• In these pioneering studies by Steven Rosenberg, tumour-infiltrating lymphocytes (TILs) were isolated from patients with melanoma, then activated and expanded before reinfusion into the patients. (nature.com)
  • Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. (nwbio.com)
  • Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown activity in melanoma, but has not been previously evaluated in metastatic non-small cell lung cancer. (nature.com)
  • In contrast to other cancers such as adenocarcinomas of the lung or melanoma, primary brain tumors like GB and low grade gliomas (LGG) are known as rather immunologically "cold" tumors, typically with low numbers of tumor-infiltrating lymphocytes (TILs) ( 4 ), and the mere amount of TILs is not associated with patient survival ( 5 ). (frontiersin.org)
  • Activation-induced cell death of human melanoma specific cytotoxic T lymphocytes is mediated by apoptosis-inducing factor. (uchc.edu)
  • Rescuing melanoma epitope-specific cytolytic T lymphocytes from activation-induced cell death, by SP600125, an inhibitor of JNK: implications in cancer immunotherapy. (uchc.edu)
  • Activated γδ T cells exhibit strong cytotoxic activity and cytokine secretion functions and are effective antitumor lymphocytes with simple and direct recognition modes and rapid responses. (explorationpub.com)
  • They combined the variable region of an antibody with the constant regions of the TCR chains, thus producing chimeric antigen receptors (CARs) that provided T cells with antibody-type specificity. (nature.com)
  • However, this complex alone is insufficient to trigger productive T cell responses, which require the concomitant engagement of co-stimulatory receptors. (nature.com)
  • NK cells express germ-line receptors that are either stimulatory or inhibitory, and the summation of these signals determines activation status ( Caligiuri, 2008 ). (elifesciences.org)
  • Adoptive cell therapy using engineered T-cell receptors (TCRs) targeting cancer-testis antigens, such as Melanoma-associated antigen 3 (MAGE-A3), is a potential approach for the treatment of NSCLC. (thno.org)
  • Autologous as well as allogeneic CD8 + T cells transduced with tumor antigen specific T cell receptors (TCR) may cause significant tumor lysis upon adoptive transfer. (oncotarget.com)
  • NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. (frontiersin.org)
  • Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. (frontiersin.org)
  • Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). (biomedcentral.com)
  • Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have several potential target oncogenes for molecularly targeted therapy, such as tyrosine kinase inhibitors. (biomedcentral.com)
  • Alternative inhibitory receptors have been identified that may also be targeted for anti-tumor immune therapy. (biomedcentral.com)
  • These include the T cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene-3 (LAG-3), TIGIT, and B-and T-lymphocyte-associated protein (BTLA) receptors associated with T cell exhaustion and V-domain immunoglobulin suppressor of T cell activation (VISTA), a receptor found on tumor-infiltrating myeloid cells. (biomedcentral.com)
  • In the first published gene therapy clinical trial, TILs engineered to express a foreign gene with a retrovirus to mark the infused cells were safely transferred to patients. (nature.com)
  • However, although treatment with TILs was effective in some tumours (such as melanoma), the lack of specificity and the difficulty in recruiting TILs from most other cancer types compromised the therapeutic potential. (nature.com)
  • We conducted a single-arm open-label phase 1 trial ( NCT03215810 ) of TILs administered with nivolumab in 20 patients with advanced non-small cell lung cancer following initial progression on nivolumab monotherapy. (nature.com)
  • Autologous TILs were expanded ex vivo from minced tumors cultured with interleukin-2. (nature.com)
  • Cell therapy with autologous TILs is generally safe and clinically active and may constitute a new treatment strategy in metastatic lung cancer. (nature.com)
  • Interleukin-2 (IL-2) expanded TILs had the predominant CD8 + phenotype and the capacity to lyse cells of the cultured autologous tumour. (tmu.edu.tw)
