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

Abstract

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.

• Authors: Laura Ridolfi, Massimiliano Petrini, Anna Maria Granato, Giusy Gentilcore, Ester Simeone, Paolo Antonio Ascierto, Elena Pancisi, Valentina Ancarani, Laura Fiammenghi, Massimo Guidoboni, Francesco de Rosa, Linda Valmorri, Emanuela Scarpi, Stefania Vittoria Luisa Nicoletti, Stefano Baravelli, Angela Riccobon, Ruggero Ridolfi
• Journal: Journal of translational medicine (J Transl Med) Vol. 11 Pg. 135 (May 31 2013) ISSN: 1479-5876 [Electronic] England
• PMID: 23725550 (Publication Type: Journal Article)

Chemical References

• CTLA-4 Antigen
• CTLA4 protein, human
• Cancer Vaccines
• FOXP3 protein, human
• Forkhead Transcription Factors
• Interleukin-2
• Interleukin-2 Receptor alpha Subunit
• Dacarbazine
• Hemocyanins
• keyhole-limpet hemocyanin
• Temozolomide

Topics

• Adult
• Aged
• CTLA-4 Antigen (metabolism)
• Cancer Vaccines (therapeutic use)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Dendritic Cells (cytology)
• Female
• Forkhead Transcription Factors (metabolism)
• Hemocyanins
• Humans
• Interleukin-2 (metabolism)
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Male
• Melanoma (immunology, therapy)
• Middle Aged
• T-Lymphocytes, Regulatory (cytology)
• Temozolomide
• Treatment Outcome