Defining the Pharmacodynamic Profile and Therapeutic Index of NHS-IL12 Immunocytokine in Dogs with Malignant Melanoma.
Defining the Pharmacodynamic Profile and Therapeutic Index of NHS-IL12 Immunocytokine in Dogs with Malignant Melanoma.
复制标题
DOI：
10.1371/journal.pone.0129954
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Khanna C
中科院分区：
文献类型：
--
作者：
Paoloni M;Mazcko C;Selting K;Lana S;Barber L;Phillips J;Skorupski K;Vail D;Wilson H;Biller B;Avery A;Kiupel M;LeBlanc A;Bernhardt A;Brunkhorst B;Tighe R;Khanna C
白细胞介素 (IL)-12 是一种促炎细胞因子，可介导 1 型辅助 T 细胞反应和细胞毒性 T 细胞活化，有助于其作为抗癌剂的用途。 IL-12 的全身给药通常会导致不可接受的毒性；因此，将 IL-12 直接递送至肿瘤的策略正在研究中。本研究的目的是协助 NHS-IL12 的临床前开发，NHS-IL12 是一种由抗体组成的免疫细胞因子，靶向与 IL-12 相关的坏死肿瘤区域。具体来说，本研究旨在评估 NHS-IL12 在患有天然癌症的狗中的安全性、血清药代动力学、抗肿瘤活性和免疫调节。比较肿瘤学试验联盟 (COTC) 对患有黑色素瘤的狗皮下注射 NHS-IL12 进行了快速剂量递增研究。 11 只狗被纳入四个剂量递增队列；此后，另外七只狗接受了规定的 0.8 mg/m2 耐受剂量的治疗。该固定剂量的扩大队列（总共十只狗）被累积用于进一步的药代动力学和药效学评估。收集 NHS-IL12 水平、血清细胞因子浓度、外周血单核细胞特征（治疗后）和引流淋巴结免疫分析以及肿瘤活检（治疗前和治疗后）。不良事件包括血小板减少、肝酶病、发烧和血管炎。干扰素 (IFN)-γ 诱导、不良事件和 NHS-IL12 暴露（最大浓度和浓度-时间曲线下面积）之间的相关性呈剂量依赖性。治疗后血清 IL-10 水平和瘤内 CD8+ 群体增加。根据实体瘤反应评估标准 (RECIST) 标准，在接受 NHS-IL12 0.8 mg/m2 和 1.6 mg/m2 治疗的两只狗中观察到部分反应。 NHS-IL12 被安全地给予患有黑色素瘤的狗，并观察到免疫学和临床活性。这项研究成功地确定了通过皮下途径全身递送 NHS-IL12 的狭窄治疗窗。结果将为 NHS-IL12 在癌症患者中的首次人体临床试验的设计和实施提供信息。
Interleukin (IL)-12 is a pro-inflammatory cytokine that mediates T-helper type 1 responses and cytotoxic T-cell activation, contributing to its utility as anti-cancer agent. Systemic administration of IL-12 often results in unacceptable toxicity; therefore, strategies to direct delivery of IL-12 to tumors are under investigation. The objective of this study was to assist the preclinical development of NHS-IL12, an immunocytokine consisting of an antibody, which targets necrotic tumor regions, linked to IL-12. Specifically this study sought to evaluate the safety, serum pharmacokinetics, anti-tumor activity, and immune modulation of NHS-IL12 in dogs with naturally occurring cancers. A rapid dose-escalation study of NHS-IL12 administered subcutaneously to dogs with melanoma was conducted through the Comparative Oncology Trials Consortium (COTC). Eleven dogs were enrolled in four dose-escalation cohorts; thereafter, an additional seven dogs were treated at the defined tolerable dose of 0.8 mg/m2. The expanded cohort at this fixed dose (ten dogs in total) was accrued for further pharmacokinetics and pharmacodynamics assessment. NHS-IL12 levels, serum cytokine concentrations, and peripheral blood mononuclear cell characterization (post-treatment) and draining lymph node immune profiling, and tumor biopsies (pre- and post-treatment) were collected. Adverse events included thrombocytopenia, liver enzymopathies, fever, and vasculitis. Correlation between interferon (IFN)-γ induction, adverse events, and NHS-IL12 exposure (maximum concentration and area under the concentration-time curve) were dose-dependent. Serum IL-10 levels and intratumoral CD8+ populations increased after treatment. Partial responses, according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, were observed in two dogs treated with NHS-IL12 0.8 mg/m2 and 1.6 mg/m2. NHS-IL12 was administered safely to dogs with melanoma and both immunologic and clinical activity was observed. This study successfully defined a narrow therapeutic window for systemic delivery of NHS-IL12 via the subcutaneous route. Results will inform the design and implementation of first-in-human clinical trials of NHS-IL12 in cancer patients.
登录
查看更多内容
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
影响因子：
5.1
作者：
Finocchiaro, L. M. E.;Glikin, G. C.
通讯作者：
Glikin, G. C.
影响因子：
15.8
作者：
Gordon I;Paoloni M;Mazcko C;Khanna C
通讯作者：
Khanna C
影响因子：
3.7
作者：
Paoloni MC;Tandle A;Mazcko C;Hanna E;Kachala S;Leblanc A;Newman S;Vail D;Henry C;Thamm D;Sorenmo K;Hajitou A;Pasqualini R;Arap W;Khanna C;Libutti SK
通讯作者：
Libutti SK
影响因子：
4.3
作者：
Jia, Lee;Schweikart, Karen;Munn, David H.
通讯作者：
Munn, David H.