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Clinical Trials |
Units of Hepatobiliary and Gastro-Pancreatic Surgery [V. M., J. C., M. S., E. R.], Immunotherapy of Human Tumors [M. G. C., L. R., G. P.], Biomedical Statistics [L. M., T. C.], Radiology [A. M.], and Pathology [S. A.], Istituto Nazionale per lo Studio e la Cura Tumori, 20133 Milan, Italy; Sigma-Tau S.p.A., 00040 Rome, Italy [R. C., M. C.]; Antigenics Inc., New York, New York 10111 [J. J. L.]; and Department of Microbiology and Immunology, University of Connecticut, Farmington, Connecticut 06030 [P. K. S.]
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.
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