Correlation between NK function and response to trastuzumab in metastatic breast cancer patients

Beano, Alessandra; Signorino, Elena; Evangelista, Andrea; Brusa, Davide; Mistrangelo, Marinella; Polimeni, Maria Antonia; Spadi, Rosella; Donadio, Michela; Ciuffreda, Libero; Matera, Lina

doi:10.1186/1479-5876-6-25

Cited by 130 publications

(95 citation statements)

References 31 publications

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“…This proposition is in line with the observation that a metastasis-free survival rate of patients can be associated with an enhanced NK cell activity (32). The clinical relevance of our data are further supported by published observations on the ADCC activity of trastuzumab in metastatic breast cancer patients (33). In this study, the in vitro ADCC activity toward Her2 overexpressing tumor cells, which was quantitatively comparable to that which was seen against Hsp70 membrane-positive tumor cells in the current study, could be correlated to the short-term antitumor responses in trastuzumab-treated breast cancer patients (33).…”

Section: Discussionsupporting

confidence: 79%

Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody

Stangl

Gehrmann

Riegger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

185

204

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Immunization of mice with a 14-mer peptide TKDNNLLGRFELSG, termed "TKD," comprising amino acids 450-461 (aa [450][451][452][453][454][455][456][457][458][459][460][461] ) in the C terminus of inducible Hsp70, resulted in the generation of an IgG1 mouse mAb cmHsp70.1. The epitope recognized by cmHsp70.1 mAb, which has been confirmed to be located in the TKD sequence by SPOT analysis, is frequently detectable on the cell surface of human and mouse tumors, but not on isogenic cells and normal tissues, and membrane Hsp70 might thus serve as a tumor-specific target structure. As shown for human tumors, Hsp70 is associated with cholesterol-rich microdomains in the plasma membrane of mouse tumors. Herein, we show that the cmHsp70.1 mAb can selectively induce antibody-dependent cellular cytotoxicity (ADCC) of membrane Hsp70 + mouse tumor cells by unstimulated mouse spleen cells. Tumor killing could be further enhanced by activating the effector cells with TKD and IL-2. Three consecutive injections of the cmHsp70.1 mAb into mice bearing CT26 tumors significantly inhibited tumor growth and enhanced the overall survival. These effects were associated with infiltrations of NK cells, macrophages, and granulocytes. The Hsp70 specificity of the ADCC response was confirmed by preventing the antitumor response in tumor-bearing mice by coinjecting the cognate TKD peptide with the cmHsp70.1 mAb, and by blocking the binding of cmHsp70.1 mAb to CT26 tumor cells using either TKD peptide or the C-terminal substrate-binding domain of Hsp70.immunotherapy | syngeneic tumor model | tumor antibody dependent cellular cytotoxicity | epitope mapping | surface antigen

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Section: Discussionsupporting

confidence: 79%

Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody

Stangl

Gehrmann

Riegger

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

185

204

View full text Add to dashboard Cite

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“…Gennari and colleagues reported that the level of ADCC during trastuzumab exposure was associated with a higher efficacy of trastuzumab (16). These data were confirmed in a study done in the metastatic setting (17). All of these studies suggested that trastuzumab induced immune response that in turn mediates antitumor activity.…”

Section: Intratumoral Immune Parameters To Identify Patients Resistansupporting

confidence: 73%

Molecular Pathways: Involvement of Immune Pathways in the Therapeutic Response and Outcome in Breast Cancer

Varga

Dieci

Dubsky

et al. 2013

Clinical Cancer Research

175

142

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The immune system could mediate the antitumor activity of several anticancer treatments. Several chemotherapy compounds, including anthracyclines and oxaliplatin, induce immunogenic cell death that in turn activates antitumor immune response. Trastuzumab induces antibody-dependant cell-mediated cytotoxicity. On the basis of this background, immune markers have recently been the focus of intense translational research to predict and monitor the efficacy of treatments. Gene expression arrays and immunohistochemistry have assessed immune activation and infiltration by macrophages, natural killer, and T and B lymphocytes. Using these approaches, several retrospective analyses of large trials have shown that activation of immune pathway may predict treatment efficacy and outcome in patients with breast cancers. As examples, intratumoral infiltration by lymphocytes and interferon-response in primary tumor predicted the efficacy of neoadjuvant chemotherapy. Intratumoral infiltration by lymphocytes was associated with good prognosis in patients with triple-negative breast cancer treated with adjuvant chemotherapy. More recently, it has been suggested that lymphocyte infiltration could also predict efficacy of trastuzumab. Finally, small retrospective studies have suggested that postchemotherapy lymphocyte infiltrates could be associated with better outcome in patients who did not reach pathologic complete response. This body of evidence suggests that assessing immune infiltration and activation could be useful in the future to stratify breast cancer patients. In addition, they provide evidence for the development of immunotherapies in breast cancer patients.

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“…The important mode of action is antibodydependent cellular cytotoxicity (ADCC), a reaction by which the cell-bound antibody recruits immune effector cells bearing Fcc receptors. Natural killer cells expressing Fcc receptor III (CD16) play a critical role in ADCC [19].…”

Section: Introductionmentioning

confidence: 99%

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

Witthauer

Schlereth

Brischwein

et al. 2008

Breast Cancer Res Treat

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In the present study, the efficacy of a new drug, i.e. the bispecific single-chain antibody MT110 targeting the epithelial antigen EpCAM and the T-cell antigen CD3 was tested ex vivo in malignant pleural effusions (MPEs). EpCAM ? epithelial cells were found in 78% of the MPEs (n = 18). Ex vivo treatment of seven MPEs resulted in a dose-dependent specific lysis of 37 ± 27% (±SD) EpCAM ? cells with 10 ng/ml (P = 0.03) and 57 ± 29.5% EpCAM ? cells with 1,000 ng/ml MT110 (P = 0.016) after 72 h. As a prerequisite for redirected lysis, stimulation of he autologous CD4 ? and CD8 ? cells in MPE by 1,000 ng/ml MT110 resulted in 21 ± 17% CD4 ? /CD25 ? and 29.4 ± 22% CD8 ? /CD25 ? cells (P = 0.016, respectively) after 72 h. This was confirmed by a 22-fold release of TNF-a and 230-fold release of IFN-c (1,000 ng/ml, 48 h, P = 0.03, respectively). Thus, relapsed breast cancer patients resistant to standard treatment might benefit from targeted therapy using MT110.Keywords Malignant pleural effusion Á Breast cancer Á Bispecific antibody Á EpCAM Á CD3 Á MT110 Á Ex vivo therapy

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Correlation between NK function and response to trastuzumab in metastatic breast cancer patients

Cited by 130 publications

References 31 publications

Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody

Targeting membrane heat-shock protein 70 (Hsp70) on tumors by cmHsp70.1 antibody

Molecular Pathways: Involvement of Immune Pathways in the Therapeutic Response and Outcome in Breast Cancer

Lysis of cancer cells by autologous T cells in breast cancer pleural effusates treated with anti-EpCAM BiTE antibody MT110

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