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

被引:69
作者
Lipson, Evan J. [1 ,2 ]
Sharfman, William H. [1 ,2 ]
Chen, Shuming [2 ,3 ]
McMiller, Tracee L. [2 ,3 ]
Pritchard, Theresa S. [2 ,3 ]
Salas, January T. [2 ,3 ]
Sartorius-Mergenthaler, Susan [1 ,2 ]
Freed, Irwin [1 ,2 ]
Ravi, Sowmya [2 ,4 ]
Wang, Hao [2 ,5 ]
Luber, Brandon [2 ,5 ]
Sproul, Janice Davis [1 ,2 ]
Taube, Janis M. [2 ,4 ,6 ]
Pardoll, Drew M. [1 ,2 ]
Topalian, Suzanne L. [2 ,3 ]
机构
[1] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21287 USA
[2] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA
[3] Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21287 USA
[4] Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21287 USA
[5] Johns Hopkins Univ, Sch Med, Dept Oncol, Div Biostat & Bioinformat, Baltimore, MD 21287 USA
[6] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA
基金
美国国家卫生研究院;
关键词
Melanoma; Vaccine; Immunotherapy; Adjuvant; GM-CSF; COLONY-STIMULATING FACTOR; T-CELLS; TUMOR VACCINE; CANCER-IMMUNOTHERAPY; IMMUNE-RESPONSE; DOSE INTERFERON-ALPHA-2B; SPATIAL-DISTRIBUTION; METASTATIC MELANOMA; ANTITUMOR IMMUNITY; PANCREATIC-CANCER;
D O I
10.1186/s12967-015-0572-3
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
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页数:14
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