Specht Hanno M, Ahrens Norbert, Blankenstein Christiane, Duell Thomas, Fietkau Rainer, Gaipl Udo S, Günther Christine, Gunther Sophie, Habl Gregor, Hautmann Hubert, Hautmann Matthias, Huber Rudolf Maria, Molls Michael, Offner Robert, Rödel Claus, Rödel Franz, Schütz Martin, Combs Stephanie E, Multhoff Gabriele
Radiation Oncology, Klinikum rechts der Isar, Technische Universität München , Munich , Germany.
Transfusion Medicine, Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg , Regensburg , Germany.
Front Immunol. 2015 Apr 15;6:162. doi: 10.3389/fimmu.2015.00162. eCollection 2015.
Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups.
热休克蛋白70（Hsp70）在肿瘤细胞中经常过度表达。在包括肺癌、结直肠癌、乳腺癌、头颈部鳞状细胞癌、前列腺癌和胰腺癌、胶质母细胞瘤、肉瘤及血液系统恶性肿瘤等多种实体瘤中均可显示出异常的细胞表面定位，但在相应的正常组织中则未出现。通过使用cmHsp70.1单克隆抗体的流式细胞术可直接在肿瘤活检的单细胞悬液上确定膜（m）Hsp70阳性表型，或使用新型脂质Hsp70 ELISA间接在患者血清中确定。mHsp70阳性肿瘤表型与高侵袭性肿瘤相关，可导致侵袭、转移及对细胞死亡的抵抗。然而，发现自然杀伤（NK）细胞而非T细胞在用天然存在的Hsp70肽（TKD）加低剂量白细胞介素-2（TKD/IL-2）激活后可杀伤mHsp70阳性肿瘤细胞。在一项I期临床试验中，已证明体外TKD/IL-2刺激的自体NK细胞对转移性结直肠癌和非小细胞肺癌（NSCLC）患者具有安全性和耐受性。基于先前研究有前景的临床结果，2014年启动了一项II期随机临床研究。这项多中心概念验证试验的主要目的是检验用TKD/IL-2激活的自体NK细胞对NSCLC患者进行铂类放化疗（RCTx）后的辅助治疗是否具有临床疗效。由于mHsp70阳性肿瘤表型与不良临床结局相关，因此仅招募mHsp70阳性肿瘤患者入组该试验。本研究的主要终点将是比较体外激活的NK细胞治疗患者与仅接受RCTx治疗患者的无进展生存期。作为次要终点，将在两个研究组中确定总生存期、毒性、生活质量和生物学反应。
