转移性结直肠癌肝切除术后接种自体肿瘤来源的热休克蛋白gp96。

Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer.

作者信息

Mazzaferro Vincenzo, Coppa Jorgelina, Carrabba Matteo G, Rivoltini Licia, Schiavo Marcello, Regalia Enrico, Mariani Luigi, Camerini Tiziana, Marchianò Alfonso, Andreola Salvatore, Camerini Roberto, Corsi Marco, Lewis Jonathan J, Srivastava Pramod K, Parmiani Giorgio

机构信息

Units of Hepatobiliary and Gastro-Pancreatic Surgery, Istituto Nazionale per lo Studio e la Cura Tumori, 20133 Milan, Italy.

出版信息

Clin Cancer Res. 2003 Aug 15;9(9):3235-45.

DOI:

PMID:12960108

Abstract

PURPOSE

Heat shock proteins (HSP) from tumor cells contain the gp96 polypeptide associated with cancer-specific antigenic peptides. Mice that are immunized with HSP/peptide-complex (HSPPC) derived from cancer tissue reject tumor from which HSPs are purified. We tested in humans whether vaccination with HSPPC-gp96 (Oncophage) from autologous liver metastases of colorectal carcinoma induces cancer-specific T-cell responses in patients rendered disease free by surgery.

EXPERIMENTAL DESIGN

Twenty-nine consecutive patients underwent radical resection of liver metastases [Memorial Sloan-Kettering Cancer Center (MSKCC) score 1-3 (good prognosis), 18 patients; score 4-5 (bad prognosis), 11 patients] and received autologous tumor-derived HSPPC-96. Two vaccine cycles were administered (four weekly injections followed by four biweekly injections after 8 weeks). Class-I HLA-restricted, anti-colon cancer lines T-cell response was measured by ELISPOT assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Feasibility, safety, and possible clinical benefits were also evaluated.

RESULTS

Either a de novo induced or a significant increase of preexisting class I HLA-restricted T-cell-mediated anti-colon cancer response was observed in 15 (52%) of 29 patients. Frequency of CD3+, CD45RA+, and CCR7- T lymphocytes increased in immune responders. No relevant toxicity was observed. As expected, patients with good prognosis had a significantly better clinical outcome than those with poor prognosis [2-year overall survival (OS), 89 versus 64%, P = 0.001; disease-free survival (DFS), 46 versus 18%, P = 0.001]. Patients with immune response had a statistically significant clinical advantage over nonresponding subjects (2-year OS, 100% versus 50%, P = 0.001; DFS, 51% versus 8%, P = 0.0001). Occurrence of immune response led to better tumor-free survival, whatever the predicted prognosis was (hazard ratio, 0.11-0.12 with/without stratification; P = 0.0012-0.0003).

CONCLUSIONS

HSPPC-96 vaccination after resection of colorectal liver metastases is safe and elicits a significant increase in CD8+ T-cell response against colon cancer. In this limited number of patients, two-year OS and DFS were significantly improved in subjects with postvaccination antitumor immune response, independently from other clinical prognostic factors.

摘要

目的

肿瘤细胞的热休克蛋白（HSP）包含与癌症特异性抗原肽相关的gp96多肽。用源自癌组织的热休克蛋白/肽复合物（HSPPC）免疫的小鼠可排斥从中纯化出热休克蛋白的肿瘤。我们在人体中测试了用来自结直肠癌自体肝转移灶的HSPPC-gp96（安柯瑞）进行疫苗接种是否能在通过手术实现无病状态的患者中诱导癌症特异性T细胞反应。

实验设计

29例连续患者接受了肝转移灶的根治性切除[纪念斯隆凯特琳癌症中心（MSKCC）评分1 - 3（预后良好），18例患者；评分4 - 5（预后不良），11例患者]，并接受了自体肿瘤来源的HSPPC-96。给予两个疫苗周期（每周注射4次，8周后每两周注射4次）。通过酶联免疫斑点法（ELISPOT）检测接种前后外周血单个核细胞（PBMC）上I类HLA限制性抗结肠癌系T细胞反应。还评估了可行性、安全性和可能的临床益处。

结果

在29例患者中的15例（52%）观察到了I类HLA限制性T细胞介导的抗结肠癌反应的从头诱导或预先存在反应的显著增加。免疫反应者中CD3 +、CD45RA +和CCR7 - T淋巴细胞的频率增加。未观察到相关毒性。正如预期的那样，预后良好的患者的临床结局明显优于预后不良的患者[2年总生存期（OS），89%对64%，P = 0.001；无病生存期（DFS），46%对18%，P = 0.001]。有免疫反应的患者相对于无反应的受试者具有统计学上显著的临床优势（2年OS，100%对50%，P = 0.001；DFS，51%对8%，P = 0.0001）。无论预测的预后如何，免疫反应的发生都导致了更好的无瘤生存期（分层/不分层的风险比，0.11 - 0.12；P = 0.0012 - 0.0003）。