A phase II trial of trastuzumab in combination with low-dose interleukin-2 (IL-2) in patients (PTS) with metastatic breast cancer (MBC) who have previously failed trastuzumab - PubMed (original) (raw)

Clinical Trial

A phase II trial of trastuzumab in combination with low-dose interleukin-2 (IL-2) in patients (PTS) with metastatic breast cancer (MBC) who have previously failed trastuzumab

Aruna Mani et al. Breast Cancer Res Treat. 2009 Sep.

Abstract

Trastuzumab mediates the lysis of HER2-expressing breast cancer cell lines by interleukin-2 (IL-2) primed natural killer (NK) cells. We hypothesized that IL-2 would augment the anti-tumor effects of trastuzumab in MBC in patients who had progressed on or within 12 months of receiving a trastuzumab-containing regimen. Secondary objectives were to measure antibody-directed cellular cytotoxicity (ADCC) against HER2 over-expressing target cells, and to measure serum cytokines. Patients received trastuzumab (4 mg/kg intravenously (IV)) every 2 weeks in combination with daily low-dose IL-2 (1 million IU/m(2) subcutaneously (SC)) and pulsed intermediate-dose IL-2 (12 million IU/m(2) SC). Samples were analyzed for NK cell expansion and ADCC against a HER2-positive breast cancer cell line. In addition, interferon-gamma (IFN-gamma), mRNA expression in peripheral blood mononuclear cells (PBMC) and the following serum cytokines were measured: IFN-gamma, monokine-induced by IFN-gamma (MIG), and interferon-inducible protein ten (IP-10). The median number of treatment cycles was four (range 1-23) and the treatment was well tolerated. There were no objective responses. NK cells were not expanded and ADCC was not enhanced. Eight (62%) patients had a twofold or higher increase in mRNA transcript for IFN-gamma, two (15%) patients had elevated serum levels of IFN-gamma and 12 (92%) had increases angiogenic MIG and IP-10. In trastuzumab-refractory patients adding IL-2 did not produce responses and did not result in NK cell expansion. However, these patients had the ability to respond to IL-2 as evidenced by increases in IFN-gamma transcripts and chemokines. The lack of NK cell expansion may explain the absence of clinical benefit.

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Figures

Fig. 1

Fig. 1

Treatment schema

Fig. 2

Fig. 2

ADCC by patient PBMCs against trastuzumab-coated SKBR3 tumor cells was measured pre- and post-IL-2 treatment. ADCC values were calculated as the percent lysis of trastuzumab-coated SKBR3 tumor cells after subtraction of lysis of these cells in the absence of trastuzumab. ADCC was not significant in any patient

Fig. 3

Fig. 3

Serum IFN-γ was measured at the indicated time points (C cycle; D day). Represented here are the only three patients in whom there was detectable IFN-γ. Results were normalized against a _β_-actin internal control

Fig. 4

Fig. 4

IFN-γ transcripts were measured by RT-PCR both pre- and post-IL-2 treatment, and are displayed here as fold increase. Transcripts increased in eight patients after IL-2 treatment

Fig. 5

Fig. 5

a Serum levels of MIG and b IP-10 were measured at various time points. Shown here are the baseline and peak levels

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