Pilot Clinical Trial of Type 1 Dendritic Cells Loaded with Autologous Tumor Lysates Combined with GM-CSF, Pegylated IFN, and Cyclophosphamide for Metastatic Cancer Patients

被引：51

作者：

Alfaro, Carlos ^{[1
,2
]}

Perez-Gracia, Jose L. ^{[3
]}

Suarez, Natalia ^{[1
,4
]}

Rodriguez, Javier ^{[3
]}

Fernandez de Sanmamed, Miguel ^{[1
,3
]}

Sangro, Bruno ^{[5
]}

Martin-Algarra, Salvador ^{[3
]}

Calvo, Alfonso ^{[6
]}

Redrado, Miriam ^{[6
]}

Agliano, Alice ^{[6
]}

Gonzalez, Alvaro ^{[4
]}

Rodriguez, Inmaculada ^{[1
]}

Bolanos, Elixabet ^{[1
,2
]}

Hervas-Stubbs, Sandra ^{[1
]}

Perez-Calvo, Javier ^{[2
]}

Benito, Alberto ^{[7
]}

Penuelas, Ivan ^{[8
]}

Vigil, Carmen ^{[8
]}

Richter, Jose ^{[8
]}

Martinez-Forero, Ivan ^{[1
]}

Melero, Ignacio ^{[1
,2
,3
]}

机构：

[1] Univ Navarra, Ctr Appl Med Res, Gene Therapy & Hepatol Unit, Pamplona 31008, Spain

[2] Univ Navarra, Univ Navarra Clin, Cell Therapy Unit, Pamplona 31008, Spain

[3] Univ Navarra, Univ Navarra Clin, Dept Oncol, Pamplona 31008, Spain

[4] Univ Navarra, Univ Navarra Clin, Dept Biochem, Pamplona 31008, Spain

[5] Univ Navarra, Univ Navarra Clin, Hepatol Dept, Pamplona 31008, Spain

[6] Univ Navarra, Ctr Appl Med Res, Div Oncol, Pamplona 31008, Spain

[7] Univ Navarra, Univ Navarra Clin, Dept Radiol, Pamplona 31008, Spain

[8] Univ Navarra, Univ Navarra Clin, Dept Nucl Med, Pamplona 31008, Spain

来源：

JOURNAL OF IMMUNOLOGY | 2011年 / 187卷 / 11期

关键词：

REGULATORY T-CELLS; LOW-DOSE CYCLOPHOSPHAMIDE; PHASE-I; VACCINATION; THERAPY; DC; INTERLEUKIN-12; IMMUNOTHERAPY; COMBINATION; STRATEGIES;

D O I：

10.4049/jimmunol.1102209

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-alpha, TNF-alpha, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-gamma-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [In-111] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing. The Journal of Immunology, 2011, 187: 6130-6142.

引用

页码：6130 / 6142

页数：13

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