Recombinant Fowlpox GM-CSF Vaccine Adjuvant

Abstract CpG ODN are being actively investigated as cancer vaccine adjuvants because they mature plasmacytoid dendritic cells (pDC) into potent antigen-presenting cells. In addition, TLR ligands induce a broad range of other immunologic effects in pDC including the secretion of interferon α (IFNa) and chemokines which alter lymphocyte migration. Whether these CpG-ODN driven TLR ligand signals enhance antigen specific Immunity and/or trafficking In humans Is presently unknown. We evaluated the efficacy of the CpG-ODN, 1018-ISS, as a vaccine adjuvant given with GM-CSF to induce T cell immunity in humans to the tumor antigen hTERT. Seventeen patients with advanced solid tumors were treated with 6 cycles of GM-CSF (x 3d), CpG-ODN (escalating from 3mg - 100mg × 1d) followed by a peptide vaccine (a CD8 epitope from hTERT), in a Phase I dose escalation study. Surprisingly, only one of seventeen patients showed a detectable hTERT-specific tetramer T cell response. However, the majority of patients developed marked peripheral blood (PB) lymphopenia after CpG-ODN. Time-course flow cytometry analysis of PB revealed that CD8, CD4, NK and B cell counts were all depressed immediately after CpG-ODN. The effect was transient, with normal counts returning after a week, suggesting that CpG-ODN induced alteration in cell migration rather than cell death. To find further evidence for altered migration we examined vaccine sites. Clinically, vaccine sites showed significant swelling/induration within hours of CpG-ODN administration, though none was dose-limiting. Immunohistochemistry of vaccine biopsies showed significant, perivascular accumulation of CD4 and CD8 T cells clustered around CD123+ pDC. Biopsies after CpG-ODN, but not after GM-CSF, showed a marked increase in expression of MxA, an interferon-inducible gene suggesting that the local activation of pDC with resultant IFNa secretion. qRT-PCR confirmed significant increases in a panel of IFNa-inducible genes in the PB after CpG-ODN, indicating a systemic effect of IFNa secretion. Lastly, we showed directly that CpG-ODN markedly increased the ability of purified pDC to induce T cell migration in an in vitro transwell assay, demonstrating that CpG-ODN stimulation of human pDC not only induces IFNa, but also other chemokines that are sufficient to chemoattract T cells. Our results show that CpG-ODN with GM-CSF may not be an effective adjuvant strategy for peptide tumor vaccines; but sequenced GM-CSF/CpG-ODN causes a chemokine response that effects T cell migration to the peripheral tissues. These findings suggest a role for CpG beyond that of a vaccine adjuvant as a mediator of lymphocyte migration, targeting immune responses to specific peripheral tissues. Therapeutic intratumoral GM-CSF/CpG-ODN injection could profoundly alter the local immunologic milieu, recruiting activated pDC and T cells to the tumor site, and tipping the balance towards an effective tumor-specific immune response.

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Immunization With Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor as a Vaccine Adjuvant Elicits Both a Cellular and Humoral Response to Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

Blood ◽

10.1182/blood.v93.8.2653.408k07_2653_2659 ◽

1999 ◽

Vol 93 (8) ◽

pp. 2653-2659

Author(s):

Douglas G. McNeel ◽

Kathy Schiffman ◽

Mary L. Disis

Keyword(s):

T Cell ◽

Immune Responses ◽

Antibody Response ◽

Vaccine Adjuvant ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Cellular Immune ◽

Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important cytokine for the generation and propagation of antigen-presenting cells and for priming a cellular immune response. We report here that use of recombinant human GM-CSF (rhGM-CSF), administered as an adjuvant in a peptide-based vaccine trial given monthly by intradermal injection, led to the development of a T-cell and antibody response to rhGM-CSF. An antibody response occurred in the majority of patients (72%). This antibody response was not found to be neutralizing. In addition, by 48-hour delayed type hypersensitivity (DTH) skin testing, 17% of patients were shown to have a cellular immune response to the adjuvant rhGM-CSF alone. Thymidine incorporation assays also showed a peripheral blood T-cell response to rhGM-CSF in at least 17% of the patients. The generation of rhGM-CSF–specific T-cell immune responses, elicited in this fashion, is an important observation because rhGM-CSF is being used as a vaccine adjuvant in various vaccine strategies. rhGM-CSF–specific immune responses may be incorrectly interpreted as antigen-specific immunity, particularly when local DTH responses to vaccination are the primary means of immunologic evaluation. We found no evidence of hematologic or infectious complications as a result of the development of rhGM-CSF–specific immune responses.

