• In 2016, CD19-specific chimeric antigen receptor (CAR)-modified T cells were used to treat patients with relapsed and refractory CD19+ B cell malignancies, including B cell acute lymphoblastic leukemia (B-ALL) harboring rearrangement of the mixed lineage leukemia (MLL) gene with CD19 CAR-T cells. (wikipedia.org)
  • We have previously determined the structure of the MHC class I molecule HLA-A1 bound to a melanoma antigen-encoding gene (MAGE)-A1-derived peptide in complex with a recombinant antibody fragment with TCR-like specificity, Fab-Hyb3. (rcsb.org)
  • In 2006 administration of normal circulating lymphocytes transduced with a retrovirus encoding a T-cell receptor (TCR) that recognized the MART-1 melanoma-melanocyte antigen, mediated tumor regression. (wikipedia.org)
  • 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)
  • Infection of a panel of human melanoma cell lines by AdCMVMAGE-1, a novel recombinant adenovirus which incorporates the full-length MAGE-1 cDNA, was shown to induce production of high levels of MAGE-1 protein. (illinois.edu)
  • Incubation of transduced HLA-AI expressing melanoma cell lines with 2 anti-MAGE-1.A1 CTL clones resulted in specific recognition and lysis of target cells, indicating that the exogenous MAGE-1 protein was processed and presented in a normal manner. (illinois.edu)
  • Importantly for future clinical trials, stimulation of peripheral blood lymphocytes (PBLs) from a melanoma patient by AdCMVMAGE- 1-transduced autologous cells resulted in the generation of specific CTLs against the MAGE-1 antigen. (illinois.edu)
  • 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)
  • Variable inter- and intra-tumoral antigen expression was observed in human melanoma tumor samples as shown by heterogenous antigen expression of PRAME and MAGEC2 that varied from cell to cell within the same tumor. (nationalstemcelltherapy.com)
  • To this aim, non-self-antigens derived from microorganisms (MoAs) may be of great benefit. (biomedcentral.com)
  • On the contrary, TAAs are wild-type self-antigens highly expressed on tumor cells compared to corresponding normal cells. (biomedcentral.com)
  • Indeed, they are abundantly accessible natural non-self-antigens, which do not need any manipulation for improving antigenity or immunogenicity. (biomedcentral.com)
  • Cancer cells can be recognized by mutated or viral antigens expressed only in the tumor, or self-antigens normally expressed during embryonic development and in non-somatic adult tissues. (akampion.com)
  • The ability to identify potent cancer-specific TCRs has been limiting for the field of TCR-T. In the case of self-antigens, T cells bearing those TCRs are eliminated during T cell development to avoid recognition and attack of healthy tissues. (akampion.com)
  • The TCRs from HuTCR mice are of higher affinity for tumor self-antigens than TCRs isolated from human donors and are naturally optimized to maintain a high specificity profile, making HuTCR mice a powerful high-throughput platform for rapidly generating TCRs with best-in-class potential. (akampion.com)
  • Regulation of immunities and maintenance of tolerance to self-antigens are critical to keep health. (creative-biolabs.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)
  • Importantly, T cells artificially expressing the MAGE-A3-Mp4 specific TCRs exhibited strong MAGE-A3+ tumor cell recognition and killing effect. (thno.org)
  • Cross-reactivity risk analysis of the candidates TCRs showed high binding stability to MAGE-A3-Mp4 epitope and low risk of cross-reaction. (thno.org)
  • This work identified candidate TCRs potentially suitable for TCR-T design targeting HLA-A2 restricted MAGE-A3 tumor antigen. (thno.org)
  • These initial preclinical results suggest that multiplexing TCRs has the potential to overcome both tumor antigen heterogeneity and HLA loss-of-heterozygosity (LOH). (nationalstemcelltherapy.com)
  • Non-small cell lung cancer (NSCLC) samples showed wide prevalence of clonal and partial HLA LOH of the HLA-A*02:01 allele occurring in ~40% of NSCLC samples indicating that these tumors would not have responded to single TCRs targeting HLA-A*02:01 epitopes. (nationalstemcelltherapy.com)
