Loskog Angelica, Maleka Aglaia, Mangsbo Sara, Svensson Emma, Lundberg Christina, Nilsson Anders, Krause Johan, Agnarsdóttir Margrét, Sundin Anders, Ahlström Håkan, Tötterman Thomas H, Ullenhag Gustav
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden.
Department of Oncology, Uppsala University Hospital, 75185 Uppsala, Sweden.
Br J Cancer. 2016 Apr 12;114(8):872-80. doi: 10.1038/bjc.2016.42. Epub 2016 Mar 31.
Current approaches for treating metastatic malignant melanoma (MM) are not effective enough and are associated with serious adverse events. Due to its immunogenicity, melanoma is an attractive target for immunostimulating therapy. In this phase I/IIa study, local AdCD40L immunostimulatory gene therapy was evaluated in patients with MM.
AdCD40L is an adenovirus carrying the gene for CD40 ligand. Patients that failed standard treatments were enrolled. Six patients received four weekly intratumoral AdCD40L injections. Next, nine patients received low-dose cyclophosphamide conditioning before the first and fourth AdCD40L injection. The blood samples were collected at multiple time points for chemistry, haematology and immunology evaluations. Radiology was performed at enrolment and repeated twice after the treatment.
AdCD40L was safe with mild transient reactions. No objective responses were recorded by MRI, however, local and distant responses were seen on FDG-PET. The overall survival at 6 months was significantly better when cyclophosphamide was added to AdCD40L. The patients with the best survival developed the highest levels of activated T cells and experienced a pronounced decrease of intratumoral IL8.
AdCD40L therapy for MM was well tolerated. Local and distant responses along with better survival in the low-dose cyclophosphamide group are encouraging.
目前治疗转移性恶性黑色素瘤（MM）的方法效果不够显著，且伴有严重不良事件。由于黑色素瘤具有免疫原性，因此是免疫刺激疗法的一个有吸引力的靶点。在这项I/IIa期研究中，对MM患者进行了局部AdCD40L免疫刺激基因治疗的评估。
AdCD40L是一种携带CD40配体基因的腺病毒。纳入标准治疗失败的患者。6例患者每周接受4次瘤内注射AdCD40L。接下来，9例患者在首次和第四次注射AdCD40L之前接受低剂量环磷酰胺预处理。在多个时间点采集血样进行化学、血液学和免疫学评估。在入组时进行放射学检查，并在治疗后重复两次。
AdCD40L安全，反应轻微且短暂。MRI未记录到客观缓解，但FDG-PET显示有局部和远处反应。当AdCD40L联合环磷酰胺时，6个月时的总生存率显著提高。生存情况最佳的患者激活T细胞水平最高，瘤内IL8明显下降。
MM患者对AdCD40L治疗耐受性良好。低剂量环磷酰胺组出现局部和远处反应以及更好的生存率，令人鼓舞。
