Pharmacological administration of granulocyte/macrophage-colony-stimulating factor is of significant importance for the induction of a strong humoral and cellular response in patients immunized with recombinant carcinoembryonic antigen

Abstract

Eighteen colorectal carcinoma patients without macroscopic disease after surgery were immunized using recombinant (r) human (h) carcinoembryonic antigen (CEA) with (n=9) or without (n=9) the addition of soluble granulocyte/macrophage-colony-stimulating factor (GM-CSF). The dose of rhCEA per immunization was 100 microg (n=6), 316 microg (n=6) or 1000 microg (n=6). rhCEA was given s.c. on day 1 and 80 microg/day of GM-CSF s.c. on days 1-4. The schedule was repeated six times during a period of 9 months. All patients in the GM-CSF group developed a strong rhCEA-dose-dependent IgG antibody response while only one-third of the non-GM-CSF patients mounted a weak antibody response. All patients (9/9) in the GM-CSF group developed a strong rhCEA-specific proliferative T cell response as well as type I T cells (interferon gamma secretion). In 45% of the patients also a weak type II T cell response (interleukin-4 secretion) was evoked. Both MHC-class-I- and -II restricted rhCEA-specific T cells were noted. A specific cellular response (proliferation and/or cytokine secretion) against native hCEA could be found in 8/9 patients in the GM-CSF group, although at a significantly lower level than against rhCEA. In the non-GM-CSF group a weak rhCEA-specific T cell response was induced. Three patients had a proliferative response, 4 patients type I T cells and 6 patients type II T cells. No signs of autoimmune reactions were noted. Local pharmacological administration of GM-CSF seemed to be a prerequisite for the induction of a strong immunity against baculovirus-produced hCEA protein. However, the cellular response against native CEA was of a significantly lower magnitude.

Durable Carcinoembryonic Antigen (CEA)-Specific Humoral and Cellular Immune Responses in Colorectal Carcinoma Patients Vaccinated with Recombinant CEA and Granulocyte/Macrophage Colony-Stimulating Factor

“…16). Our preliminary findings, reported earlier (10), clearly illustrated that a vaccine containing whole CEA protein could reverse any existing anergy and elicit an immune response. The intrinsic immune reactivity toward a self-antigen such as CEA, however, is very minimal.…”

“…We therefore adapted the present study to include repeated immunizations and a potent adjuvant-like GM-CSF to break the anergy/ unresponsiveness toward CEA (17). We have previously reported that GM-CSF given as an adjuvant substantially augmented both cellular and humoral immune responses against the rCEA protein (10,18). The capacity of GM-CSF to augment an antitumor immune response is most likely due to the ability to enhance antigen presentation by dendritic cells in vivo (19 -21).…”

“…We and others have vaccinated colon cancer patients with recombinant CEA (rCEA; Ref. 10), anti-idiotypic antibodies mimicking CEA (11), or CEA expressed in virus (12)(13)(14) and demonstrated the induction of a cellular and humoral immune response. A trend toward an improved clinical outcome was also noted in some of the studies (11,14).…”

Signal sequence deletion and fusion to tetanus toxoid epitope augment antitumor immune responses to a human carcinoembryonic antigen (CEA) plasmid DNA vaccine in a murine test system

“…14 Patients with colon cancer immunized with rCEA mounted both antibody and T-cell responses against CEA that were enhanced by adding granulocyte/macrophage-colony-stimulating factor (GM-CSF). 15 Unlike several infectious diseases, which are well controlled by humoral responses, solid tumors such as colon carcinoma are likely to require cellular responses for effect. Studies in animals reveal that tumor regression is more often associated with cellular than with humoral immunity.…”

Incorporation of Glycosylphosphatidylinositol-Anchored Granulocyte- MacrophageColony-Stimulating Factor or CD40 Ligand Enhances Immunogenicity of Chimeric Simian Immunodeficiency Virus-Like Particles

“…Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to expand myeloid-derived dendritic cell (DC) populations (20,47), to augment antigeninduced humoral and cellular immune responses, and to affect the Th1/Th2 cytokine balance (45). It has been extensively used as an effective genetic and protein adjuvant to enhance immunogenicity of tumor and vaccine antigens (6,14,16,28,29,31,35,42,48,50,54,56). Another immunostimulatory molecule is CD40 ligand (CD40L), which is a surface molecule primarily expressed on mature CD4 ϩ T cells.…”