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Nihon Hinyokika Gakkai Zasshi. the... Aug 1993In 1960, the beneficial effect on allograft survival of 6-mercaptopurine (6-MP) was demonstrated. In 1961, azathioprine, a less toxic derivative of 6-MP, was synthesized... (Review)
Review
In 1960, the beneficial effect on allograft survival of 6-mercaptopurine (6-MP) was demonstrated. In 1961, azathioprine, a less toxic derivative of 6-MP, was synthesized and soon became the main form of maintenance therapy. Around the same time, clinical studies of the effects of corticosteroids on the immune system were being conducted and successful reversal of rejection with cortisone was recognized. Subsequently, steroids were added to azathioprine and this regimen constituted maintenance immunosuppressive therapy in most centers for over 20 years. However, these first generation immunosuppressive medications are the cause of the majority of complications following renal transplantation. Both azathioprine and steroids effect nearly all immunologic and inflammatory responses and may predispose to infection and certain malignant diseases. Despite refinement in the use of these agents with improved patient survival, little improvement in graft survival was appreciated. The second generation immunosuppressive agents, antilymphocyte globulin (ALG), emerged in the form of polyclonal antibodies derived from xenotypic antisera and directed against the entire cellular response. Unfortunately, many limitations have been encountered with respect to the administration of ALG. Cyclosporine A is more specific and attacks a subset of the lymphocyte population, the T helper lymphocytes. When cyclosporine A is used in combination with prednisone, the immunologic cycle that causes rejection is interrupted twice by virtue of the fact that prednisone prevents the production of IL-1 by macrophages and cyclosporine A with the production of lymphokines, especially IL-2 (T-cell growth factor). Although cyclosporine A is at present better immunosuppressive drug to azathioprine, it is not without a number of side-effects. Nephrotoxicity, however, is the most worrying complication in patients receiving cyclosporine A. Of most importance to the urologist, however, is the interaction with cyclosporine A by many of the drugs used to treat various urologic infections. The advent of hybridoma technology which has become so important to the urologic oncologist has also impacted upon transplantation and resulted in the development of a new generation of antilymphocyte antibodies. The bulk of clinical experience has been obtained with OKT3, a monoclonal antibody directed against the T3 antigen complex found on all T-lymphocytes. A large multi-center experience has showed the remarkable efficacy of OKT3 in providing rapid depletion of peripheral blood T cell levels and reversal of established rejection not responded to conventional high-dose steroid therapy and in reducing the frequency and delay of the onset of rejection reactions.
Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Prednisolone
PubMed: 8411796
DOI: 10.5980/jpnjurol1989.84.1359 -
JCI Insight Mar 2019Epithelial ovarian cancer (EOC) often presents with metastases and ascites. Granulocytic myeloid-derived suppressor cells are an immature population that impairs...
Epithelial ovarian cancer (EOC) often presents with metastases and ascites. Granulocytic myeloid-derived suppressor cells are an immature population that impairs antitumor immunity. Since suppressive granulocytes in the ascites of patients with newly diagnosed EOC were morphologically mature, we hypothesized that PMN were rendered suppressive in the tumor microenvironment (TME). Circulating PMN from patients were not suppressive but acquired a suppressor phenotype (defined as ≥1 log10 reduction of anti-CD3/CD28-stimulated T cell proliferation) after ascites supernatant exposure. Ascites supernatants (20 of 31 supernatants) recapitulated the suppressor phenotype in PMN from healthy donors. T cell proliferation was restored with ascites removal and restimulation. PMN suppressors also inhibited T cell activation and cytokine production. PMN suppressors completely suppressed proliferation in naive, central memory, and effector memory T cells and in engineered tumor antigen-specific cytotoxic T lymphocytes, while antigen-specific cell lysis was unaffected. Inhibition of complement C3 activation and PMN effector functions, including CR3 signaling, protein synthesis, and vesicular trafficking, abrogated the PMN suppressor phenotype. Moreover, malignant effusions from patients with various metastatic cancers also induced the C3-dependent PMN suppressor phenotype. These results point to PMN impairing T cell expansion and activation in the TME and the potential for complement inhibition to abrogate this barrier to antitumor immunity.
