Therapeutic Effects of Autologous Lymphocytes Activated with Trastuzumab for Xenograft Mouse Models of Human Breast Cancer

Abstract

Trastuzumab (TTZ) is molecular targeted drug used for metastatic breast cancer patients overexpressing human epidermal growth factor receptor 2 (HER2). Therapeutic effects of lymphocytes activated with TTZ (TTZ-LAK). p185 HER2 has partial homology with the epidermal growth factor receptor and shares intrinsic tyrosine kinase activity with that receptor. HER2 overexpressed in human breast cancers correlated with poor clinical outcome in women with breast cancers.1-3) HER2 is known as epidermal growth factor receptor (ErbB) 2 of the tyrosine kinase (TK) receptor, belonging to ErbB growth factor receptor family. There are four members of HER family receptors; epidermal growth factor receptor (EGFR)/ErbB1/ HER1, HER2/ErbB2, HER3/ErbB3, and HER/ErbB4.3) HER family receptors are activated by ligand-induced dimerization, or receptor pairing. Dimerization is a critical step in HER family-mediated signaling, and HER receptors are able to homodimerize or heterodimerize with other HER family members. HER2 is the preferred dimerization partner for all HER family receptors. However, there are no known endogenous ligands that bind to HER2. 4)The extracellular domain of HER2 is in a conformation that is open and ready for dimerization. So, molecules such as monoclonal antibodies would bind to the extracellular domain of HER2 to suppress those activity. Several monoclonal antibodies (mAbs) directed against HER2 ectodomain that specifically inhibit the growth of tumor cell lines overexpressing HER2 have been developed. 5) Trastuzumab (TTZ) is a humanized immunoglobulin G1 kappa (IgG1κ) light chain mAb in which the complementary-determining regions (CDR) of a HER2-specific mouse mAb were joined to in human immunoglobulin variable regions.5) TTZ binds to the domain IV of the extracellular segment of the HER2/neu receptor. Because TTZ belong to IgG1, its effects may be related to Fab (antigen binding fragment) or Fc (crystallizable fragment) regions.6) It has been reported that antibody-dependent cellular cytotoxicity (ADCC) plays an important role in the antitumor activity of TTZ. 7) Although the mechanisms underlying the action of TTZ are still not fully understood, inhibitory effects of TTZ by cell cycle arrest in G1 and induction of apoptosis on the growth of HER2-positive breast cancer cells in vitro have been reported.8) The combination chemotherapy with TTZ has been shown to improve survival for women with HER2-overexpressing metastatic breast cancer patients. [9][10][11] However, there were severe side-effects in combination chemotherapy. 1,6,12,13) On the other hand, immunotherapy using lymphocyte stimulated with immunomodulators such as cytokines was noted in cancer therapy as attractive approach, since there is no serious side effects in immunotherapy. Significant prolongation in survival and disease free period in group of immunotherapy compared with no-treatment group have been reported. 14)Yoshida et al. have studied metastasis mechanism of cancer cells 15,16) and for clinical applications of immunotherapy using CD3-a...

Maitake Beta-Glucan Enhances the Therapeutic Effect of Trastuzumab <i>via</i> Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity

“…MD-Fraction Enhances Trastuzumab-Mediated ADCC by Activating NK Cells Athymic nude mice lack peripheral T cells, but retain NK cells and macrophages, which exhibit higher cytotoxic activity than euthymic mice. 23,24) Therefore, we investigated the possible contribution of immune cells to the enhanced antitumor effect of MD-Fraction on trastuzumab in xenograft models. Administration of MD-Fraction to tumor-free nude mice significantly increased the spleen weight (Fig.…”

Establishment of an In Vivo Xenograft Mouse Model of a Subcutaneous Submillimeter HT-29 Tumor Formed from a Single Spheroid Transplanted Using Radiation-Crosslinked Gelatin Hydrogel Microwell

“…Small submillimeter tumors are useful tools for developing novel medicines and methods for detecting or treating small cancer nodules [3]. However, the establishment of useful in vivo tumor xenograft models that are applicable to study submillimeter tumors is challenging [4]. In conventional studies, in vivo xenograft mouse models of subcutaneous tumors approximately 5 mm in size (65 mm 3 in volume), made by subcutaneous injection of colorectal cancer cell suspension, have been generally used.…”