  • The availability of the soft tissue melanoma cell line, the SCID mouse xenograft tumour system as well as autologous TILs described herein would provide useful materials for identifying T-cell-defined antigens as well as a model system for devising individualised cancer biotherapeutic strategies. (tmu.edu.tw)
  • Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. (elifesciences.org)
  • Here, we describe the pre-clinical in vitro and in vivo study of irradiated haNK cells engineered to express a second-generation chimeric antigen receptor (CAR) targeting programmed death-ligand 1 (PD-L1). (elifesciences.org)
  • [ 2 ] Options for second-line therapy in patients with relapsed/refractory disease include chemotherapy-free regimens with biologic targeted agents such as covalent Bruton tyrosine kinase (BTK) inhibitors, lenalidomide,venetoclax, and chimeric antigen receptor (CAR) T-cell therapy. (medscape.com)
  • In 2006, Rosenberg and colleagues transferred TCR T cells specifically recognizing the melanoma antigen MART-1 in 15 patients, two of whom achieved regression and still showed high levels of engineered cells in circulation one year after the infusion. (nature.com)
  • Other successful studies quickly followed, such as those demonstrating sustained complete and partial responses in patients with melanoma and treatment of synovial cell sarcoma with TCR T cells against the NY-ESO-1 antigen. (nature.com)
  • Banchereau J, Ueno H, Dhodapkar M, Connolly J, Finholt JP, Klechevsky E, Blanck JP, Johnston DA, Palucka AK, Fay J. Immune and clinical outcomes in patients with stage IV melanoma vaccinated with peptide-pulsed dendritic cells derived from CD34+ progenitors and activated with type I interferon. (nwbio.com)
  • Activation induced cell death (AICD) of human melanoma antigen-specific TCR engineered CD8 T cells involves JNK, Bim and p53. (uchc.edu)
  • Death receptor-independent activation-induced cell death in human melanoma antigen-specific MHC class I-restricted TCR-engineered CD4 T cells. (uchc.edu)
  • CD4+CD25- T cells transduced to express MHC class I-restricted epitope-specific TCR synthesize Th1 cytokines and exhibit MHC class I-restricted cytolytic effector function in a human melanoma model. (uchc.edu)
  • Silencing of endogenous IL-10 in human dendritic cells leads to the generation of an improved CTL response against human melanoma associated antigenic epitope, MART-1 27-35. (uchc.edu)
  • The establishment and characterisation of paired autologous tumour cell line (MST-1) and tumour-infiltrating lymphocyte (TIL) culture from a tumour mass of a 14-year-old Taiwanese girl with soft tissue melanoma are described. (tmu.edu.tw)
  • Immunostaining revealed that major melanoma-associated antigens, such as S100 protein, HMB-45, melanotransferrin, chondroitin sulphate proteoglycan, and the gangliosides GD2 and GD3, were consistently expressed by the tumour tissue, severe combined immunodeficiency (SCID) mouse xenograft and derived cell lines. (tmu.edu.tw)
  • This observation and the expression of the major melanoma-associated antigens were all indicative of the melanocytic origin of MST-1 tumour. (tmu.edu.tw)
  • Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. (nwbio.com)
  • Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. (nwbio.com)
  • Phase I/II study of vaccination with electrofused allogeneic dendritic cells/autologous tumor-derived cells in patients with stage IV renal cell carcinoma. (nwbio.com)
  • Large-scale immunomagnetic selection of CD14+ monocytes to generate dendritic cells for cancer immunotherapy: a phase I study. (nwbio.com)
  • Babatz J, Röllig C, Löbel B, Folprecht G, Haack M, Günther H, Köhne CH, Ehninger G, Schmitz M, Bornhäuser M. Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells. (nwbio.com)
  • Maturation and trafficking of monocyte-derived dendritic cells in monkeys: implications for dendritic cell-based vaccines. (nwbio.com)
  • Vaccination of prostatectomized prostate cancer patients in biochemical relapse, with autologous dendritic cells pulsed with recombinant human PSA. (nwbio.com)
