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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 administered intradermally increases systemic GM-CSF levels in a dose-dependent manner. a Serum GM-CSF concentrations measured 2 days after the first administration of Melanoma GVAX were significantly higher in patients receiving a dose of 2E8 cells (Cohorts B and C, mean 19.8 ± 2.72) compared to 5E7 cells (Cohort A, mean 4.8 ± 1.5). There was no significant difference between patients receiving high-dose vaccine in Cohorts B (no CPM) versus C (with CPM) (not shown). All patients had detectable serum GM-CSF after the first vaccination (detection limit 1 pg/ml). b Serum GM-CSF concentrations were significantly lower 2 days after the fourth vaccine (6.8 ± 1.5) compared to the first vaccine (17.5 ± 2.6). Bars depict the mean ± SEM; p values from 2-sided Mann–Whitney U test (a) or paired Wilcoxon signed-rank test (b). C treatment cycle, D treatment day. Pre-vaccine sera from Cohort C were collected on D0 prior to CPM administration, and from Cohorts A and B, on D1 prior to vaccine administration.
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Fig4: Melanoma GVAX administered intradermally increases systemic GM-CSF levels in a dose-dependent manner. a Serum GM-CSF concentrations measured 2 days after the first administration of Melanoma GVAX were significantly higher in patients receiving a dose of 2E8 cells (Cohorts B and C, mean 19.8 ± 2.72) compared to 5E7 cells (Cohort A, mean 4.8 ± 1.5). There was no significant difference between patients receiving high-dose vaccine in Cohorts B (no CPM) versus C (with CPM) (not shown). All patients had detectable serum GM-CSF after the first vaccination (detection limit 1 pg/ml). b Serum GM-CSF concentrations were significantly lower 2 days after the fourth vaccine (6.8 ± 1.5) compared to the first vaccine (17.5 ± 2.6). Bars depict the mean ± SEM; p values from 2-sided Mann–Whitney U test (a) or paired Wilcoxon signed-rank test (b). C treatment cycle, D treatment day. Pre-vaccine sera from Cohort C were collected on D0 prior to CPM administration, and from Cohorts A and B, on D1 prior to vaccine administration.

Mentions: GM-CSF secretion from Melanoma GVAX cells injected intradermally was detectable systemically in all patients. Based on serum GM-CSF kinetics reported in trials of GVAX vaccines in other cancer types [41–43], we analyzed patient sera collected 2 days following the first and fourth vaccinations. Pre-treatment GM-CSF concentrations were below the limit of detection for all patients, but increased significantly and in a dose-dependent manner 2 days after the first vaccination (p = 0.0086). This increase was less pronounced after C4 compared to C1 (p = 0.0003) (Figure 4), suggesting more rapid elimination of allogeneic Melanoma GVAX with repeated inoculations [43].Figure 4


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 administered intradermally increases systemic GM-CSF levels in a dose-dependent manner. a Serum GM-CSF concentrations measured 2 days after the first administration of Melanoma GVAX were significantly higher in patients receiving a dose of 2E8 cells (Cohorts B and C, mean 19.8 ± 2.72) compared to 5E7 cells (Cohort A, mean 4.8 ± 1.5). There was no significant difference between patients receiving high-dose vaccine in Cohorts B (no CPM) versus C (with CPM) (not shown). All patients had detectable serum GM-CSF after the first vaccination (detection limit 1 pg/ml). b Serum GM-CSF concentrations were significantly lower 2 days after the fourth vaccine (6.8 ± 1.5) compared to the first vaccine (17.5 ± 2.6). Bars depict the mean ± SEM; p values from 2-sided Mann–Whitney U test (a) or paired Wilcoxon signed-rank test (b). C treatment cycle, D treatment day. Pre-vaccine sera from Cohort C were collected on D0 prior to CPM administration, and from Cohorts A and B, on D1 prior to vaccine administration.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Melanoma GVAX administered intradermally increases systemic GM-CSF levels in a dose-dependent manner. a Serum GM-CSF concentrations measured 2 days after the first administration of Melanoma GVAX were significantly higher in patients receiving a dose of 2E8 cells (Cohorts B and C, mean 19.8 ± 2.72) compared to 5E7 cells (Cohort A, mean 4.8 ± 1.5). There was no significant difference between patients receiving high-dose vaccine in Cohorts B (no CPM) versus C (with CPM) (not shown). All patients had detectable serum GM-CSF after the first vaccination (detection limit 1 pg/ml). b Serum GM-CSF concentrations were significantly lower 2 days after the fourth vaccine (6.8 ± 1.5) compared to the first vaccine (17.5 ± 2.6). Bars depict the mean ± SEM; p values from 2-sided Mann–Whitney U test (a) or paired Wilcoxon signed-rank test (b). C treatment cycle, D treatment day. Pre-vaccine sera from Cohort C were collected on D0 prior to CPM administration, and from Cohorts A and B, on D1 prior to vaccine administration.
Mentions: GM-CSF secretion from Melanoma GVAX cells injected intradermally was detectable systemically in all patients. Based on serum GM-CSF kinetics reported in trials of GVAX vaccines in other cancer types [41–43], we analyzed patient sera collected 2 days following the first and fourth vaccinations. Pre-treatment GM-CSF concentrations were below the limit of detection for all patients, but increased significantly and in a dose-dependent manner 2 days after the first vaccination (p = 0.0086). This increase was less pronounced after C4 compared to C1 (p = 0.0003) (Figure 4), suggesting more rapid elimination of allogeneic Melanoma GVAX with repeated inoculations [43].Figure 4

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