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Flt3 ligand as a vaccine adjuvant in association with HER-2/neu peptide-based vaccines in patients with HER-2/neu–overexpressing cancers

Blood ◽

10.1182/blood.v99.8.2845 ◽

2002 ◽

Vol 99 (8) ◽

pp. 2845-2850 ◽

Cited By ~ 57

Author(s):

Mary L. Disis ◽

Kristine Rinn ◽

Keith L. Knutson ◽

Donna Davis ◽

Dania Caron ◽

...

Keyword(s):

T Cell ◽

Ex Vivo ◽

Phase 1 ◽

Small Sample ◽

Vaccine Adjuvant ◽

Vaccine Adjuvants ◽

Flt3 Ligand ◽

Intracellular Domain ◽

Gm Csf ◽

Her 2

Abstract Dendritic cells (DCs) are potent antigen-presenting cells and have shown promise to function as “natural” vaccine adjuvants. Currently, most cancer vaccine trials using DCs generate autologous DCs ex vivo for each patient. Systemic treatment with Flt3 ligand (FL) results in a marked increase of DCs in tissues such as spleen and lymph nodes in mice and in the peripheral blood and skin of humans. In light of these observations, we questioned whether FL could be used systemically as a vaccine adjuvant to stimulate DC mobilization in vivo, circumventing the need to generate DCs ex vivo. Ten patients with HER-2/neu–overexpressing cancer were enrolled in a phase 1 study to receive a HER-2/neu peptide-based vaccine targeting the intracellular domain of the HER-2/neu protein. All patients received 20 μg/kg FL per day subcutaneously for 14 days. Five patients received the HER-2/neu peptide-based vaccine alone on day 7 of the 14-day cycle, and 5 patients received the vaccine admixed with 150 μg granulocyte macrophage–colony-stimulating factor (GM-CSF) on day 7 of the FL cycle. T-cell proliferative responses to HER-2/neu peptides and intracellular domain protein suggest that vaccine regimens including FL as an adjuvant were not effective in eliciting a significant HER-2/neu protein-specific T-cell proliferative response. However, including FL as a vaccine adjuvant was effective in boosting the precursor frequency of interferon-γ–secreting HER-2/neu–specific T cells. The small sample size of each group, however, did not allow a statistically significant comparison of immune responses between the FL alone and FL with GM-CSF arms. Finally, vaccine regimens including FL as a vaccine adjuvant were associated with the development of apparent autoimmune phenomena in some patients.

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Opposite immune functions of GM-CSF administered as vaccine adjuvant in cancer patients

Annals of Oncology ◽

10.1093/annonc/mdl158 ◽

2007 ◽

Vol 18 (2) ◽

pp. 226-232 ◽

Cited By ~ 188

Author(s):

G. Parmiani ◽

C. Castelli ◽

L. Pilla ◽

M. Santinami ◽

M.P. Colombo ◽

...

Keyword(s):

Cancer Patients ◽

Vaccine Adjuvant ◽

Immune Functions ◽

Gm Csf

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A randomized, placebo-controlled trial of subcutaneous administration of GM-CSF as a vaccine adjuvant: effect on cellular and humoral immune responses

Vaccine ◽

10.1016/s0264-410x(02)00463-2 ◽

2002 ◽

Vol 21 (3-4) ◽

pp. 221-230 ◽

Cited By ~ 11

Author(s):

Jyoti Somani ◽

Sagar Lonial ◽

Hilary Rosenthal ◽

Suzanne Resnick ◽

Irina Kakhniashvili ◽

...

