Dose-dense chemotherapy improves mechanisms of antitumor immune response
Menée à l'aide d'un modèle murin et sur 14 patientes atteintes d'un cancer ovarien récidivant et résistant aux sels de platine, cette étude met én évidence un nouveau mécanisme immunitaire induit par un protocole de chimiothérapie "dose dense" combinant cisplatine et paclitaxel
Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects is not completely clear. In this study, we assessed whether a DD combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared to a maximum-tolerated dose (MTD) regimen, in treating platinum-resistant ovarian cancer as modeled in mice. Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed. The DD regimen was less toxic to the immune system, reduced immunosuppression by the tumor microenvironment, and triggered recruitment of macrophages and tumor-specific CD8+ T cell responses to tumors (as determined by IL-2 and IFN-γ secretion). In this model, we found that the DD regimen exerted greater therapeutic effects than the MTD regimen, justifying its further clinical investigation. Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin (AUC2) and paclitaxel (60-80 mg/m2) as the third or fourth-line treatment. Serum was collected over the course of treatment and serial IFN-γ and IL-2 levels were used to determine CD8+ T cell activation. Of the 4 patients with disease control, 3 had serum levels of IL-2 and IFN-γ associated with cytotoxic CD8+ T cell activity. The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment-mediated promotion of tumor-specific immunity, especially the antitumor CD8+ T cell response. Since the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment.