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Dose-dense chemotherapy improves mechanisms of antitumor immune response.

ABSTRACT: Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are 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 with 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 interleukin (IL)-2 and IFN-? 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/m(2)) as the third- or fourth-line treatment. Serum was collected over the course of treatment, and serial IFN-? and IL-2 levels were used to determine CD8(+) T-cell activation. Of the four patients with disease control, three had serum levels of IL-2 and IFN-? 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. Because the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment.

SUBMITTER: Chang CL

PROVIDER: S-EPMC3537885 | biostudies-other | 2013 Jan

REPOSITORIES: biostudies-other

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Dose-dense chemotherapy improves mechanisms of antitumor immune response.

Chang Chih-Long CL Hsu Yun-Ting YT Wu Chao-Chih CC Lai Yan-Zen YZ Wang Connie C Yang Yuh-Cheng YC Wu T-C TC Hung Chien-Fu CF

Cancer research 20121029 1

Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are 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 with 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 imm ...[more]

PMID: 23108141

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Project description:PURPOSE:This study examined tumor growth delay resulting from partial irradiation in preclinical mouse models. METHODS AND MATERIALS:We investigated 67NR murine orthotopic breast tumors in both immunocompetent and nude mice. Treatment was delivered to 50% or 100% of the tumor using a 2 × 2 cm collimator on a microirradiator. Radiation response was modulated by treatment with anti-CD8 and anti-intercellular adhesion molecule (anti-ICAM) antibodies. Similar experiments were performed using the less immunogenic Lewis lung carcinoma mouse model. Tumor growth delay and ?-H2AX phosphorylation were measured, and immune response was assessed by immunofluorescence and flow cytometry at 1 and 7 days after radiation therapy. Tumor expression of cellular adhesion molecules was also measured at different times after radiation therapy. RESULTS:Partial irradiation led to tumor responses similar to those of fully exposed tumors in immunocompetent mice, but not in nude mice. After a single dose of 10 Gy, infiltration of CD8+ T cells was observed along with increased expression of ICAM. The response to 10 Gy in hemi-irradiated tumors was abrogated by treatment with either anti-CD8 or anti-ICAM antibodies. Similar responses were obtained in the less immunogenic Lewis lung carcinoma mouse model delivering 15 Gy to half the tumor volume. Treatment with FTY720, a compound that inhibits T-cell egress from lymph nodes, did not affect tumor response at the time of CD8+ T cells infiltration in the nonirradiated area of the tumor. This result indicated that the most likely source of these cells is the irradiated portion of the hemi-irradiated tumors. In addition, a significant abscopal effect was observed after partial irradiation with a single dose of 10 Gy in the 67NR model. CONCLUSIONS:In these models, radiation controls tumor growth both directly through cell killing and indirectly through immune activation. This outcome raises the possibility that this effect could be induced in the clinic.

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Dose-dense chemotherapy improves mechanisms of antitumor immune response.

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Dose-dense chemotherapy improves mechanisms of antitumor immune response.

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