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Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting.

Lipson EJ, Sharfman WH, Chen S, McMiller TL, Pritchard TS, Salas JT, Sartorius-Mergenthaler S, Freed I, Ravi S, Wang H, Luber B, Sproul JD, Taube JM, Pardoll DM, Topalian SL - J Transl Med (2015)

Bottom Line: Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002).Cyclophosphamide did not affect numbers of circulating Tregs.NCT01435499.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans Street, Room 507, Baltimore, MD, 21287, USA. evanlipson@jhmi.edu.

ABSTRACT

Background: Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting.

Methods: Patients with stage IIB-IV melanoma were enrolled following complete surgical resection. Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m(2) to deplete T regulatory cells (Tregs; n = 8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines.

Results: Among 20 treated patients, 18 completed 4 vaccinations. Minimal treatment-related toxicity was observed. One patient developed vitiligo and patches of white hair during the treatment and follow-up period. Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05). Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002). Cyclophosphamide did not affect numbers of circulating Tregs. No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting.

Conclusion: Melanoma GVAX was safe and tolerable in the adjuvant setting. Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets. These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents.

Trial registration: NCT01435499.

No MeSH data available.


Related in: MedlinePlus

Melanoma GVAX coordinately increases numbers of activated circulating monocytes and decreases circulating MDSCs. Flow cytometric analysis revealed significantly increased numbers (a) and activation (b) of circulating monocytes (CD14+ , CD11b+) 2 days following the first and fourth vaccinations. Monocyte activation was quantified as mean fluorescence intensity (MFI) of HLA-DR expression. Decreased percentages of myeloid-derived suppressor cells (CD14+ , CD11b+ , HLA-DR low or negative) among monocytes were observed at the same time intervals (c). Bars depict the mean ± SEM; p values from 2-sided Wilcoxon signed-rank test. MDSC myeloid derived suppressor cells, C treatment cycle, D treatment day.
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Fig5: Melanoma GVAX coordinately increases numbers of activated circulating monocytes and decreases circulating MDSCs. Flow cytometric analysis revealed significantly increased numbers (a) and activation (b) of circulating monocytes (CD14+ , CD11b+) 2 days following the first and fourth vaccinations. Monocyte activation was quantified as mean fluorescence intensity (MFI) of HLA-DR expression. Decreased percentages of myeloid-derived suppressor cells (CD14+ , CD11b+ , HLA-DR low or negative) among monocytes were observed at the same time intervals (c). Bars depict the mean ± SEM; p values from 2-sided Wilcoxon signed-rank test. MDSC myeloid derived suppressor cells, C treatment cycle, D treatment day.

Mentions: Because the acute biologic effects of GM-CSF on myeloid cell populations can be dose-dependent, with excessive doses generating MDSCs rather than activating antigen presenting cells [23], we evaluated the impact of Melanoma GVAX on the absolute numbers and proportions of circulating monocytes and MDSCs in blood collected before and 2 days after the first and fourth Melanoma GVAX treatment cycles. We observed significantly increased numbers and activation (HLA-DR expression) of circulating monocytes after vaccination (p < 0.0001) (Figure 5a, b, respectively). Additionally, decreased percentages of MDSCs (CD14+ , CD11b+ , HLA-DR low or negative) among monocytes were seen (p = 0.002) (Figure 5c). Serum GM-CSF levels measured 2 days following the first dose of Melanoma GVAX (cycle 1, day 3) correlated significantly with concurrent changes in monocyte numbers and activation state (HLA-DR expression) in 19 patients assessed (Figure 6). Thus, the amount of GM-CSF secreted by Melanoma GVAX (200–400 ng/1E6 cells/24 h in vitro) appeared to have a positive systemic effect on the balance between activated monocytes and MDSCs.Figure 5


Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting.

