Phase I study of immunization with dendritic cells modified with fowlpox encoding carcinoembryonic antigen and costimulatory molecules.

Abstract

PURPOSE:

To determine the safety and immunologic and clinical efficacy of a dendritic cell vaccine modified to hyperexpress costimulatory molecules and tumor antigen.

EXPERIMENTAL DESIGN:

In this phase I study, we administered one or two cycles of four triweekly s.c./intradermal injections of ex vivo generated dendritic cells modified with a recombinant fowlpox vector encoding carcinoembryonic antigen (CEA) and a triad of costimulatory molecules [rF-CEA(6D)-TRICOM]. Controls consisted of immature dendritic cells loaded with tetanus toxoid and a HLA A2-restricted peptide derived from cytomegalovirus pp65 protein.

RESULTS:

Fourteen patients (11 with colorectal cancer and 3 with non-small cell lung cancer) were enrolled and 12 completed at least one cycle of immunization. There were no grade 3/4 toxicities directly referable to the immunizations. One patient had a decrease in the CEA level from 46 to 6.8 and a minor regression in adenopathy that occurred several months after completion of the immunizations. Five other patients were stable through at least one cycle of immunization (3 months). Direct analysis of peripheral blood mononuclear cells using the ELISpot assay showed an increase in the frequency of CEA-specific T cells in 10 patients (range, 10-541 CEA-specific cells/10(5) peripheral blood mononuclear cells). There was a trend for a greater peak frequency of CEA-specific T cells among those with either a minor response or a stable disease following at least one cycle of therapy. A second cycle was not associated with higher T-cell frequencies. Cytokine flow cytometry showed CEA-specific immune response among both CD4(+) and CD8(+) T cells in all immune responders.

CONCLUSION:

This immunization strategy is safe and activates potent CEA-specific immune responses.

• Authors: Michael A Morse, Timothy M Clay, Amy C Hobeika, Takuya Osada, Shubi Khan, Stephen Chui, Donna Niedzwiecki, Dennis Panicali, Jeffrey Schlom, H Kim Lyerly
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 8 Pg. 3017-24 (Apr 15 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15837756 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• B7-1 Antigen
• CD58 Antigens
• Cancer Vaccines
• Carcinoembryonic Antigen
• Cytokines
• HLA-A2 Antigen
• Recombinant Fusion Proteins
• Tetanus Toxoid
• Intercellular Adhesion Molecule-1

Topics

• B7-1 Antigen (genetics, immunology)
• CD58 Antigens (genetics, immunology)
• Cancer Vaccines (administration & dosage, immunology, therapeutic use)
• Carcinoembryonic Antigen (genetics, immunology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, immunology)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, immunology)
• Cytokines (metabolism)
• Dendritic Cells (immunology, metabolism)
• Female
• Flow Cytometry
• Fowlpox virus (genetics)
• HLA-A2 Antigen (immunology)
• Humans
• Immunotherapy, Adoptive (methods)
• Injections, Intradermal
• Intercellular Adhesion Molecule-1 (genetics, immunology)
• Leukocytes, Mononuclear (drug effects, immunology, metabolism)
• Lung Neoplasms (drug therapy, immunology)
• Male
• Recombinant Fusion Proteins (genetics, immunology, pharmacology)
• Tetanus Toxoid (immunology)
• Treatment Outcome