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


METHODS
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.
Mazzaferro
Vincenzo
V
Units of Hepatobiliary and Gastro-Pancreatic Surgery, Istituto Nazionale per lo Studio e la Cura Tumori, 20133 Milan, Italy. vincenzo.mazaferro@istitutotumori.mi.it
Coppa
Jorgelina
J
Carrabba
Matteo G
MG
Rivoltini
Licia
L
Schiavo
Marcello
M
Regalia
Enrico
E
Mariani
Luigi
L
Camerini
Tiziana
T
Marchianò
Alfonso
A
Andreola
Salvatore
S
Camerini
Roberto
R
Corsi
Marco
M
Lewis
Jonathan J
JJ
Srivastava
Pramod K
PK
Parmiani
Giorgio
G
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics*; D017252:CD3 Complex / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000737:chemistry; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000473:pathology / Q000601:surgery* / Q000628:therapy*; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006650:Histocompatibility Testing; D006801:Humans; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008113:Liver Neoplasms / Q000556:secondary* / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010455:Peptides / Q000737:chemistry; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D012044:Regression Analysis; D013601:T-Lymphocytes / Q000378:metabolism; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; C515370:CCR7 protein, human; D017252:CD3 Complex; D019496:Cancer Vaccines; D010455:Peptides; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C052646:sarcoma glycoprotein gp96 rejection antigens; D017493:Leukocyte Common Antigens