Clinical Program in Pediatric Sarcomas

在2012财年，我们发表了异基因干细胞移植治疗高危儿童肉瘤患者的临床研究结果。这项研究(NCI 02-C-0259)使用非清髓性异基因外周血干细胞移植治疗超高危儿童实体瘤患者。我们证明，该方法耐受性良好，没有治疗相关的死亡率，还进行了新的观察，即尽管异基因干细胞移植后复发，但非常高风险的儿童实体瘤患者的化疗反应性增强，生存时间延长。我们还提供了在移植时没有疾病证据的患者中有良好存活率的证据。这些结果为迄今为止未被认可的化疗敏感性和免疫环境之间的相互作用提供了证据，这种相互作用可能在非移植环境中被利用，并促使进一步研究同种异基因干细胞移植治疗非常高风险的儿童实体瘤。为此，在2012财年，我们启动了第二代异基因干细胞移植试验，该试验建立在上文讨论的02-c-02590中吸取的经验教训的基础上。简而言之，虽然02-C-0259平台耐受性良好，但移植物抗宿主病的发生率足够高，足以阻止任何基于免疫的疗法的认真努力，我们看到肿瘤复发的风险非常高。因此，我们开发了一种新的方法，在这种情况下使用NK细胞来增强抗肿瘤效果，临床前研究表明，NK细胞不会导致GVHD。2011年，我们发表了一种利用人工抗原提呈细胞产生高活性NK细胞的新方法。在这项工作中，我们证明了抑制性受体不能抑制这些NK细胞的活性。相反，激活信号，主要由天然细胞毒性受体家族组成，介导强大的肿瘤杀伤，而不是通过杀伤抑制受体的信号。在此基础上，我们现在已经启动了第二代异基因干细胞移植治疗高危儿童恶性肿瘤的临床试验，其中包括在干细胞移植后淋巴细胞减少期间输注激活的NK细胞。这是这种细胞首次用于人类，无论是儿科还是其他方面，因此是非常新颖的。到目前为止，已经有6名患者接受了激活的NK细胞，我们观察到了有趣的抗肿瘤作用，以及一些证据表明这些细胞可能会诱发GVHD。审判的应计费用正在进行中。在2012财年，我们几乎完成了针对儿童黑色素瘤患者的儿科抗CTLA4的唯一I期研究。我们已经看到了黑色素瘤患者出现部分反应的证据，以及疾病稳定的一些证据。我们还证明，儿童在使用这种制剂时会经历显著的自身免疫毒性，可能在治疗过程中更早。在2012财年，我们发表了HGS-ETR2的I期研究结果，HGS-ETR2是一种TRAIL受体激动剂，用于治疗儿童实体瘤患者。结果表明，该制剂耐受性良好，一些初步证据表明，肝母细胞瘤具有稳定的疾病和生物标记物反应的活性，以及先前照射过的肿瘤中HGS-ETR2活性增强的挑衅性证据。研究结果目前发表在《临床肿瘤学杂志》上。目前，这种药物无法进行进一步研究，但我们希望未来有机会在儿科结合放射和/或其他方式研究TRAIL受体激动剂。我们还进行了一项公开试验，使用针对患有肉瘤的儿童的基因工程T细胞受体。具体地说，我们将在NY-ESO-1+人类白细胞抗原A2+滑膜肉瘤的儿童和成人患者中应用靶向NY-ESO-1的T细胞受体。这项试验试图重现类似的T细胞与高剂量IL2对肉瘤和黑色素瘤患者进行的试验中看到的有希望的结果，并代表了与宾夕法尼亚大学的合作。到目前为止，尽管我们为这项研究筛选了15名患者，但没有患者出现。在2012财年，我们几乎完成了对高危儿童肉瘤巩固免疫疗法研究的患者的治疗。这项试验直接转化了我们的基础研究，为标准化疗导致淋巴细胞减少的高危儿童肉瘤患者提供基于树突状细胞的肿瘤疫苗。患者还接受去除抑制性T细胞的自体淋巴细胞，重组人白细胞介素7和辅助抗原，Keyhold Limet血蓝蛋白(KLH)，以增强免疫反应。该方案非常新颖，代表了第一次在儿童中使用重组人白细胞介素7，也是目前唯一在肿瘤疫苗试验中使用的重组人白细胞介素7的例子。共有44名患者入选，29名患者接受了已耗尽的自体T细胞和树突状细胞疫苗，这些细胞已被耗尽为抑制者群体，并以KLH和自体肿瘤裂解物为脉冲。其中24名患者还接受了重组人白介素7佐剂。我们观察到对KLH的强烈反应，对肿瘤裂解物的适度免疫反应，以及重组人白介素7的强大免疫修复作用。在其余15名患者中，4名患者因肿瘤裂解物/淋巴细胞收集不足而不符合条件，11名患者在初次治疗期间因进展性疾病而无法接受治疗。到目前为止的结果表明，与没有使用重组人白细胞介素7的历史试验相比，对KLH的强烈免疫反应和对肿瘤裂解物的显著免疫反应，增强了免疫重建，以及有希望的无病和总存活率。

In FY12, we published our clinical results of a pilot study of allogeneic stem cell transplantation for patients with high-risk pediatric sarcomas. This study (NCI 02-c-0259) 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. 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. We also provided evidence for a favorable survival rate in patients without evidence for disease at the time of transplantation. These results provide evidence for heretofore unappreciated interactions between chemosensitivity and the immune milieu which is potentially exploitable in non-transplant settings and invite further studies of allogeneic stem cell transplant for very high risk pediatric solid tumors. To that end, in FY12, we initiated a second generation trial of allogeneic stem cell transplantation trial which built upon the lessons learned in 02-c-02590 discussed above. Briefly, while the 02-c-0259 platform was well tolerated, the incidence of GVHD was high enough to prevent any serious efforts at immune based therapies and we saw a very high risk of tumor recurrence. Thus, we developed a novel approach to increase antitumor effects in this settings using NK cells, which