Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA.
J Transl Med. 2010 Jan 29;8:9. doi: 10.1186/1479-5876-8-9.
Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma.
Patients with a Karnofsky Performance Status >70% and stage III or stage IV melanoma had to have a metastasis >3 cm in diameter resectable as part of routine clinical management. HSPPC-96 tumor-derived vaccines were prepared in one of three dose levels (2.5, 25, or 100 microg/dose) and administered as an intradermal injection weekly for 4 consecutive weeks. In vivo induction of immunity was evaluated using delayed-type hypersensitivity (DTH) to HSPPC-96, irradiated tumor, and dinitrochlorobenzene (DNCB). The gamma-interferon (IFNgamma) ELISPOT assay was used to measure induction of a peripheral blood mononuclear cell response against autologous tumor cells at baseline and at the beginning of weeks 3, 4, and 8.
Among 36 patients enrolled, 72% had stage IV melanoma and 83% had received prior systemic therapy. The smallest tumor specimen from which HSPPC-96 was prepared weighed 2 g. Twelve patients (including 9 with stage IV and indicator lesions) had a negative DNCB skin test result at baseline. All 36 patients were treated and evaluable for toxicity and response. There were no serious toxicities. There were no observed DTH responses to HSPPC-96 or to autologous tumor cells before or during treatment. The IFNgamma-producing cell count rose modestly in 5 of 26 patients and returned to baseline by week 8, with no discernible association with HSPPC-96 dosing or clinical parameters. There were no objective responses among 16 patients with stage IV disease and indicator lesions. Among 20 patients treated in the adjuvant setting, 11 with stage IV melanoma at baseline had a progression-free and overall survival of 45% and 82%, respectively, with a median follow-up of 10 years.
Treatment with autologous tumor-derived HSPPC-96 was feasible and safe at all doses tested. Observed immunological effects and antitumor activity were modest, precluding selection of a biologically active dose. Nevertheless, the 25-microg dose level was shown to be practical for further study.
糖蛋白 96（一种非多态性热休克蛋白）与细胞内肽结合。自体肿瘤衍生的热休克蛋白肽复合物 96（HSPPC-96）可在动物模型中引发强烈的肿瘤特异性 T 细胞反应和保护性免疫。我们试图研究从转移性黑色素瘤患者的肿瘤标本中制备 HSPPC-96 疫苗的可行性、安全性和抗肿瘤活性。
卡氏行为状态评分>70%的患者和 III 期或 IV 期黑色素瘤患者必须有可切除的直径>3 厘米的转移灶，作为常规临床管理的一部分。HSPPC-96 肿瘤衍生疫苗按三种剂量水平（2.5、25 或 100 微克/剂量）之一制备，并每周皮内注射一次，连续 4 周。通过 HSPPC-96、辐照肿瘤和二硝基氯苯（DNCB）的迟发型超敏反应（DTH）评估体内诱导的免疫。使用干扰素-γ（IFNγ）ELISPOT 测定法测量基线和第 3、4 和 8 周开始时对自体肿瘤细胞的外周血单核细胞反应的诱导。
在入组的 36 名患者中，72%为 IV 期黑色素瘤，83%接受过系统治疗。制备 HSPPC-96 的最小肿瘤标本重 2 克。12 名患者（包括 9 名 IV 期和指示性病变患者）在基线时 DNCB 皮肤试验结果为阴性。所有 36 名患者均接受治疗并可评估毒性和反应。没有严重的毒性。在治疗前和治疗期间，没有观察到 HSPPC-96 或自体肿瘤细胞的 DTH 反应。在 26 名患者中有 5 名患者的 IFNγ产生细胞计数略有增加，到第 8 周时恢复基线，与 HSPPC-96 剂量或临床参数无明显关联。16 名 IV 期疾病和指示性病变患者无客观反应。在 20 名辅助治疗的患者中，基线时 11 名 IV 期黑色素瘤患者的无进展和总生存率分别为 45%和 82%，中位随访 10 年。
在所有测试剂量下，自体肿瘤衍生的 HSPPC-96 的治疗是可行和安全的。观察到的免疫效应和抗肿瘤活性适中，排除了选择生物活性剂量的可能性。然而，25 微克剂量水平被证明适用于进一步的研究。