  • Bleumer I, Tiemessen DM, Oosterwijk-Wakka JC, Völler MC, De Weijer K, Mulders PF, Oosterwijk E. Preliminary analysis of patients with progressive renal cell carcinoma vaccinated with CA9-peptide-pulsed mature dendritic cells. (nwbio.com)
  • Antigen presentation by MART-1 adenovirus-transduced interleukin-10-polarized human monocyte-derived dendritic cells. (uchc.edu)
  • MST-1 cells grown in vitro were heterogeneous in morphology, ranging from floating round cells, loosely attached round/oval or elongated cells with prominent pseudopod-like processes, to well-attached spindle and elongated dendritic cells without obvious pseudopods. (tmu.edu.tw)
  • Although immune checkpoint blockade (ICB) reinvigorates anti-tumor immune responses by disrupting co-inhibitory T-cell signaling, relapse frequently occurs after ICB treatment and acquired resistance often emergence after initial response [ 4 ]. (thno.org)
  • Adoptive cell therapies (ACT) leverage this cytotoxic capacity of T cells to eradicate tumours. (nature.com)
  • T cell-based immunotherapy, such as immune checkpoint blockade or adoptive T cell transfer, is limited by the ability of T cells to detect major histocompatibility complex (MHC)-presented antigen by tumor cells. (elifesciences.org)
  • Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo . (frontiersin.org)
  • Finally, it retrospectively analyze the activation strategies and clinical relevance of existing γδ T cell adoptive immunotherapies. (explorationpub.com)
  • Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. (bvsalud.org)
  • Statistical and machine-learning based analyses demonstrated that the MAGE-A3-Mp4 epitope-specific CD8+ T cell clones were mostly in effector and proliferating state. (thno.org)
  • Knockdown of T-bet expression in Mart-127-35 -specific T-cell-receptor-engineered human CD4(+) CD25(-) and CD8(+) T cells attenuates effector function. (uchc.edu)
  • Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. (elifesciences.org)
  • The T cells expressing CARs recognized and eliminated target cells, and produced interleukin 2 in the presence of the antigen, providing a proof of concept that this approach triggers a cellular immune response. (nature.com)
  • In 2010, James Kochenderfer and colleagues achieved a breakthrough with a CAR T cell therapy, reporting tumour regression in a patient with advanced follicular lymphoma, who received two infusions of autologous T cells genetically engineered to express a CAR specifically recognizing the antigen CD19 expressed on B cells. (nature.com)
  • The finding that CAR T cells had activity in patients advanced the field of ACT, which saw dramatic progress in the following years and remarkable results in B-cell malignancies, including paediatric and adult acute lymphoblastic leukaemia (ALL), aggressive B cell lymphomas, chronic lymphocytic leukaemia and multiple myeloma treated with CD19 CAR T cells. (nature.com)
  • In 2017, two studies - the phase II ZUMA-1 trial led by Sattva Neelapu and a case-series study led by Carl June - validated the efficacy of CD19 CAR T cells in patients with refractory B-cell leukaemia and lymphoma. (nature.com)
  • Later that year, CD19 CAR T cells received US FDA approval for the treatment of children with ALL and adults with aggressive lymphomas. (nature.com)
  • Another ACT developed in parallel to CAR T cells is engineering T cells to express TCRs that recognize tumour-associated antigens. (nature.com)
  • In this study, we comprehensively screened HLA-A2 restricted MAGE-A3 tumor epitopes and characterized the corresponding TCRs using in vitro artificial antigen presentation cells (APC) system, single-cell transcriptome and TCR V(D)J sequencing, and machine-learning. (thno.org)
  • Furthermore, the tumor-reactive TCRs with killing potency was screened and verified. (thno.org)
  • Importantly, T cells artificially expressing the MAGE-A3-Mp4 specific TCRs exhibited strong MAGE-A3+ tumor cell recognition and killing effect. (thno.org)
  • This work identified candidate TCRs potentially suitable for TCR-T design targeting HLA-A2 restricted MAGE-A3 tumor antigen. (thno.org)
  • Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. (elifesciences.org)
  • PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. (elifesciences.org)
  • Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. (elifesciences.org)
  • According to current challenges, there is a need to explore innovative immunotherapies, maximize the tumor-killing efficacy of γδ T cells, and attenuate or eliminate tumor immunosuppression. (explorationpub.com)
  • Physiologic recognition of tumour antigens by T cells is mediated by the TCR-CD3 complex. (nature.com)
  • Natural killer (NK) cell-based immunotherapy may overcome genetic mechanisms of resistance to T cell-based immunotherapy through antigen- and MHC-independent recognition of malignant cells. (elifesciences.org)
  • After TCR identification, we generated HLA-A*02:01/peptide restricted TCR transgenic T cells by retroviral transduction and tested T cell expansion rates as well as A*02:01/peptide recognition and ES killing in ELISpot and xCELLigence assays. (oncotarget.com)
  • TCR transgenic T cells demonstrated HLA-A*02:01/ADRB3 295 mediated ES recognition and killing in ELISpot and xCELLigence assays. (oncotarget.com)
  • Neoantigen-reactive T cell clonotypes increased and persisted in peripheral blood after treatment. (nature.com)
  • Flow cytometric analysis of the tumour DNA content showed an index of 1.8 relative to normal peripheral blood lymphocyte DNA. (tmu.edu.tw)
  • Inhibition of superoxide generation upon T-cell receptor engagement rescues Mart-1(27-35)-reactive T cells from activation-induced cell death. (uchc.edu)
  • These cells may be a key factor ultimately mediating the deviation of the antagonistic response between tumor inhibition and tumor promotion. (explorationpub.com)
  • Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. (bvsalud.org)
  • TRV-β sequencing of tumor and peripheral T cells as the project 'TIL trial for NSCLC' are available in the immuneACCESS free public database at https://clients.adaptivebiotech.com/immuneaccess . (nature.com)
  • Advanced non-small cell lung cancer (NSCLC) is the most common type of lung cancer with poor prognosis. (thno.org)
  • A cohort of HLA-A2+ NSCLC donors demonstrated that the number of epitope specific CD8+ T cells increased in NSCLC than healthy controls when measured with tetramer derived from the candidate MAGE-A3 epitopes, especially epitope Mp4 (MAGE-A3: 160-169, LVFGIELMEV). (thno.org)
  • Non-small cell lung cancer (NSCLC), the most common subtype, comprised approximately 85% of the newly diagnosed lung cancer cases [ 2 ]. (thno.org)
  • BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). (bvsalud.org)
  • Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). (bvsalud.org)
  • Glioblastoma (GB) is the most frequent malignant primary brain tumor in adults, without any curative treatment options available at present. (frontiersin.org)
  • Treatment selection takes into account patient age, fitness, and whether autologous stem cell transplantation (ASCT) is planned. (medscape.com)
  • Dendritic cell immunotherapy for patients with metastatic renal cell carcinoma: University of Tokyo experience. (nwbio.com)
  • We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients. (frontiersin.org)
  • To view a multidisciplinary tumor board case discussion, see Memorial Sloan Kettering e-Tumor Boards: Metastatic Clear Cell Renal Cell Carcinoma . (medscape.com)
  • Surgical resection remains the only known effective treatment for localized renal cell carcinoma, and it also is used for palliation in metastatic disease. (medscape.com)
  • Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses. (nwbio.com)
  • In 2002, Michel Sadelain and colleagues optimized CAR design by integrating the intracellular domains of TCR and the key co-stimulatory receptor CD28 within a single molecule to help sustain T cell expansion, function and persistence. (nature.com)
  • The primary end point was safety and secondary end points included objective response rate, duration of response and T cell persistence. (nature.com)
  • In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. (bvsalud.org)
  • However, systematic analysis of T cell immune responses to MAGE-A3 antigen and corresponding antigen-specific TCR is still lacking. (thno.org)
  • Suppression of inducible CD4 regulatory cells by MHC class I-restricted human tumor epitope specific TCR engineered multifunctional CD4 T cells. (uchc.edu)