  • To do this, they use their T-cell receptors (TCRs) to scan the surface of other cells for foreign antigens presented on Human Leukocyte Antigen (HLA) complexes. (akampion.com)
  • Genetic engineering of T cells with TCRs recognizing antigens aberrantly or over-expressed in cancers can redirect these T cells to the tumor, potentially offering curative responses to cancer patients. (akampion.com)
  • Immunizing HuTCR mice with human tumor antigens, for which mice are not tolerant, allows for the identification of both CD4+ and CD8+ T cells with TCRs that have optimized affinity / specificity profiles capable of mediating significant anti-tumor activity. (akampion.com)
  • They are using high-throughput strategies to identify and generate native high-affinity TCRs from multiple donors to target 'cancer-testis antigens' that are expressed on various cancers but not on normal tissues (except for male germ cells in adults). (fredhutch.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)
  • 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)
  • Through ReceptorScan, we identified TSC-200-A02 that targets an HLA-A*02:01 restricted epitope of HPV16-E7 and with TargetScan we identified TSC-204-C07 targeting a novel HLA-C*07:02 restricted epitope of MAGE-A1. (nationalstemcelltherapy.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)
  • Dr. Chapuis and colleagues established a platform for developing gene-modified adoptive T cell therapies targeting an array of tumor antigens in solid and liquid tumors. (fredhutch.org)
  • Therefore, conformational changes within the HLA-A1:MAGE-A1:Fab-Hyb3 complex include MHC residues that are also involved in reorientations in complexes with natural ligands, pointing to their central importance for the peptide-dependent recognition of MHC molecules. (rcsb.org)
  • We identified HLA-A*02:01/peptide-restricted T cells directed against ADRB3 295 . (oncotarget.com)
  • 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)
  • Inefficient exogenous loading of a tapasin-dependent peptide onto HLA-B*44:02 can be improved by acid treatment or fixation of target cells. (ox.ac.uk)
  • Here, we identify an antigenic peptide, which is derived from the MAGE-A1-encoded protein (160-169) and presented to CTLs by HLA-B*44:02. (ox.ac.uk)
  • Although this peptide is encoded by MAGE-A1, processed endogenously and presented by tumor cells, the corresponding synthetic peptide is hardly able to sensitize target cells to CTL recognition when pulsed exogenously. (ox.ac.uk)
  • Endogenous processing and presentation of this peptide is strictly dependent on the presence of tapasin, which is believed to help peptide loading by stabilizing a peptide-receptive form of HLA-B*44:02. (ox.ac.uk)
  • Either strategy allows efficient exogenous loading of the peptide, presumably by generating or stabilizing a peptide-receptive, empty conformation of the HLA. (ox.ac.uk)
  • In 2010 administration of lymphocytes genetically engineered to express a chimeric antibody receptor (CAR) against B cell antigen CD19 was shown to mediate regression of an advanced B cell lymphoma. (wikipedia.org)
  • The finding that many human melanomas express distinct antigens that can be recognised by specific cytolytic T lymphocytes (CTL) implies that immunotherapeutic strategies against this cancer might prove effective. (illinois.edu)
  • Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. (nwbio.com)
  • Peripheral blood lymphocytes (PBMC) and sera were collected at baseline, wk12, and wk24 to perform phenotypic and functional T cell assays, and to investigate humoral responses against a panel of tumor-associated antigens (TAAs) and soluble NKG2D ligands (sNKG2DL). (bmj.com)
  • Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. (nwbio.com)
  • Antigen presentation by MART-1 adenovirus-transduced interleukin-10-polarized human monocyte-derived dendritic cells. (uchc.edu)
  • Antigen gene transfer to cultured human dendritic cells using recombinant avipoxvirus vectors. (lookformedical.com)
