Limits...
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

Vaccine site immune cell changes during treatment. Significant increases in the mean scores of dermal eosinophils and lymphocyte PD-1 expression from C1 to C4 were observed in Melanoma GVAX vaccine site biopsies. Paired analyses performed using the Wilcoxon signed-rank test; asterisks indicate p < 0.05. Scoring criteria are described in “Methods”. Vertical bars depict SEM. C treatment cycle.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Vaccine site immune cell changes during treatment. Significant increases in the mean scores of dermal eosinophils and lymphocyte PD-1 expression from C1 to C4 were observed in Melanoma GVAX vaccine site biopsies. Paired analyses performed using the Wilcoxon signed-rank test; asterisks indicate p < 0.05. Scoring criteria are described in “Methods”. Vertical bars depict SEM. C treatment cycle.

Mentions: When inflammatory infiltrates were compared in vaccine site skin biopsies from C1 vs. C4, a significant increase in the intensity of eosinophils was observed in C4, specifically in the dermal compartment (p = 0.024; Figure 3). Within the subcutaneous compartment, an increase in eosinophils from a mean grade of 3 to a mean grade of 4 was observed from cycle 1 to cycle 4, but this difference was not statistically significant. Furthermore, differences in neutrophil infiltrates were not observed when analyzed by treatment cycle or by compartment (data not shown). IHC staining of the same specimens revealed a significant increase in PD-1+ lymphocytes from C1 to C4 (p = 0.037, Figure 3), consistent with a vaccine-specific recall response. No significant changes were observed in the densities of CD3+ , CD4+ , CD8+ , or FoxP3+ T cells, CD20+ B cells, CD68+ macrophages, or CD1a+ Langerhans cells (data not shown).Figure 3


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)

Vaccine site immune cell changes during treatment. Significant increases in the mean scores of dermal eosinophils and lymphocyte PD-1 expression from C1 to C4 were observed in Melanoma GVAX vaccine site biopsies. Paired analyses performed using the Wilcoxon signed-rank test; asterisks indicate p < 0.05. Scoring criteria are described in “Methods”. Vertical bars depict SEM. C treatment cycle.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Vaccine site immune cell changes during treatment. Significant increases in the mean scores of dermal eosinophils and lymphocyte PD-1 expression from C1 to C4 were observed in Melanoma GVAX vaccine site biopsies. Paired analyses performed using the Wilcoxon signed-rank test; asterisks indicate p < 0.05. Scoring criteria are described in “Methods”. Vertical bars depict SEM. C treatment cycle.
Mentions: When inflammatory infiltrates were compared in vaccine site skin biopsies from C1 vs. C4, a significant increase in the intensity of eosinophils was observed in C4, specifically in the dermal compartment (p = 0.024; Figure 3). Within the subcutaneous compartment, an increase in eosinophils from a mean grade of 3 to a mean grade of 4 was observed from cycle 1 to cycle 4, but this difference was not statistically significant. Furthermore, differences in neutrophil infiltrates were not observed when analyzed by treatment cycle or by compartment (data not shown). IHC staining of the same specimens revealed a significant increase in PD-1+ lymphocytes from C1 to C4 (p = 0.037, Figure 3), consistent with a vaccine-specific recall response. No significant changes were observed in the densities of CD3+ , CD4+ , CD8+ , or FoxP3+ T cells, CD20+ B cells, CD68+ macrophages, or CD1a+ Langerhans cells (data not shown).Figure 3

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