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41.
TCRγ9δ2(OT3) is a tumor-specific TCR with an unique complementarity-determining region 3 (CDR3) sequence, referred to as OT3, in its δ2 chain. This region was identified in tumor-infiltrating lymphocytes (TILs) from human ovarian epithelial carcinoma. We demonstrated that TCRγ9δ2(OT3)-Fc, a fusion protein composed of the complete extracellular domains of the γ9 and δ2 chains linked to the Fc domains of human IgG1, exhibited successful binding to multiple human carcinoma cell lines. In vitro, TCRγ9δ2(OT3)-Fc mediated cell killing via antibody-dependent cellular cytotoxicity (ADCC) in a dose-dependent manner. In vivo, TCRγ9δ2(OT3)-Fc significantly inhibited tumor growth and enhanced survival in human ovarian carcinoma xenograft models. Our findings suggest that the TCRγ9δ2(OT3)-Fc fusion protein possesses both the antigen-recognition properties of TCR γδ and the Fc-mediated effector functions of the antibody. 相似文献
42.
Regina Demlova Lenka Zdrazilova-Dubska Jaroslav Sterba Giorgio Stanta Dalibor Valik 《European journal of surgical oncology》2018,44(9):1289-1294
Individualized medicine has the potential to tailor anticancer therapy with the best response and highest safety margin to provide better patient care. However, modern targeted therapies are still being tested through clinical trials comparing preselected patient cohorts and assessed upon behaviour of group averages. Clinically manifesting malignant disease requires identification of host- and tumour-dependent variables such as biological characteristics of the tumour and its microenvironment including immune response features, and overall capacity of the host to receive, tolerate and efficiently utilize treatment. Contemporary medical oncology including clinical trial design need to refocus from assessing group averages to individuality taking into consideration time dependent host-associated characteristics and reinventing outliers to be appreciated as naturally occurring variables collectively determining the ultimate outcome of malignant disease. 相似文献
43.
44.
Yamauchi C Fujii S Kimura T Kuwata T Wada N Mukai H Matsumoto N Fukayama M Ochiai A 《International journal of cancer. Journal international du cancer》2011,128(9):2125-2137
Trastuzumab is a recombinant antibody drug that is widely used for the treatment of HER2-overexpressing breast carcinoma. Despite encouraging clinical results, many HER2-overexpressing carcinomas are primarily resistant to trastuzumab. We attempted to explain trastuzumab resistance and search for solutions. Since the killer cell lectin-like receptor G1 (KLRG1), an inhibitory receptor expressed on subsets of natural killer (NK) cells recognizes E-cadherin as ligands and may inhibit immune responses by regulating the effector function of NK cells, we used HER2-overexpressing carcinoma cells which were expressing E-cadherin to investigate the role of antibody-dependent cellular cytotoxicity (ADCC) through KLRG1 on NK cells in vitro and vivo. The results indicated that HER2-overexpressing carcinoma cells were killed by trastuzumab-mediated ADCC and the ADCC activity was reflected the degree of E-cadherin expression on carcinoma cells. We found that expression of E-cadherin was shown to be a predictor of response to trastuzumab-based treatment for HER2-overexpressing carcinomas, furthermore, trastuzumab-mediated ADCC was markedly enhanced by KLRG1-negative peripheral blood mononuclear cells (PBMCs(KLRG1(-))). 相似文献
45.
Background
Human epidermal growth factor receptor 2 (HER2) is overexpresed in 15–20% of all breast cancers. Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings. However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. The present review addresses efficacy and toxicity of dual targeting in HER2-positive breast cancer.Materials and methods
A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.Results
This paper describes efficacy and safety of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings. Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway are described.Conclusion
Dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer. However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use. There is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective. 相似文献46.
47.
A number of antibody products have now become accepted as effective anti-cancer therapies. Despite being mainly designed to act by inhibiting functional tumour antigens, there is increasing evidence that Fc-mediated engagement of the immune system is an important contributor to the efficacy of several of these therapies. The optimisation of this engagement offers the potential not only to augment efficacy against existing targets, but also to exploit non-functional tumour antigens. Antibodies that achieve efficacy wholly or predominantly through Fc-mediated mechanisms, represent rich opportunities for future therapeutics in oncology. This mini review summarises some of the key challenges, which need to be addressed to select the most effective molecules. These include the identification of optimal antibody characteristics and improvement of the drug discovery process, in particular, the relevance and predictive power of existing in vitro and in vivo screening methods. Advances in our understanding of tumour immunobiology and successful application of technologies designed to enhance immune system engagement will further aid this process. 相似文献
48.
