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

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

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Article number135
JournalJournal of Translational Medicine
Volume11
Issue number1
DOIs
Publication statusPublished - 31 May 2013
Externally publishedYes

Fingerprint

temozolomide
T-cells
Regulatory T-Lymphocytes
Dendritic Cells
Interleukin-2
Melanoma
Vaccination
Tumors
Disease control
Lymphocytes
Immunosuppressive Agents
Neoplasms
Tumor Microenvironment
Lymphocyte Count
Adaptive Immunity
Blood
Innate Immunity
Immunotherapy
Cytokines
Cell Count

Keywords

  • Dendritic cell
  • Foxp3+Tregs
  • Low-dose temozolomide
  • Melanoma
  • Vaccine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients. / Ridolfi, Laura; Petrini, Massimiliano; Granato, Anna Maria; Gentilcore, Giusy; Simeone, Ester; Ascierto, Paolo Antonio; Pancisi, Elena; Ancarani, Valentina; Fiammenghi, Laura; Guidoboni, Massimo; de Rosa, Francesco; Valmorri, Linda; Scarpi, Emanuela; Nicoletti, Stefania Vittoria Luisa; Baravelli, Stefano; Riccobon, Angela; Ridolfi, Ruggero.

In: Journal of Translational Medicine, Vol. 11, No. 1, 135, 31.05.2013.

Research output: Contribution to journalArticle

Ridolfi, L, Petrini, M, Granato, AM, Gentilcore, G, Simeone, E, Ascierto, PA, Pancisi, E, Ancarani, V, Fiammenghi, L, Guidoboni, M, de Rosa, F, Valmorri, L, Scarpi, E, Nicoletti, SVL, Baravelli, S, Riccobon, A & Ridolfi, R 2013, 'Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients', Journal of Translational Medicine, vol. 11, no. 1, 135. https://doi.org/10.1186/1479-5876-11-135
Ridolfi, Laura ; Petrini, Massimiliano ; Granato, Anna Maria ; Gentilcore, Giusy ; Simeone, Ester ; Ascierto, Paolo Antonio ; Pancisi, Elena ; Ancarani, Valentina ; Fiammenghi, Laura ; Guidoboni, Massimo ; de Rosa, Francesco ; Valmorri, Linda ; Scarpi, Emanuela ; Nicoletti, Stefania Vittoria Luisa ; Baravelli, Stefano ; Riccobon, Angela ; Ridolfi, Ruggero. / Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients. In: Journal of Translational Medicine. 2013 ; Vol. 11, No. 1.
@article{77348414facb489e9d34b8343240a50e,
title = "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.",
keywords = "Dendritic cell, Foxp3+Tregs, Low-dose temozolomide, Melanoma, Vaccine",
author = "Laura Ridolfi and Massimiliano Petrini and Granato, {Anna Maria} and Giusy Gentilcore and Ester Simeone and Ascierto, {Paolo Antonio} and Elena Pancisi and Valentina Ancarani and Laura Fiammenghi and Massimo Guidoboni and {de Rosa}, Francesco and Linda Valmorri and Emanuela Scarpi and Nicoletti, {Stefania Vittoria Luisa} and Stefano Baravelli and Angela Riccobon and Ruggero Ridolfi",
year = "2013",
month = "5",
day = "31",
doi = "10.1186/1479-5876-11-135",
language = "English",
volume = "11",
journal = "Journal of Translational Medicine",
issn = "1479-5876",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients

AU - Ridolfi, Laura

AU - Petrini, Massimiliano

AU - Granato, Anna Maria

AU - Gentilcore, Giusy

AU - Simeone, Ester

AU - Ascierto, Paolo Antonio

AU - Pancisi, Elena

AU - Ancarani, Valentina

AU - Fiammenghi, Laura

AU - Guidoboni, Massimo

AU - de Rosa, Francesco

AU - Valmorri, Linda

AU - Scarpi, Emanuela

AU - Nicoletti, Stefania Vittoria Luisa

AU - Baravelli, Stefano

AU - Riccobon, Angela

AU - Ridolfi, Ruggero

PY - 2013/5/31

Y1 - 2013/5/31

N2 - 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.

AB - 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.

KW - Dendritic cell

KW - Foxp3+Tregs

KW - Low-dose temozolomide

KW - Melanoma

KW - Vaccine

UR - http://www.scopus.com/inward/record.url?scp=84878359155&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878359155&partnerID=8YFLogxK

U2 - 10.1186/1479-5876-11-135

DO - 10.1186/1479-5876-11-135

M3 - Article

VL - 11

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

IS - 1

M1 - 135

ER -