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Focal Irradiation and Systemic TGF? Blockade in Metastatic Breast Cancer.

ABSTRACT: Purpose: This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGF? blockade during radiotherapy in metastatic breast cancer patients.Experimental Design: Prospective randomized trial comparing two doses of TGF? blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum.Results: Twenty-three patients were randomized, median age 57 (range 35-77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02-7.30; P = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool.Conclusions: TGF? blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group. Clin Cancer Res; 24(11); 2493-504. ©2018 AACR.

SUBMITTER: Formenti SC

PROVIDER: S-EPMC5999326 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Focal Irradiation and Systemic TGFβ Blockade in Metastatic Breast Cancer.

Formenti Silvia C SC Lee Percy P Adams Sylvia S Goldberg Judith D JD Li Xiaochun X Xie Mike W MW Ratikan Josephine A JA Felix Carol C Hwang Lin L Faull Kym F KF Sayre James W JW Hurvitz Sara S Glaspy John A JA Comin-Anduix Begoña B Demaria Sandra S Schaue Dörthe D McBride William H WH

Clinical cancer research : an official journal of the American Association for Cancer Research 20180223 11

<b>Purpose:</b> This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.<b>Experimental Design:</b> Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 w ...[more]

PMID: 29476019

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Project description:PurposeTo evaluate the acute changes in leukocyte populations after focal irradiation and to assess the role of interleukin 6 (IL-6) in acute and late radiation injury.Methods and materialsMice were surgically implanted with a radiopaque marker on the surface of the small intestine. Mice were then imaged with cone beam computed tomography to locate the marker and irradiated with 18 Gy of 5 × 5 mm collimated x-rays onto the marked intestine using the Small Animal Radiation Research Platform. Intestinal sections and blood were harvested 1, 3.5, 7, and 14 days and 2 months postirradiation (post-IR) for histology and complete blood count, respectively. Immune cell populations were assessed by immunofluorescence in the acute phase. Collagen deposition was assessed 2 months post-IR. IL-6-/- intestinal sections were assessed post-IR for morphology, EdU, Ki67, and TUNEL in comparison to IL-6+/+ mice. Furthermore, a set of IL-6+/+ mice were treated with anti-IL-6R to assess the role of IL-6 in late intestinal injury.ResultsIntestinal radiation damage peaked 14 days post-IR, and fibrosis had developed by 60 days post-IR. There was a marked infiltration of immune cells into the irradiated intestine, with increased neutrophils, macrophages, B-cells, and CD4+ T cells maintained from 3.5 to 14 days post-IR. CD8+ T cells were decreased from days 7 to 14 post-IR. Systemically, leukocytes were increased in the peripheral blood 14 days post-IR with anemia being maintained from 14 days to 2 months. IL-6 was significantly increased in the serum post-IR. IL-6-/- mice demonstrated worsened intestinal injury acutely post-IR. Moreover, anti-IL-6R-treated mice presented with worsened intestinal fibrosis 2 months post-IR.ConclusionsFocal irradiation of the intestine produced a significant increase in immune cells in the irradiated area and systemic inflammation and anemia. Blockade of IL-6 signaling was found to exacerbate acute intestinal injury and late intestinal injury after focal irradiation.

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Focal Irradiation and Systemic TGF? Blockade in Metastatic Breast Cancer.

Publications

Focal Irradiation and Systemic TGFβ Blockade in Metastatic Breast Cancer.

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