Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients

Journal of Translational Medicine

Ruggero Ridolfi¹  Angela Riccobon¹  Stefano Baravelli²  Stefania Vittoria Luisa Nicoletti¹  Emanuela Scarpi⁴  Linda Valmorri⁴  Francesco de Rosa¹  Massimo Guidoboni¹  Laura Fiammenghi¹  Valentina Ancarani¹  Elena Pancisi¹  Paolo Antonio Ascierto³  Ester Simeone³  Giusy Gentilcore³  Anna Maria Granato¹  Massimiliano Petrini¹  Laura Ridolfi¹ 

[1] Immunotherapy Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, FC, Italy;Blood Transfusion Unit, Morgagni Pierantoni Hospital, Forlì, Italy;Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione “G. Pascale”, Naples, Italy;Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy

关键词: Low-dose temozolomide;    Foxp3+Tregs;    Dendritic cell;    Melanoma;    Vaccine;   

Others  :  1205880
DOI  :  10.1186/1479-5876-11-135

 received in 2012-12-17, accepted in 2013-05-13,  发布年份 2013

【 摘 要 】

Background

In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4⁺CD25⁺⁺Foxp3⁺ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion.

Methods

Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2.

Results

Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells.

Conclusions

Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome.

【 授权许可】

   
2013 Ridolfi et al.; licensee BioMed Central Ltd.

【 图 表 】

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