Abstract
For the treatment of metastatic renal cell cancer several strategies are used among which the mTOR inhibitor everolimus. As mTOR plays an important role in the immune system, e.g., by controlling the expression of the transcription factor FoxP3 thereby regulating regulatory T cells (Tregs), it plays a key role in the balance between tolerance and inflammation. Previous reports showed stimulatory effects of mTOR inhibition on the expansion of Tregs, an effect that can be considered detrimental in terms of cancer control. Since metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs, a phase 1 clinical trial was conducted to comprehensively investigate the immune-modulating effects of several dosages and schedules of CTX in combination with the standard dose of everolimus, with the explicit aim to achieve selective Treg depletion. Our data show that 50 mg of CTX once daily and continuously administered, in combination with the standard dose of 10 mg everolimus once daily, not only results in depletion of Tregs, but also leads to a reduction in MDSC, a sustained level of the CD8+ T-cell population accompanied by an increased effector to suppressor ratio, and reversal of negative effects on three peripheral blood DC subsets. These positive effects on the immune response may contribute to improved survival, and therefore this combination therapy is further evaluated in a phase II clinical trial.
Highlights
Materials and methodsKidney cancer is one of the ten most common cancer types in both men and women, with an estimated number of 338,000 new cases per year [1]
Except for cohort 4, in which a significant decrease in CD8+ T cells was observed in comparison to cohort 0 at time point 4, no major differences were observed between cohorts in CD8+ T-cell frequencies
Based on the Treg-depleting data in cohort 2 and the observation that the Treg-depleting effect of CTX was less pronounced in subsequent cohorts, with even an increase in Treg percentages in cohort 5 and 6, the decision was made to proceed to the expansion cohort wherein an additional 5 patients were treated with the combination of 10 mg everolimus and 50 mg CTX continuously
Summary
Kidney cancer is one of the ten most common cancer types in both men and women, with an estimated number of 338,000 new cases per year [1]. Since Tregs have immune suppressive capacities, this Treg-promoting effect of everolimus can be considered a detrimental effect in the treatment of cancer In support of this notion, increased Treg numbers have been associated with poor survival in patients with cancer, including mRCC [11,12,13]. Patients were treated in cohorts of five patients, with six different doses and schedules of CTX. We report on the results of the extensive and comprehensive immune monitoring that was performed in this phase 1 study, where patients were treated with either everolimus alone or the combination of everolimus and different CTX administration dosages and schedules. Forty patients with mRCC and previously treated with a VEGF targeting regimen were treated with everolimus in combination with different doses and schedules of metronomic oral CTX. Statistical analyses were performed using GraphPad Prism software (version 7, 2016)
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