preclinical studies suggest will not cause GVHD. We published a novel approach of using artificial antigen presenting cells to generate highly activated NK cells in 2011. In this work, we demonstrated that inhibitory receptors were not able to inhibit the activity of these NK cells. Rather, activating signals, primarily comprising the family of natural cytotoxicity receptors mediate potent tumor killing, regardless of signaling via killer inhibitory receptors. On this basis, we have now initiated a second generation clinical trial of allogeneic stem cell transplantation in high risk pediatric malignancy that incorporates infusions of activated NK cell during the period of lymphopenia following stem cell transplant. This represents the first time such cells have been used in humans, pediatric or otherwise, and thus is highly novel. Thus far, six patients have received activated NK cells and we have observed interesting antitumor effects as well as some evidence to suggest that these cells may induce GVHD. Accrual to the trial is ongoing. In FY12 we nearly completed 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. We also have demonstrated that children experience significant autoimmune toxicity with this agent, perhaps earlier during the course of therapy. In FY12, we published our results of a Phase I study of HGS-ETR2, a TRAIL receptor agonist in pediatric patients with solid tumors. Results demonstrated tolerability of the agent, some preliminary evidence for activity as evidenced by stable disease and a biomarker response in hepatoblastoma as well as provocative evidence for enhanced activity of HGS-ETR2 in tumors that have been previously irradiated. Results are currently in Press in the Journal of Clinical of Oncology. Currently this drug is not available for further study but we are hopeful that there may be opportunities to study TRAIL receptor agonists in the future in pediatrics in combination with radiation and/or other modalities.We also have an open trial using a genetically engineered T cell receptor targeting children with sarcomas. Specifically, 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. Thus far, no patients have accrued although we have screened > 15 patients for this study. We anticipate enrolling patients during the upcoming year.In FY12, we nearly completed treatment of patients on our study of consolidation immunotherapy for high-risk pediatric sarcomas. 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 29 patients have received autologous T cells that have been depleted to suppressor populations and dendritic cell vaccines pulsed with KLH and autologous tumor lysate. Twenty-four of the patients have also received adjuvant rhIL7. We have observed vigorous responses to KLH, modest immune responses to tumor lysate and potent immunorestorative effects of rhIL7. Of the remaining 15, 4 are ineligible due to insufficient collection of tumor lysate/lymphocytes and 11 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.