  • Addeo, A., Banna, G. L., Metro, G. & Di Maio, M. Chemotherapy in combination with immune checkpoint inhibitors for the first-line treatment of patients with advanced non-small cell lung cancer: a systematic review and literature-based meta-analysis. (nature.com)
  • Fig. 3: Examples of complete responses mediated by TIL-recognizing tumor antigens. (nature.com)
  • The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. (oncotarget.com)
  • This was the first clinical use of TCR T cell therapy, and although initial studies had demonstrated the feasibility and safety of introducing engineered T cells in patients, this trial also showed their remarkable efficiency. (nature.com)
  • In exploratory analyses, we found T cells recognizing multiple types of cancer mutations were detected after TIL treatment and were enriched in responding patients. (nature.com)
  • Fig. 4: Summary of tumor-specific antigens tested for all patients. (nature.com)
  • Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. (frontiersin.org)
  • T cells, which can efficiently identify and kill infected cells, can also kill cancer cells if they recognize them. (nature.com)
  • In 1989, Zelig Eshhar and colleagues realized that the inability of T cells to recognize surface tumour antigens could be overcome by replacing domains of the T cell receptor (TCR) with antibody parts with specificity towards proteins on these cells. (nature.com)
  • Taking advantage of the diverse γδ TCR repertoire or other ligand-receptor interactions, γδ T cells can recognize a broad spectrum of tumor-associated antigens (TAAs) in a major histocompatibility complex (MHC)-independent manner, thereby activating downstream pleiotropic effects. (explorationpub.com)
  • Mantle cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive pregerminal center cells localized in primary follicles or in the mantle region of secondary follicles. (medscape.com)
  • Mantle cell lymphoma (MCL) is recognized in the Revised European-American Lymphoma and World Health Organization classifications as a distinct clinicopathologic entity. (medscape.com)
  • Other similar second-generation CARs subsequently emerged, incorporating different co-stimulatory domains, such as 4-1BB, which Crystal Mackall and colleagues showed can decrease the T cell exhaustion induced by continuous CAR signalling, thereby improving antitumour efficacy. (nature.com)
  • Two courses of four weekly infusions of rituximab with or without interferon-2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas. (cancercentrum.se)
  • it was frequently categorized as diffuse small-cleaved cell lymphoma (by the International Working Formulation) or centrocytic lymphoma (by the Kiel classification). (medscape.com)
  • The therapeutic approach to renal cell carcinoma (RCC) is guided by the probability of cure, which is related directly to the stage or degree of tumor dissemination. (medscape.com)
  • Go to Renal Cell Carcinoma Treatment Protocols , Clear Cell Renal Cell Carcinoma , and Sarcomatoid and Rhabdoid Renal Cell Carcinoma for complete information on these topics. (medscape.com)
  • We identified HLA-A*02:01/peptide-restricted T cells directed against ADRB3 295 . (oncotarget.com)
  • Comparison of peptide motive binding affinities revealed extended fratricide among ADRB3 295 specific TCR transgenic T cells in contrast to CHM1 319 . (oncotarget.com)
  • We identified the HLA-A2 restricted T cell epitopes from MAGE-A3 that could effectively induce the activation and cytotoxicity of CD8+ T cells using artificial APC in vitro . (thno.org)
  • Transcriptomic profiling of T-cell populations in non-muscle invasive and muscle invasive bladder cancer. (lu.se)
  • Described here are some of the general requirements of in vitro test methods for skin sensitization, and progress that has been made in developing suitable approaches with particular emphasis on the utility of dendritic cell culture systems. (cdc.gov)
  • In this review, we use the Heilig nomenclature to describe human γδ T cells [ 1 ]. (explorationpub.com)
  • Fig. 5: Change in phenotype and genotype of peripheral T cells after TIL infusion. (nature.com)