Topics: Aged; CD28 Antigens; Cell Proliferation; Complement C3; Cytokines; Female; Granulocytes; Humans; Immunity; Lymphocyte Activation; Muromonab-CD3; Myeloid-Derived Suppressor Cells; Neutrophils; Ovarian Neoplasms; T-Lymphocytes; Tumor Microenvironment
PubMed: 30730851
DOI: 10.1172/jci.insight.122311 -
Digestive Diseases and Sciences Oct 1991Liver rejection in the era of cyclosporine-based immunosuppression is approximately 60-70%. Approximately 15-25% of liver transplant patients will require hemodialysis... (Review)
Review
Liver rejection in the era of cyclosporine-based immunosuppression is approximately 60-70%. Approximately 15-25% of liver transplant patients will require hemodialysis following transplantation. These facts argue for a potent, less nephrotoxic immunosuppressive regimen, especially during the period of vulnerability to these events. Prophylactic use of OKT3 has been suggested as a means to decrease the need for hemodialysis while maintaining potent immunosuppression. The goal of this review is to examine potential benefits and pitfalls of this regimen. A lack of documentation of long-term patient and graft survival, the potential susceptibility to infectious complications, development of sensitization, and the cost must be weighed against the decreased need for hemodialysis and the control of early rejection episodes.
Topics: Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Incidence; Infections; Liver Transplantation; Muromonab-CD3; Renal Dialysis
PubMed: 1914765
DOI: 10.1007/BF01296810 -
SLAS Discovery : Advancing Life... Jul 2020Immunotherapies including PD-L1 blockade have shown remarkable increases in the T cell-directed antitumor response; however, efficacy is seen only in a minority of...
Immunotherapies including PD-L1 blockade have shown remarkable increases in the T cell-directed antitumor response; however, efficacy is seen only in a minority of patients. Recently, pooled CRISPR-Cas9 knockout (CRISPRn) screens in tumor/immune co-culture systems have identified a number of genes that confer resistance to T cell killing in pathways including antigen presentation and cytokine signaling, providing insight into tumor mechanisms that cause resistance to immunotherapies. The development of an arrayed CRISPRn screen in a tumor/immune co-culture system would allow the identification of novel targets for immuno-oncology, characterization of hits from pooled screens, and multiple assay endpoints to be measured per gene. Here, a small-scale arrayed CRISPRn screen was successfully developed to investigate the effects on a co-culture of T cells and Cas9-expressing PC9 lung adenocarcinoma cells modified to express anti-CD3 antibody on the cell surface (PC9-OKT3 T cell system). A focused CRISPRn library was designed to target genes involved in known resistance mechanisms (including antigen presentation, cytokine signaling, and apoptosis) as well as genes involved in immune synapse interactions. The viability of PC9 cells was assessed in two-dimensional adherent co-cultures via longitudinal imaging analysis. Knockout of epidermal growth factor receptor (EGFR) and PLK1 in tumor cells cultured alone or with T cells resulted in increased tumor cell death, as expected, whereas knockout of the test gene ICAM1 showed subtle donor-specific resistance to T cell killing. Taken together, these data provide proof of concept for arrayed CRISPRn screens in tumor/immune co-culture systems and warrant further investigation of in vitro co-culture models.
Topics: Adenocarcinoma of Lung; Antibodies, Anti-Idiotypic; B7-H1 Antigen; CRISPR-Cas Systems; Cell Cycle Proteins; Cell Line, Tumor; Coculture Techniques; Drug Screening Assays, Antitumor; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors; Muromonab-CD3; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; T-Lymphocytes; Polo-Like Kinase 1
PubMed: 32375580
DOI: 10.1177/2472555220916457 -
Protein & Cell Jul 2017The generation of T cells with maximal anti-tumor activities will significantly impact the field of T-cell-based adoptive immunotherapy. In this report, we found that...
The generation of T cells with maximal anti-tumor activities will significantly impact the field of T-cell-based adoptive immunotherapy. In this report, we found that OKT3/IL-2-stimulated T cells were phenotypically more heterogeneous, with enhanced anti-tumor activity in vitro and when locally administered in a solid tumor mouse model. To further improve the OKT3/IL-2-based T cell manufacturing procedure, we developed a novel T cell stimulation and expansion method in which peripheral blood mononuclear cells were electroporated with mRNA encoding a chimeric membrane protein consisting of a single-chain variable fragment against CD3 and the intracellular domains of CD28 and 4-1BB (OKT3-28BB). The expanded T cells were phenotypically and functionally similar to T cells expanded by OKT3/IL-2. Moreover, co-electroporation of CD86 and 4-1BBL could further change the phenotype and enhance the in vivo anti-tumor activity. Although T cells expanded by the co-electroporation of OKT3-28BB with CD86 and 4-1BBL showed an increased central memory phenotype, the T cells still maintained tumor lytic activities as potent as those of OKT3/IL-2 or OKT3-28BB-stimulated T cells. In different tumor mouse models, T cells expanded by OKT3-28BB RNA electroporation showed anti-tumor activities superior to those of OKT3/IL-2 T cells. Hence, T cells with both a less differentiated phenotype and potent tumor killing ability can be generated by RNA electroporation, and this T cell manufacturing procedure can be further optimized by simply co-delivering other splices of RNA, thus providing a simple and cost-effective method for generating high-quality T cells for adoptive immunotherapy.
