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

Abstract

BackgroundIn 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.MethodsTwenty-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.ResultsAmong 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.ConclusionsOur 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.

Tissue invasion and metastasis: Molecular, biological and clinical perspectives

“…For this purpose, several therapeutic approaches that use small Reduces the number of Tregs [121] molecule inhibitors, antibodies or phytochemicals that specifically target molecules and signaling pathways involved in the recruitment, activation and function of tumor infiltrating non-malignant cells have been tested in both animal models and human. Table 1 summarizes the most up-to-date drugs available with potential use in cancer therapy, known effects on tumor cells and activity against tumor-stromal microenvironment communications.…”

“…Finally sclareol and temozolomide reduce tumor growth and the number of tumor infiltrating Tregs [120,121]. Therefore, although further studies will be needed to determine which cell(s) is/are the best therapeutic target(s) and which drugs are the most efficient and selective, there is no doubt that the therapeutic targeting of tumor microenvironment cells represents a valuable strategy to complement conventional anticancer strategies.…”

Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells

“…[8][9][10]57 To improve clinical efficacy, it is probably necessary to combine vaccination with checkpoint modulators or other strategies countering immunological tolerance. 6,25,52,[66][67][68][69][70][71] As a combination strategy will increase the risk of side effects, it is encouraging that our vaccine study indicated low toxicity, even after long-term follow-up. One may further note that the longterm survivors (M22 and M109) responded well to treatment with ipilimumab.…”

Antitumor dendritic cell–based vaccines: lessons from 20 years of clinical trials and future perspectives

“…By depleting the immune cells, these drugs eliminate negative regulators such Tregs and MDSCs, promoting a favorable environment for DC-induced expansion of antitumor effector cells in the recovery phase. In a pilot clinical trial, Ridolfi et al 161 showed that the administration of low doses of temozolomide to melanoma patients before DC vaccination specifically reduced the CD4 1 CD25 1 Foxp3 1 Tregs. In turn, cyclophosphamide was shown to enhance antitumor immunity through mechanisms that rely on Treg elimination and resetting DC homeostasis.…”