Conaghan P Ashraf S Tytherleigh M Wilding J Tchilian E Bicknell D Mortensen NJ Bodmer W 《British journal of cancer》2008,98(7):1217-1225
The distribution of carcinoembryonic antigen (CEA) in colorectal cancer (CRC) differs from that in normal colorectal tissue, being found on all borders of the cell membrane and hence enabling access to intravenous antibody, making CEA a good target for antibody-based therapy. The distinctive anti-CEA antibody, PR1A3, binds only membrane-bound CEA. Humanised PR1A3 (hPR1A3) was assessed both in vitro cytotoxicity and binding assays with colorectal cancer cell lines expressing varying levels of CEA. Human peripheral blood mononuclear cells (PBMCs) and purified natural killer (NK) cells were used as effectors. The in vitro assays demonstrated hPR1A3 CEA-specific binding and antibody-dependent and CEA-specific killing of human colorectal cancer cell lines by human PBMCs. The effect increased with increasing concentration of antibody and surface CEA, and was lost by using the parent murine IgG1 PR1A3. Killing was also blocked by antibody to the Fc-gammaIIIA receptor. Purified human NK cells were effective at much lower effector:target ratios than unfractionated PBMCs, indicating that NK cells were the main mediators of hPR1A3-based CEA-specific killing. The results support the development of hPR1A3 for therapy of colorectal cancer. 相似文献
49.
Jonathan D. Katz Parunag Nishanian Ronald Mitsuyasu Benjamin Bonavida 《Journal of clinical immunology》1988,8(6):453-458
The acquired immunodeficiency syndrome (AIDS) is defined in clinical terms by the development of Kaposi's sarcoma and/or severe opportunistic infections in persons without predisposing conditions. A hallmark of the syndrome has been a decrease in the number of CD4+ T helper cells. The reduction in the frequency of the CD4+ lymphocytes has been postulated to be primarily the result of human immunodeficiency virus (HIV) tropism and cytophathogenicity for the T-cell subset. Yet only a small percentage of cells is actually infected with HIV. Recently, we provided evidence indicating that AIDS patients' natural killer cells can mediate normal levels of antibody-dependent cellular cytotoxicity (ADCC) despite exhibiting a defect in natural killer (NK) effector function (J Immunol 139:55, 1987). This finding prompted us to investigate whether AIDS patients' effector cells could mediate ADCC against circulating CD4+ T cells infected with or expressing HIV antigen. The findings reported herein demonstrate that AIDS effector cells can mediate lysis of CEM (CD4+ T-cell line) coated with HIV protein in the presence of HIV-specific antibody. Lysis was specific, as non-HIV-coated CEM or the addition of HIV-negative serum resulted in no lysis. We then examined HIV-coated peripheral blood-derived CD4+ T lymphocytes as targets in ADCC. We demonstrate that in the presence of HIV-specific antibody, HIV-coated CD4+ T lymphocytes serve as targets for ADCC by AIDS effector cells. The lytic activity obtained with AIDS effector cells was comparable to that obtained with normal effector cells. These results demonstrate that AIDS effector cells can mediate ADCC against HIV-coated CD4+ T lymphocytes and suggest that ADCC may play a rolein vivo in the pathogenesis of AIDS. 相似文献
50.
Matthias G. Pauthner Joseph P. Nkolola Colin Havenar-Daughton Ben Murrell Samantha M. Reiss Raiza Bastidas Jérémie Prévost Rebecca Nedellec Benjamin von Bredow Peter Abbink Christopher A. Cottrell Daniel W. Kulp Talar Tokatlian Bartek Nogal Matteo Bianchi Hui Li Jeong Hyun Lee Salvatore T. Butera Dennis R. Burton 《Immunity》2019,50(1):241-252.e6