Abstract
Background: Interleukine-2 and Cyclophosphamide are known to influence the circulating T cells and are used for immune manipulation in cancer patients. We analyzed the influence on the Treg population in three different dendritic cell (DC) vaccine trials including either concurrent interleukine-2 (IL-2), combined IL-2 and metronomic Cyclophosphamide (MCy), or only MCy.Methods: Melanoma patients received treatment with autologous DCs. IL-2 was applied in trial I and II and MCy was applied in trial I and III. Flowcytometry analysis was performed on fresh drawn blood-samples measuring CD4, CD25 and CD127.Results: In the trials where IL-2 was applied a marked increase in the proportion of CD4+CD25+CD127- Tregs from baseline to the 4th vaccine was observed. This was followed by a decrease, although not to baseline values. Additional analysis showed that the inhibitory function was predominant in the CD49d- subpopulation of Tregs which only increased slightly during treatment. The absolute lymphocyte count (ALC) and the number of CD4+ T cells also increased in these trials. In the trial where only MC was applied the Tregs remained stable throughout the trial whereas decrease in the ALC and CD4+ T cells were observed.Conclusion: We found that adjuvant treatment with low doses of IL-2 during DC vaccination therapy causes a significant increase in blood level of classically defined, CD4+CD25+CD127-, Tregs but far less in the CD49d- subpopulation and that the use of MC was unable to reduce Treg blood level and unable to counteract IL-2 dependent increase in the CD4+CD25+CD127- T cells.These findings have implications for the clinical use of IL-2 as well as MCy as immune modulators.
Highlights
Malignant melanoma is a cancer with increasing incidence and a poor prognosis
Cell; Ce: Celecoxib; Cy: Cyclophosphamide; metronomic Cyclophosphamide (MCy): Metronomic Cyclophosphamide; TMZ: Temozolomide; dendritic cell (DC): Dendritic Cell; SD: Stable Disease; PD: Progressive Disease; DC-MCy-IL2: DC vaccine with IL-2 + MCy; DC-IL2: DC vaccine with IL-2; DCMCy: DC vaccine with MCy; TMZ150: Temozolomide150 mg /m2/day for a week followed by one week break
We investigated the effect of MCy as an immune modulator either alone or in combination with Interleukine-2 (IL-2) as adjuvant treatment in our dendritic cell (DC) vaccination trials
Summary
Malignant melanoma is a cancer with increasing incidence and a poor prognosis. Once metastasized there remains no standard curable treatment IL-2, Dacarbazine and Temozolamide are often used. The first phase III trial ever to show improved overall survival in melanoma patients has been published recently. Dendritic cell vaccination is one of the immune-therapeutic strategies that have been tested in a number of trials in metastatic melanoma patients [2]. In some of these studies a fraction of patients achieved clinical responses, but even more patients achieved immunological responses. We analyzed the influence on the Treg population in three different dendritic cell (DC) vaccine trials including either concurrent interleukine-2 (IL-2), combined IL-2 and metronomic Cyclophosphamide (MCy), or only MCy
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