Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
Clin Cancer Res. 2017 Nov 1;23(21):6441-6449. doi: 10.1158/1078-0432.CCR-17-0379. Epub 2017 Sep 22.
Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells. Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m/dose, days 2-5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained. Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation. Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. .
抗 GD2 mAb 通过抗体依赖的细胞介导的细胞毒性作用，可能增强化疗的效果。这项初步试验研究了一种独特的抗 GD2 mAb hu14.18K322A 的固定剂量，与化疗、细胞因子和单倍体自然杀伤 (NK) 细胞联合使用。复发性/难治性神经母细胞瘤患儿接受多达六个疗程的 hu14.18K322A（40mg/m/剂量，第 2-5 天）、GM-CSF 和白细胞介素 2 联合化疗：环磷酰胺/拓扑替康（第 1、2 个疗程）、伊立替康/替莫唑胺（第 3、4 个疗程）和异环磷酰胺/卡铂/依托泊苷（第 5、6 个疗程）。亲代 NK 细胞在第 2、4 和 6 个疗程中给予。获得了 hu14.18K322A 的药代动力学研究、可溶性白细胞介素 2 受体α（sIL2Rα）水平和人抗人抗体（HAHA）的血清。13 例预处理过的患者（9 例曾接受过抗 GD2 治疗）完成了 65 个疗程。1 例患者出现不可接受的毒性（血小板计数 >35 天，4 级）。4 例患者因不良反应（hu14.18K322A 过敏反应、病毒感染、手术死亡、第二恶性肿瘤）停止治疗。常见的毒性包括 3/4 级骨髓抑制（13/13 例患者）和 1/2 级疼痛（13/13 例患者）。11 例患者接受了 29 次 NK 细胞输注。反应率为 61.5%（4 例完全缓解，1 例很好的部分缓解，3 例部分缓解），5 例疾病稳定。无进展生存期中位数为 274 天（范围，239-568 天）；13 例患者中有 10 例（77%）存活 1 年。hu14.18K322A 的药代动力学不受化疗或 HAHA 的影响。所有患者的 sIL2Rα 水平均升高，表明免疫激活。化疗加 hu14.18K322A、细胞因子和 NK 细胞是可行的，在复发性/难治性神经母细胞瘤患者中产生了有临床意义的反应。在复发性和新诊断的神经母细胞瘤患者中，有必要进一步研究这种方法。
