Vaccination with Autologous Tumor-derived Heat-Shock Protein Gp96 after Liver Resection for Metastatic Colorectal Cancer

• Published in: Clinical cancer research Vol. 9; no. 9; pp. 3235 - 3245
• Main Authors: MAZZAFERRO, Vincenzo, COPPA, Jorgelina, CAMERINI, Roberto, CORSI, Marco, LEWIS, Jonathan J, SRIVASTAVA, Pramod K, PARMIANI, Giorgio, CARRABBA, Matteo G, RIVOLTINI, Licia, SCHIAVO, Marcello, REGALIA, Enrico, MARIANI, Luigi, CAMERINI, Tiziana, MARCHIANO, Alfonso, ANDREOLA, Salvatore
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-08-2003
• Subjects: Adult; Aged; Antigens, Neoplasm - chemistry; Antigens, Neoplasm - genetics; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - chemistry; CD3 Complex - biosynthesis; CD8-Positive T-Lymphocytes - immunology; Cohort Studies; Colorectal Neoplasms - pathology; Colorectal Neoplasms - surgery; Colorectal Neoplasms - therapy; Disease-Free Survival; Enzyme-Linked Immunosorbent Assay; Female; Histocompatibility Testing; Humans; Immunophenotyping; Immunotherapy; Leukocyte Common Antigens - biosynthesis; Leukocytes, Mononuclear - metabolism; Liver Neoplasms - secondary; Liver Neoplasms - surgery; Male; Medical sciences; Middle Aged; Neoplasm Metastasis; Peptides - chemistry; Pharmacology. Drug treatments; Prognosis; Proportional Hazards Models; Prospective Studies; Receptors, CCR7; Receptors, Chemokine - biosynthesis; Regression Analysis; T-Lymphocytes - metabolism; Treatment Outcome; Antineoplastic agent; Human; Rectal disease; Resection; Tumor associated antigen; Liver; Vaccination; Autologous system; Malignant tumor; Colonic disease; Treatment; Immunotherapy; Heat shock protein; Rectum; Digestive diseases; Intestinal disease; Advanced stage; Metastatic; Colon
• ISSN: 1078-0432; 1557-3265

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.