Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity

被引：49

作者：

Bol, Kalijn F. ^{[1
,2
]}

Aarntzen, Erik H. J. G. ^{[1
,2
,5
]}

Pots, Jeanette M. ^{[1
]}

Nordkamp, Michel A. M. Olde ^{[1
]}

van de Rakt, Mandy W. M. M. ^{[1
]}

Scharenborg, Nicole M. ^{[1
]}

de Boer, Annemiek J. ^{[1
]}

van Oorschot, Tom G. M. ^{[1
]}

Croockewit, Sandra A. J. ^{[3
]}

Blokx, Willeke A. M. ^{[4
]}

Oyen, Wim J. G. ^{[5
]}

Boerman, Otto C. ^{[5
]}

Mus, Roel D. M. ^{[5
]}

van Rossum, Michelle M. ^{[6
]}

van der Graaf, Chantal A. A. ^{[7
]}

Punt, Cornelis J. A. ^{[8
]}

Adema, Gosse J. ^{[1
]}

Figdor, Carl G. ^{[1
]}

de Vries, I. Jolanda M. ^{[1
,2
]}

Schreibelt, Gerty ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Dept Tumor Immunol, POB 9101, NL-6500 HB Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Dept Med Oncol, NL-6525 ED Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Med Ctr, Dept Hematol, NL-6525 ED Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6525 ED Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Dept Radiol & Nucl Med, NL-6525 ED Nijmegen, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Dept Dermatol, NL-6525 ED Nijmegen, Netherlands

[7] Radboud Univ Nijmegen, Med Ctr, Dept Pulm Dis, NL-6525 ED Nijmegen, Netherlands

[8] Univ Amsterdam, Acad Med Ctr, Dept Med Oncol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

来源：

CANCER IMMUNOLOGY IMMUNOTHERAPY | 2016年 / 65卷 / 03期

基金：

欧洲研究理事会;

关键词：

Dendritic cells; Immunotherapy; Melanoma; Toll-like receptor ligands; Maturation; Prophylactic vaccines; T-CELLS; MESSENGER-RNA; STAGE-III; IMMUNE-RESPONSES; VACCINATION; IMMUNOTHERAPY; INDUCTION; PEPTIDE; CD4(+); CANCER;

D O I：

10.1007/s00262-016-1796-7

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E-2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E-2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail.

引用

页码：327 / 339

页数：13

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