Biologic Activity of Autologous, Granulocyte-Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines

被引：27

作者：

Goldberg, John M. ^{[1
,2
,3
]}

Fisher, David E. ^{[1
,2
,4
]}

Demetri, George D. ^{[5
,6
,7
]}

Neuberg, Donna ^{[8
,9
]}

Allsop, Stephen A. ^{[6
,7
,10
,11
]}

Fonseca, Catia ^{[6
,7
,10
,11
]}

Nakazaki, Yukoh ^{[6
,7
,10
,11
]}

Nemer, David ^{[6
,7
,10
,11
]}

Raut, Chandrajit P. ^{[12
,13
]}

George, Suzanne ^{[6
,7
]}

Morgan, Jeffrey A. ^{[6
,7
]}

Wagner, Andrew J. ^{[1
,2
]}

Freeman, Gordon J. ^{[6
,7
,10
,11
]}

Ritz, Jerome ^{[6
,7
,10
,11
]}

Lezcano, Cecilia ^{[14
]}

Mihm, Martin ^{[15
]}

Canning, Christine ^{[6
,7
,10
,11
]}

Hodi, F. Stephen ^{[5
,6
,7
,10
,11
]}

Dranoff, Glenn ^{[6
,7
,10
,11
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA

[3] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Dept Pediat, Miami, FL 33136 USA

[4] Harvard Univ, Sch Med, Dept Dermatol, Massachusetts Gen Hosp, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Ludwig Ctr Harvard, Boston, MA USA

[6] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[7] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA

[8] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA

[9] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[10] Dana Farber Canc Inst, Canc Vaccine Ctr, Ctr Immunooncol, Boston, MA 02215 USA

[11] Dana Farber Canc Inst, Melanoma Dis Ctr, Boston, MA 02215 USA

[12] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Surg Oncol, Boston, MA 02115 USA

[13] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA

[14] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA

[15] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Dermatol, Boston, MA 02115 USA

来源：

CLINICAL CANCER RESEARCH | 2015年 / 21卷 / 14期

关键词：

MEDIATED TUMOR DESTRUCTION; PROTEIN ML-IAP; TRANSCRIPTION FACTOR; METASTATIC MELANOMA; CANCER-IMMUNOTHERAPY; MALIGNANT-MELANOMA; ANTITUMOR IMMUNITY; GROWTH-FACTOR; GENE; INHIBITOR;

D O I：

10.1158/1078-0432.CCR-14-2932

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral-mediated gene transfer to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). Experimental Design: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. Results: Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8(+) T cells in association with PD ligand-1 (PD-L1)-expressing sarcoma cells. No tumor regressions were observed. Conclusions: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction. (C) 2015 AACR.

引用

页码：3178 / 3186

页数：9

共 55 条

[1] Vascular-endothelial-growth-factor (VEGF) expression and possible response to angiogenesis inhibitor bevacizumab in metastatic alveolar soft part sarcoma [J].