHD 的同种异体干细胞移植后，NK 细胞能够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，我们已经在这项研究中治疗了 10 名患者，并观察到 ​​GVHD 的发生率高得惊人。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增强低水平的同种异体反应性。我们随后修改了试验，纳入 GVHD 预防治疗，并正在准备公布结果。 2013 财年，我们继续入组儿科唯一一项针对儿童黑色素瘤患者的抗 CTLA4 一期研究。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，儿童使用该药物会出现自身免疫毒性，其性质和严重程度与成人中观察到的相似。 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，并向美国临床肿瘤学会展示了临床结果。这项研究有关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比率为 80%。这些结果是意向治疗的，并且明显优于我们之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，以尝试确定该疗法的哪些组成部分带来了有利的结果，以产生更多的疗法经验，并优化该疗法以输出到其他机构。我们招募了 2 名患者参加一项试验，该试验使用针对 NY-ESO-1+ 的基因工程 T 细胞受体治疗 HLA-A2+ 滑膜肉瘤患者。该试验旨在重现向肉瘤和黑色素瘤患者施用含有高剂量 IL2 的类似 T 细胞的试验中所见的有希望的结果，并代表与 Adaptimmune LLC 的合作。入组的第二名患者在治疗后获得了显着的完全缓解，并且这种缓解持续存在。继续方案注册将在 2014 财年进行。 2013 财年，我们还针对难治性 B 细胞急性淋巴细胞白血病患者启动了一项基于抗 CD19 嵌合抗原受体治疗的临床试验。迄今为止，该研究已对 10 名患者进行了治疗，并对 8 名患者进行了足够长的随访以评估疗效。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%。正如之前报道的，毒性是细胞因子释放综合征，通过支持性护理很容易控制。美国癌症研究协会的一份新闻稿强调了这项研究的早期结果，并在 2013 年 ASCO 会议的口头会议上进行了介绍。招募工作正在进行中。在 2013 财年，我们还发表了一篇手稿，证明儿科实体瘤患者中骨髓源性抑制细胞的扩增。这是该人群中循环 MDSC 的首次描述。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。它们还表达 IL7R 和 TSLPR，并通过 TSLP 进行扩增，但不通过 IL7 进行扩增。总之，我们鉴定了一种新细胞，称为免疫抑制性纤维细胞，并建议使用新的命名法：F1 与 F2 纤维细胞分别描述免疫刺激性与免疫抑制性纤维细胞。尽管已在慢性炎症状态下描述了纤维细胞，但此前尚未在人类癌症中描述过它们。我们假设该细胞包含另一种机制，癌症通过该机制逃避免疫并介导血管生成。该工作于2013年8月被选为BLOOD的Plenary Paper。