Lipson EJ, Sharfman WH, Chen S, McMiller TL, Pritchard TS, Salas JT, Sartorius-Mergenthaler S, Freed I, Ravi S, Wang H, Luber B, Sproul JD, Taube JM, Pardoll DM, Topalian SL - J Transl Med (2015)

Melanoma GVAX coordinately increases numbers of activated circulating monocytes and decreases circulating MDSCs. Flow cytometric analysis revealed significantly increased numbers (a) and activation (b) of circulating monocytes (CD14+ , CD11b+) 2 days following the first and fourth vaccinations. Monocyte activation was quantified as mean fluorescence intensity (MFI) of HLA-DR expression. Decreased percentages of myeloid-derived suppressor cells (CD14+ , CD11b+ , HLA-DR low or negative) among monocytes were observed at the same time intervals (c). Bars depict the mean ± SEM; p values from 2-sided Wilcoxon signed-rank test. MDSC myeloid derived suppressor cells, C treatment cycle, D treatment day.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4491237&req=5

Fig5: Melanoma GVAX coordinately increases numbers of activated circulating monocytes and decreases circulating MDSCs. Flow cytometric analysis revealed significantly increased numbers (a) and activation (b) of circulating monocytes (CD14+ , CD11b+) 2 days following the first and fourth vaccinations. Monocyte activation was quantified as mean fluorescence intensity (MFI) of HLA-DR expression. Decreased percentages of myeloid-derived suppressor cells (CD14+ , CD11b+ , HLA-DR low or negative) among monocytes were observed at the same time intervals (c). Bars depict the mean ± SEM; p values from 2-sided Wilcoxon signed-rank test. MDSC myeloid derived suppressor cells, C treatment cycle, D treatment day.
Mentions: Because the acute biologic effects of GM-CSF on myeloid cell populations can be dose-dependent, with excessive doses generating MDSCs rather than activating antigen presenting cells [23], we evaluated the impact of Melanoma GVAX on the absolute numbers and proportions of circulating monocytes and MDSCs in blood collected before and 2 days after the first and fourth Melanoma GVAX treatment cycles. We observed significantly increased numbers and activation (HLA-DR expression) of circulating monocytes after vaccination (p < 0.0001) (Figure 5a, b, respectively). Additionally, decreased percentages of MDSCs (CD14+ , CD11b+ , HLA-DR low or negative) among monocytes were seen (p = 0.002) (Figure 5c). Serum GM-CSF levels measured 2 days following the first dose of Melanoma GVAX (cycle 1, day 3) correlated significantly with concurrent changes in monocyte numbers and activation state (HLA-DR expression) in 19 patients assessed (Figure 6). Thus, the amount of GM-CSF secreted by Melanoma GVAX (200–400 ng/1E6 cells/24 h in vitro) appeared to have a positive systemic effect on the balance between activated monocytes and MDSCs.Figure 5

Bottom Line: Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002).Cyclophosphamide did not affect numbers of circulating Tregs.NCT01435499.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, 1550 Orleans Street, Room 507, Baltimore, MD, 21287, USA. evanlipson@jhmi.edu.

ABSTRACT

Background: Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting.

Methods: Patients with stage IIB-IV melanoma were enrolled following complete surgical resection. Melanoma GVAX was administered intradermally once every 28 days for four cycles, at 5E7 cells/cycle (n = 3), 2E8 cells/cycle (n = 9), or 2E8 cells/cycle preceded by cyclophosphamide 200 mg/m(2) to deplete T regulatory cells (Tregs; n = 8). Blood was collected before each vaccination and at 4 and 6 months after treatment initiation for immunologic studies. Vaccine injection site biopsies and additional blood samples were obtained 2 days after the 1st and 4th vaccines.

Results: Among 20 treated patients, 18 completed 4 vaccinations. Minimal treatment-related toxicity was observed. One patient developed vitiligo and patches of white hair during the treatment and follow-up period. Vaccine site biopsies demonstrated complex inflammatory infiltrates, including significant increases in eosinophils and PD-1+ lymphocytes from cycle 1 to cycle 4 (P < 0.05). Serum GM-CSF concentrations increased significantly in a dose-dependent manner 48 h after vaccination (P = 0.0086), accompanied by increased numbers of activated circulating monocytes (P < 0.0001) and decreased percentages of myeloid-derived suppressor cells among monocytes (CD14+ , CD11b+ , HLA-DR low or negative; P = 0.002). Cyclophosphamide did not affect numbers of circulating Tregs. No significant changes in anti-melanoma immunity were observed in peripheral T cells by interferon-gamma ELIPSOT, or immunoglobulins by serum Western blotting.

Conclusion: Melanoma GVAX was safe and tolerable in the adjuvant setting. Pharmacodynamic testing revealed complex vaccine site immune infiltrates and an immune-reactive profile in circulating monocytic cell subsets. These findings support the optimization of Melanoma GVAX with additional monocyte and dendritic cell activators, and the potential development of combinatorial treatment regimens with synergistic agents.

Trial registration: NCT01435499.

No MeSH data available.


Related in: MedlinePlus