Keyword(s):

Immune Responses ◽

Controlled Trial ◽

Subcutaneous Administration ◽

Vaccine Adjuvant ◽

Adjuvant Effect ◽

Gm Csf ◽

Humoral Immune ◽

Humoral Immune Responses

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An update on GM-CSF and its potential role in melanoma management

Melanoma Management ◽

10.2217/mmt-2020-0011 ◽

2020 ◽

Vol 7 (3) ◽

pp. MMT49

Author(s):

Robert O Dillman

Keyword(s):

Dendritic Cells ◽

Stem Cell ◽

Randomized Trials ◽

Potential Role ◽

Ex Vivo ◽

Vaccine Adjuvant ◽

Talimogene Laherparepvec ◽

Hematopoietic Stem ◽

Gm Csf ◽

Melanoma Treatment

GM-CSF drives the differentiation of granulocytes and monocyte/macrophages from hematopoietic stem cell progenitors. It is required for differentiating monocytes into dendritic cells (DC). Although approved for recovery of granulocytes/monocytes in patients receiving chemotherapy, G-CSF is preferred. Enthusiasm for GM-CSF monotherapy as a melanoma treatment was dampened by two large randomized trials. Although GM-CSF has been injected into tumors for many years, the efficacy of this has not been tested. There is a strong rationale for GM-CSF as a vaccine adjuvant, but it appears of benefit only for strategies that directly involve DCs, such as intratumor talimogene laherparepvec and vaccines in which DCs are loaded with antigen ex vivo and injected admixed with GM-CSF.

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Clearance of HBeAg and HBsAg of HBV in mice model by a recombinant HBV vaccine combined with GM-CSF and IFN-α as an effective therapeutic vaccine adjuvant

Oncotarget ◽

10.18632/oncotarget.25789 ◽

2018 ◽

Vol 9 (76) ◽

pp. 34213-34228 ◽

Cited By ~ 2

Author(s):

Weidong Zhao ◽

Gan Zhao ◽

Shuren Zhang ◽

Xianzheng Wang ◽

Xueping Yu ◽

...

Keyword(s):

Therapeutic Vaccine ◽

Vaccine Adjuvant ◽

Mice Model ◽

Hbv Vaccine ◽

Gm Csf

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Immunization With Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor as a Vaccine Adjuvant Elicits Both a Cellular and Humoral Response to Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor

Blood ◽

10.1182/blood.v93.8.2653 ◽

1999 ◽

Vol 93 (8) ◽

pp. 2653-2659 ◽

Cited By ~ 31

Author(s):

Douglas G. McNeel ◽

Kathy Schiffman ◽

Mary L. Disis

Keyword(s):

T Cell ◽

Immune Responses ◽

Antibody Response ◽

Vaccine Adjuvant ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Cellular Immune ◽

Stimulating Factor

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important cytokine for the generation and propagation of antigen-presenting cells and for priming a cellular immune response. We report here that use of recombinant human GM-CSF (rhGM-CSF), administered as an adjuvant in a peptide-based vaccine trial given monthly by intradermal injection, led to the development of a T-cell and antibody response to rhGM-CSF. An antibody response occurred in the majority of patients (72%). This antibody response was not found to be neutralizing. In addition, by 48-hour delayed type hypersensitivity (DTH) skin testing, 17% of patients were shown to have a cellular immune response to the adjuvant rhGM-CSF alone. Thymidine incorporation assays also showed a peripheral blood T-cell response to rhGM-CSF in at least 17% of the patients. The generation of rhGM-CSF–specific T-cell immune responses, elicited in this fashion, is an important observation because rhGM-CSF is being used as a vaccine adjuvant in various vaccine strategies. rhGM-CSF–specific immune responses may be incorrectly interpreted as antigen-specific immunity, particularly when local DTH responses to vaccination are the primary means of immunologic evaluation. We found no evidence of hematologic or infectious complications as a result of the development of rhGM-CSF–specific immune responses.

Download Full-text