Topics: Animals; CD28 Antigens; Electroporation; Humans; Immunity, Cellular; Interleukin-2; K562 Cells; Mice; Muromonab-CD3; Neoplasms, Experimental; RNA, Messenger; T-Lymphocytes; Tumor Necrosis Factor Receptor Superfamily, Member 9
PubMed: 28523432
DOI: 10.1007/s13238-017-0422-6 -
Chinese Journal of Cancer Jun 2012Establishing Epstein-Barr virus(EBV)-specific cytolytic T lymphocytes(EBV-CTLs) from peripheral blood mononuclear cells(PBMCs) for adoptive immunotherapy has been...
Establishing Epstein-Barr virus(EBV)-specific cytolytic T lymphocytes(EBV-CTLs) from peripheral blood mononuclear cells(PBMCs) for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma(NPC). In the current study, we performed ex vivo expansion of tumor-infiltrating lymphocytes(TILs) obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody(OKT3), recombinant human interleukin(IL)-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+ T cells, a variable percentage of CD3+CD8+ and CD3+CD4+ T cells, and less than 10% of CD3-CD16+ natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ) and tumor necrosis factor-alpha (TNF-α), and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.
Topics: Biopsy; CD3 Complex; CD4 Antigens; CD8 Antigens; Cells, Cultured; Herpesvirus 4, Human; Humans; Immunotherapy, Adoptive; Interferon-gamma; Interleukin-10; Interleukin-2; Interleukin-4; Lymphocytes, Tumor-Infiltrating; Monocytes; Muromonab-CD3; Nasopharyngeal Neoplasms; Receptors, IgG; T-Lymphocytes, Cytotoxic; Tumor Necrosis Factor-alpha
PubMed: 22257383
DOI: 10.5732/cjc.011.10376 -
Medecine Sciences : M/S Dec 2009Monoclonal antibodies are a specific medicinal category within the current therapeutic armamentarium. Their market share is growing fast as they are often the only... (Review)
Review
Monoclonal antibodies are a specific medicinal category within the current therapeutic armamentarium. Their market share is growing fast as they are often the only therapeutic option at some stages of certain diseases, due to their targeted action in the body and to an acceptable tolerance. The budget impact of monoclonal antibodies is increasing, leading payers and health authorities to growing attention and pressure when they have to decide on the reimbursement, coverage and pricing of these products. The launch of biosimilars after patent expiry of some of these drugs will take time in view of the complexity of these molecules, and is not likely to significantly impact the cost of these therapies.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Budgets; Denosumab; Drug Costs; Drug Industry; Drug Utilization; Europe; Health Care Sector; Humans; Insurance, Health, Reimbursement; Muromonab-CD3; Patents as Topic; RANK Ligand; United States
PubMed: 20035702
DOI: 10.1051/medsci/200925121177 -
Immunology Dec 200512F6 is a murine anti-human CD3 monoclonal antibody, which competes with OKT3 for binding to human T cells and possesses more effective T-cell suppression and activation...
12F6 is a murine anti-human CD3 monoclonal antibody, which competes with OKT3 for binding to human T cells and possesses more effective T-cell suppression and activation properties compared to OKT3. It thus exhibits the potential to be developed as an immunoregulation agent for manipulating T-cell functions and preventing acute allograft rejection. In an attempt to minimize the immunogenicity of murine 12F6 (m12F6) for potential clinical application, a humanized version of 12F6, denoted as hu12F6, was successfully constructed by complementary determining region (CDR) grafting and shown to maintain both T-cell activation and suppression activities similar to m12F6. Furthermore, in order to reduce the first dose reaction syndrome caused by T-cell activation following the first administration of anti-CD3 antibodies, two amino acid mutations were introduced into the Fc region of hu12F6, resulting in the Fc-mutated 12F6 humanized antibody (hu12F6mu). This Fc-mutated version displayed a similar antigen-binding affinity and specificity compared with hu12F6 and m12F6 but with much weaker FcR binding activity. hu12F6mu was shown to be much less potent in the induction of T-cell proliferation, cytokine release (tumour necrosis factor-alpha, interferon-gamma and interleukin-10) and early activation marker expression on the cell surface (CD69 and CD25) than parental 12F6 and OKT3 did. In contrast, hu12F6mu was effective in modulating T-cell receptor/CD3 and inhibiting mixed lymphocyte reaction with a similarity as compared to m12F6 and OKT3. In conclusion, the resultant hu12F6mu was much less mitogenic to T cells but retained potent immunosuppression, suggesting it might be an alternative to OKT3 as an immunosuppressive drug with less immunogenicity and toxicity for clinical application.
