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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

Transient melanoma progression in a patient treated in Cohort A, accompanied by vitiligo. a This patient developed the onset of vitiligo and greying hair after receiving four cycles of Melanoma GVAX. Vitiligo was initially confined to a prior lymphadenectomy incision site, but progressed to other skin sites and hair over the next few months. b Pelvic CT scan at the 6-month evaluation interval showed enlarging left pelvic lymph nodes (yellow and red arrows), biopsy-proven to be recurrent melanoma. At 8 months, these lesions had regressed without further intervention. Two months later, they enlarged again and the patient went on to receive other therapies.
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Fig1: Transient melanoma progression in a patient treated in Cohort A, accompanied by vitiligo. a This patient developed the onset of vitiligo and greying hair after receiving four cycles of Melanoma GVAX. Vitiligo was initially confined to a prior lymphadenectomy incision site, but progressed to other skin sites and hair over the next few months. b Pelvic CT scan at the 6-month evaluation interval showed enlarging left pelvic lymph nodes (yellow and red arrows), biopsy-proven to be recurrent melanoma. At 8 months, these lesions had regressed without further intervention. Two months later, they enlarged again and the patient went on to receive other therapies.

Mentions: Among 19 evaluable patients, 3 had a documented melanoma recurrence during the 6-month study period. One patient in Cohort A with resected stage III acral melanoma developed an inguinal lymph node recurrence at 6 months. On repeat CT scanning at 8 months, these lesions had regressed without further intervention, but at 10 months progression was confirmed. Of interest, this patient developed vitiligo and patches of white hair during the treatment and follow-up periods (Figure 1). A patient in Cohort B with resected stage IV melanoma developed a pulmonary metastatic recurrence. A patient in Cohort C with resected stage III melanoma developed tumor recurrence in the skin surrounding a prior melanoma excision site. The remaining 16 patients showed no signs of melanoma recurrence during the 6-month study period. All patients have been monitored for at least 14 additional months under a long-term follow-up companion protocol. Four patients—one in Cohort A, two in cohort B and one in Cohort C—have experienced melanoma recurrence between 7 and 33 months after treatment initiation. Tumor recurrence in a total of 7 of 19 patients to date is consistent with general expectations for this high-risk group.Figure 1


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)

Transient melanoma progression in a patient treated in Cohort A, accompanied by vitiligo. a This patient developed the onset of vitiligo and greying hair after receiving four cycles of Melanoma GVAX. Vitiligo was initially confined to a prior lymphadenectomy incision site, but progressed to other skin sites and hair over the next few months. b Pelvic CT scan at the 6-month evaluation interval showed enlarging left pelvic lymph nodes (yellow and red arrows), biopsy-proven to be recurrent melanoma. At 8 months, these lesions had regressed without further intervention. Two months later, they enlarged again and the patient went on to receive other therapies.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Transient melanoma progression in a patient treated in Cohort A, accompanied by vitiligo. a This patient developed the onset of vitiligo and greying hair after receiving four cycles of Melanoma GVAX. Vitiligo was initially confined to a prior lymphadenectomy incision site, but progressed to other skin sites and hair over the next few months. b Pelvic CT scan at the 6-month evaluation interval showed enlarging left pelvic lymph nodes (yellow and red arrows), biopsy-proven to be recurrent melanoma. At 8 months, these lesions had regressed without further intervention. Two months later, they enlarged again and the patient went on to receive other therapies.
Mentions: Among 19 evaluable patients, 3 had a documented melanoma recurrence during the 6-month study period. One patient in Cohort A with resected stage III acral melanoma developed an inguinal lymph node recurrence at 6 months. On repeat CT scanning at 8 months, these lesions had regressed without further intervention, but at 10 months progression was confirmed. Of interest, this patient developed vitiligo and patches of white hair during the treatment and follow-up periods (Figure 1). A patient in Cohort B with resected stage IV melanoma developed a pulmonary metastatic recurrence. A patient in Cohort C with resected stage III melanoma developed tumor recurrence in the skin surrounding a prior melanoma excision site. The remaining 16 patients showed no signs of melanoma recurrence during the 6-month study period. All patients have been monitored for at least 14 additional months under a long-term follow-up companion protocol. Four patients—one in Cohort A, two in cohort B and one in Cohort C—have experienced melanoma recurrence between 7 and 33 months after treatment initiation. Tumor recurrence in a total of 7 of 19 patients to date is consistent with general expectations for this high-risk group.Figure 1

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