Enhancing the effectiveness of a breast cancer treatment
Breast cancers expressing the protein HER2 have a particularly poor prognosis. Treatment with trastuzumab (Herceptin) benefits some patients with HER2-positive breast cancer, but it is not as effective as had been hoped. Researchers are therefore seeking ways to enhance the effectiveness of trastuzumab. In this context, a team of researchers led by Ronald Levy, at Stanford University, Stanford, has identified a sequential treatment regimen that enhances the effectivenss of trastuzumab in xenotransplant models of breast cancer.
Trastuzumab is a molecule known as an antibody that binds to HER2. Binding of trastuzumab to HER2-positive tumor cells recruits immune cells such as natural killer cells to the tumor cells. Upon encountering encountering trastuzumab-coated, HER2-overexpressing tumor cells, natural killer cells become activated and kill the tumor cells. Levy and colleagues found that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells upregulated expression of the protein CD137. Moreover, stimulating trastuzumab-activated human NK cells with an agonistic antibody specific for CD137 led to breast cancer cell killing in vitro and in xenotransplant models of breast cancer. They therefore suggest that trastuzumab treatment followed by administration of an antibody that activates natural killer cells (for example, an antibody that targets CD137) could provide a more effective way to treat patients with HER2-positive breast cancer than trastuzumab alone.
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Of the 207,000 women diagnosed with breast cancer in the United States in 2010, one-fourth had tumors overexpressing the transmembrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu). These women comprise a disproportionate number of the 40,000 annual breast cancer deaths. Trastuzumab is a humanized mAb targeting HER2. Despite improving the outcome for this poor-prognostic group of patients, response rates in metastatic breast cancer to trastuzumab as monotherapy are limited, consisting of approximately 10%–15%.
Multiple strategies have been investigated to enhance the antitumor activity of trastuzumab, which is due, at least in part, to antibody-dependent cellular cytotoxicity (ADCC). ADCC is dependent upon immune effector cells, mainly NK cells, binding via their Fc receptor (FcγRIII, CD16) to the IgG1 Fc, heavy-chain portion of trastuzumab. This leads to the activation of the NK cells, release of their cytotoxic granules, and lysis of the trastuzumab-bound breast cancer cell. Clinical results have shown that patients harboring an FcγRIIIA polymorphism with higher NK affinity for IgG1 have a better response to trastuzumab, further supporting the hypothesis that ADCC, including its mediators, is an important in vivo mechanism of trastuzumab action. Additional supporting clinical data demonstrated that responders to neoadjuvant trastuzumab exhibited a 4-fold increase in antibody-dependent lytic activity from isolated PBMCs compared with that of nonresponders. Therefore, augmenting ADCC could increase the clinical efficacy of trastuzumab therapy.
Selectively targeting activated NK cells at the tumor site would be an attractive strategy to improve ADCC without incurring the systemic toxicity of global NK cell stimulation, such as that observed with systemic IL-2 or IL-12. Recently, it was shown that human NK cells upon Fc-receptor triggering, such as the interaction with antibody-bound tumor cells, upregulate the inducible costimulatory molecule CD137. Once induced to express CD137, we hypothesize that the killing function of these activated NK cells can be enhanced by their exposure to an agonistic mAb against CD137, leading to improved antitumor activity. In the current study, we investigate the hypothesis that an agonistic mAb against CD137 can enhance the killing of human breast cancer cells by trastuzumab both in vitro and in vivo.
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Holbrook E. Kohrt, Roch Houot, Kipp Weiskopf, Matthew J. Goldstein, Ferenc Scheeren4, Debra Czerwinski, A. Dimitrios Colevas, Wen-Kai Weng, Michael F. Clarke, Robert W. Carlson, Frank E. Stockdale, Joseph A. Mollick, Lieping Chen and Ronald Levy
TITLE: Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer
Evaluating the Effectiveness of Cancer Therapy
The effectiveness of cancer therapy is usually evaluated by how well the therapy removes cancer cells. Some procedures-such as lumpectomy or mastectomy-are designed to remove all or most cancer cells at once by removing the breast where the cancer cells are. The effectiveness of these procedures is evaluated by how much of the cancer was removed. If the cancer has spread to the lymph nodes or other parts of the body, then the surgery will not be effective and other treatments might be used in conjunction with surgery. If the breast cancer was identified early and all of the cancer cells are removed, the surgery is effective at treating the cancer.
Other types of therapy, such as radiation and chemotherapy, are not designed to remove all of the cancer cells at once. Instead, these therapies are designed to slowly kill cancer cells by preventing them from reproducing. If the tumor shrinks or the number of cancer cells in the body decreases, the treatments are said to be working.
AUTHOR CONTACT:
Ronald Levy
Stanford University Medical Center, Stanford, California, USA.
Phone: 650.725.6452; Fax: 650.736.1454; E-mail: .(JavaScript must be enabled to view this email address).