Topics: Amino Acid Sequence; Animals; Antibodies, Monoclonal; Antibody Affinity; Binding, Competitive; CD3 Complex; Cell Proliferation; Cells, Cultured; Cytokines; Humans; Immune Tolerance; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Mice; Molecular Sequence Data; Muromonab-CD3; Receptors, Fc; Recombinant Fusion Proteins; T-Lymphocytes
PubMed: 16313362
DOI: 10.1111/j.1365-2567.2005.02247.x -
HPB : the Official Journal of the... Sep 2011Conventional chemotherapy and radiotherapy produce marginal survival benefits in pancreatic cancer, underscoring the need for novel therapies. The aim of this study is...
OBJECTIVE
Conventional chemotherapy and radiotherapy produce marginal survival benefits in pancreatic cancer, underscoring the need for novel therapies. The aim of this study is to develop an adoptive T cell transfer approach to target tumours expressing prostate stem cell antigen (PSCA), a tumour-associated antigen that is frequently expressed by pancreatic cancer cells.
METHODS
Expression of PSCA on cell lines and primary tumour samples was confirmed by immunohistochemistry. Healthy donor- and patient-derived T cells were isolated, activated in vitro using CD3/CD28, and transduced with a retroviral vector encoding a chimeric antigen receptor (CAR) targeting PSCA. The ability of these cells to kill tumour cells was analysed by chromium-51 (Cr(51)) release.
RESULTS
Prostate stem cell antigen was expressed on >70% of the primary tumour samples screened. Activated, CAR-modified T cells could be readily generated in clinically relevant numbers and were specifically able to kill PSCA-expressing pancreatic cancer cell lines with no non-specific killing of PSCA-negative target cells, thus indicating the potential efficacy and safety of this approach.
CONCLUSIONS
Prostate stem cell antigen is frequently expressed on pancreatic cancer cells and can be targeted for immune-mediated destruction using CAR-modified, adoptively transferred T cells. The safety and efficacy of this approach indicate that it deserves further study and may represent a promising novel treatment for patients with pancreatic cancer.
Topics: Antigens, Neoplasm; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cytotoxicity, Immunologic; Feasibility Studies; GPI-Linked Proteins; Genetic Therapy; HEK293 Cells; Humans; Immunohistochemistry; Immunotherapy, Adoptive; Lymphocyte Activation; Muromonab-CD3; Neoplasm Proteins; Pancreatic Neoplasms; Receptors, Antigen, T-Cell; Single-Chain Antibodies; T-Lymphocytes; Time Factors; Transduction, Genetic; Up-Regulation
PubMed: 21843265
DOI: 10.1111/j.1477-2574.2011.00344.x -
Journal of Enzyme Inhibition and... Dec 2021Recent findings have shown that nanovesicles preparations from either primary immune cells culture supernatants or plasma contain immunoglobulins, suggesting that a...
Recent findings have shown that nanovesicles preparations from either primary immune cells culture supernatants or plasma contain immunoglobulins, suggesting that a natural way of antibody production may be through exosome release. To verify this hypothesis, we used the OKT3 hybridoma clone, which produces a murine IgG2a monoclonal antibody used to reduce rejection in patients undergoing organ transplantation. We showed exosome-associated immunoglobulins in hybridoma supernatants, by Western blot, nanoscale flow cytometry and immunocapture-based ELISA. The OKT3-exo was also being able to trigger cytokines production in both CD4 and CD8 T cells. These results show that nanovesicles contain immunoglobulin and could be used for immunotherapy. These data could lead to a new approach to improve the effectiveness of therapeutic antibodies by exploiting their natural property to be expressed on nanovesicle membrane, that probably render them more stable and as a consequence more capable to interact with their specific ligand in the best way.
Topics: Animals; Antigens, Surface; B-Lymphocytes; CD3 Complex; Cell Line, Tumor; Cytokines; Exosomes; Gene Expression; Humans; Hybridomas; Immunoglobulin G; Lymphocyte Activation; Macrophages; Mice; Multiple Myeloma; Muromonab-CD3; Neoplasms, Experimental; Primary Cell Culture; Spleen; T-Lymphocytes
PubMed: 33404266
DOI: 10.1080/14756366.2020.1852401