New Cancer Immunotherapy Using Autologous Lymphocytes Activated with Trastuzumab

Nakagawa, Shinichirou; Matsuoka, Yusuke; Ichihara, Hideaki; Yoshida, Hitoji; Yoshida, Keishiro; Ueoka, Ryuichi

doi:10.1248/bpb.b12-00378

Cited by 6 publications

(7 citation statements)

References 19 publications

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“…Manipulations of the Fc domain structure may optimize antibody clearance and the interaction of Fc domains with cellular Fc receptors (23). Furthermore, immobilization of TTZ increased the number of PBMCs from 5 healthy donors after 48 h of culture, which indicated that this technique is effective for culturing cells for immunotherapy (24).…”

Section: Large Scale Ex Vivo Expansion Of Clinical-grade Effector Celmentioning

confidence: 99%

Large scale ex vivo expansion of clinical‑grade effector cells for adoptive immunotherapy

Chen

et al. 2017

Exp Ther Med

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Abstract. Cell-based adoptive immunotherapy for the treatment of various cancer types has attracted the attention of scientists. However, due to the absence of unitary standard protocols to produce large quantities of clinical-grade effector cells, it remains challenging to translate the experimental findings into clinical applications. The present study used methods complying with good manufacturing practice to induce effector cells from human peripheral blood mononuclear cells (PBMCs) of healthy donors by interleukin-2 and anti-Her-2 antibody with or without anti-CD3 antibodies (OKT3). The results indicated that the addition of OKT3 resulted in a greater expansion of the total cells and CD8 + T cells, and primarily induced the PBMCs to differentiate into CD3 + T cells. Regardless of the presence of OKT3, the expression of activating receptor of natural killer (NK) group 2, member D, and the inhibitory receptors of CD158a and CD158b on NK cells and NKT cells was increased, while the expression of NKp46 was inhibited on NK cells, but not on NKT cells. Furthermore, OKT3 did not affect the toxicity of the effector cells. Subgroup analysis indicated that although a variation of the composition of effector cells was present in different individuals under identical culture conditions, consistent marker expression on effector cells and target cell-killing effects were observed in different subgroups treated with or without OKT3. Furthermore, western blot analysis indicated that OKT3, apart from its involvement in cell cycle regulation, affects transcription and protein translation during processes of proliferation and differentiation. The present study provided experimental data regarding the production of effector cells for adoptive immunotherapy as a clinical application.

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Section: Large Scale Ex Vivo Expansion Of Clinical-grade Effector Celmentioning

confidence: 99%

Large scale ex vivo expansion of clinical‑grade effector cells for adoptive immunotherapy

Chen

et al. 2017

Exp Ther Med

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“…22) Activation of the lymphocytes having Fc receptor (FcR) in TTZ-LAK cells could enhance cellular cytotoxicity. On the other hand, T cells which recognized a specific antigen (HER2) produced by human breast cancer cells in TTZ-LAK cells could also induce cytotoxic T-lymphocyte (CTL) by antigen presentation to lymphocyte.…”

Section: Therapeutic Effects Of Ttz-lak For Xenograft Mouse Models Ofmentioning

confidence: 99%

“…We have already reported on inhibitory effects of lymphocytes activated with TTZ (TTZ-LAK) on the growth of human breast cancer cells in vitro. 22) However, anticancer effects of TTZ-LAK in vivo have not been elucidated.…”

mentioning

confidence: 99%

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

Nakagawa

Matsuoka

Ichihara

et al. 2013

Biological & Pharmaceutical Bulletin

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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...

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“…Therefore, how to treat LCSC must be considered after an operation, radiotherapy and/or chemotherapy. Autoimmune treatment of a malignant tumor is considered to be a feasible method, that mainly depends on the interfering and suppressing effects of killer cells induced by the tumor, infiltrating lymphocytes and lymphokines, as well as CD3 monoclonal antibodies [ 8 , 9 ]. Currently, cytokine-induced killer cells (CIK) therapy or dendritic cells (DC)-CIK cell co-cultivation has been widely used to treat malignant tumors in clinical trials, because DC and CIK have been demonstrated to possess high antitumor and cytotoxic activity against hepatocellular carcinoma (HCC) cells in vitro and in vivo [ 10 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system

et al. 2018

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BackgroundApplication of dendritic cells (DC) for cancer immunotherapy involves tumor-associated immunogenic antigens for effective therapeutic strategies. The present study investigated whether DC co-cultured with autologous cytokine-induced killer cells (CIK) could induce a more specific immune response against liver cancer stem cells (LCSC) generated from human hepatocellular carcinoma (HCC) cells in vitro and in vivo.MethodsHuman DC and CIK were generated from peripheral blood mononuclear cells (PBMCs) taken from consenting liver cancer patients. Flow cytometry was used to determine the phenotypes of DC and CIK, and cell proliferation. The tumor growth and anti-tumor activity of these cells were further evaluated using a nude mouse tumor model.ResultsWe demonstrated that DC and CIK significantly enhanced the apoptosis ratio, depending on DC-CIK cell numbers, by increasing caspase-3 protein expression and reducing proliferating cell nuclear antigen (PCNA) protein expression against LCSC. The in vivo data indicated that DC-CIK exhibited significant LCSC cell-induced tumor growth inhibition in nude mice, which was most significant with LCSC antigen loaded DCs.ConclusionsThe results showed, that DC-CIK cells could inhibit HCC and LCSC growths in vitro and in vivo and the most successful DC triggering of cell cytotoxic activity could be achieved by their LCSC antigen loading.

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New Cancer Immunotherapy Using Autologous Lymphocytes Activated with Trastuzumab

Cited by 6 publications

References 19 publications

Large scale ex vivo expansion of clinical‑grade effector cells for adoptive immunotherapy

Large scale ex vivo expansion of clinical‑grade effector cells for adoptive immunotherapy

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

Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system

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