Morse Michael A, Garst Jennifer, Osada Takuya, Khan Shubi, Hobeika Amy, Clay Timothy M, Valente Nancy, Shreeniwas Revati, Sutton Mary Ann, Delcayre Alain, Hsu Di-Hwei, Le Pecq Jean-Bernard, Lyerly H Kim
Department of Medicine, Duke University Medical Center, Durham, NC, USA.
J Transl Med. 2005 Feb 21;3(1):9. doi: 10.1186/1479-5876-3-9.
There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). METHODS: This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. RESULTS: Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1-2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52-665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. CONCLUSION: Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effectors.
持续需要开发更有效的癌症免疫治疗策略。外泌体是细胞来源的脂质囊泡，表达高水平的窄谱细胞蛋白，代表了一种结合共刺激分子递送高水平抗原的新型平台。我们开展本研究以测试负载MAGE肿瘤抗原的自体树突状细胞（DC）来源的外泌体（DEX）在非小细胞肺癌（NSCLC）患者中的安全性、可行性和疗效。
本I期研究纳入了HLA A2+的IIIb期（N = 4）和IV期（N = 9）NSCLC患者，这些患者先前已接受治疗且肿瘤表达MAGE-A3或A4。患者接受白细胞分离术以产生DC，从中制备DEX并负载MAGE-A3、-A4、-A10和MAGE-3DPO4肽。患者每周接受4剂DEX。
13名患者入组，9名完成治疗。评估了三种DEX制剂；所有制剂耐受性良好，仅出现与使用DEX相关的1-2级不良事件（注射部位反应（N = 8）、流感样疾病（N = 1）和外周手臂疼痛（N = 1））。从第一剂DEX到疾病进展的时间为30至429+天。3名患者在第一剂DEX之前出现疾病进展。第一剂DEX后患者的生存期为52-665+天。9名患者中有3名检测到针对MAGE肽的迟发型超敏反应（DTH）反应性。在患者中检测到的免疫反应如下：3名患者中有1名出现MAGE特异性T细胞反应，4名患者中有2名NK细胞杀伤活性增加。
DEX疫苗的制备是可行的，DEX疗法在晚期NSCLC患者中耐受性良好。一些患者经历了疾病的长期稳定和免疫效应器的激活。
