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-specificTcells 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.

Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo

“…Briefly, cytomegalovirus-driven LacZ (originally described in reference 19) and human carcinoembryonic antigen (CEA) (described in reference 44,31) were independently subcloned into shuttle plasmids and used to generate [E1-E3-] and [E1-E2b-E3-] vectors using a previously described, bacterial-recombination-based system (20). Complementing C-7 cell lines (containing the Ad E2 polymerase and pTP genes) were used to produce high-titer stocks of these vectors, and cesium chloride double banding was performed to purify the vectors, as previously detailed (3).…”

Vaccine properties of a novel marker gene-free recombinant modified vaccinia Ankara expressing immunodominant CMV antigens pp65 and IE1

“…It has been proposed that a superior malaria vaccine will be multistage and multi-component requiring a high capacity vector such as MVA [50]. Using dendritic cells infected with poxvirus encoding CEA and co-stimulatory molecules B7-1, ICAM-1 and LFA-3 activates potent CEA-specific immune responses [51]. Recent clinical studies indicated that MVA expressing HIV-1 Gag coupled to other CD8+ T-cell epitopes could induce multifunctional HIV-1-specific T cells in healthy subjects or in individuals with chronic HIV-1 infection [13,52].…”

Membranes, molecules and biophysics: enhancing monocyte derived dendritic cell (MDDC) immunogenicity for improved anti-cancer therapy

“…Phase I clinical trials using the CEA loaded MDDCs in colorectal cancer patients indicated that they induced both a CD4+ and CD8+ effector response, but that T suppressor activity may have impacted on the full effect of the vaccine [67]. MDDCs loaded with CEA and melanoma associated antigen 3 (MAGE-3) induced significant increases in the killing of target cells by CTLs [68].…”