  • Advances in understanding the role of dendritic cells (DCs) as the major antigen (Ag)-presenting cell type of the immune system combined with the recent development of methods for the ex vivo expansion of human DCs have opened the possibility for the transfer of tumor Ags to DCs with a view toward tumor immunotherapy. (lookformedical.com)
  • Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. (nwbio.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)
  • The vast majority of such strategies are based on tumor associated antigens (TAAs) which are shared wild type cellular self-epitopes highly expressed on tumor cells. (biomedcentral.com)
  • Antigen CD19 appears only on B cells, which go awry in lymphoma and leukemia. (wikipedia.org)
  • The ex vivo delivery of a tumour-associated antigen to autologous cells and the subsequent re-administration of these cells to the patient might prove effective in boosting the T cell immune response. (illinois.edu)
  • 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)
  • SafetyScan, an array-based screening technology for off-target reactivity, showed that TCR-200-A02-expressing CD3+ T cells did not cross-react with 108 out of 110 of the most common HLA types in the US population, allowing this TCR-T to be used in the vast majority of patients. (nationalstemcelltherapy.com)
  • Additionally, TCR-200-A02 showed no reactivity to normal cells from healthy HLA-A*02:01+ human donors, indicating no off-tumor reactivity risk. (nationalstemcelltherapy.com)
  • Circulating T cells reactive against NY-ESO-1, MART-1, gp100 and TYRP-1, were found in 12/23 pts expressing at least one of the HLA-A1, A2, -A3 or A24 alleles with induction or augmentation of TAA reactivity in the course of treatment. (bmj.com)
  • TCR transgenic T cells demonstrated HLA-A*02:01/ADRB3 295 mediated ES recognition and killing in ELISpot and xCELLigence assays. (oncotarget.com)
  • Amino-acid exchange scans clearly indicated the cross-reactive potential of HLA-A*02:01/ADRB3 295 - and HLA-A*02:01/CHM1 319 -TCR transgenic T cells. (oncotarget.com)
  • TSAs arise from cancer-related nonsynonymous mutations or other genetic alterations, which give rise to mutated peptides presented by HLA only on the cell surface of tumor cells (neoantigens). (biomedcentral.com)
  • Indeed, the term "molecular mimicry" was originally introduced in 1964 to define the similarity between antigens expressed by infectious agents and human cells, as cause of the microbial escape from the host immune response and a more aggressive infection [ 14 ]. (biomedcentral.com)
  • Dr. Chapuis wrote and successfully obtained necessary regulatory approvals, and the team is now evaluating the safety and efficacy of transplant donor-derived CD8+ T cells carrying the HLA-A*0201-restricted WT1-specific TCR C4 . (fredhutch.org)
  • The development of cancer immunotherapeutic strategies relies on the identification and validation of optimal target tumor antigens, which should be tumor-specific as well as able to elicit a swift and potent anti-tumor immune response. (biomedcentral.com)
  • In particular, the MAGE-A1antigen is frequently expressed in triple-negative breast cancer and in other poor prognosis tumor types, including squamous non-small cell lung carcinoma and advanced-stage melanomas, so the MAGE-targeting therapy they are developing may be broadly useful. (fredhutch.org)
  • While NSCLCs possess antigens that can potentially elicit T cell responses, defective tumor antigen presentation and T cell activation hinder host anti-tumor immune responses. (bvsalud.org)
  • However, systematic analysis of T cell immune responses to MAGE-A3 antigen and corresponding antigen-specific TCR is still lacking. (thno.org)
  • Amino-acid exchange scans alone predict TCR cross-reactivity with little specificity and thus require additional assessment of potentially cross-reactive HLA-A*02:01 binding candidates. (oncotarget.com)
  • Here, we compare the X-ray structure of HLA-A1:MAGE-A1 with that complexed with Fab-Hyb3 to gain insight into structural changes of the MHC molecule that might be induced by the interaction with the antibody fragment. (rcsb.org)
  • For non-self tumor antigens, such as those derived from viral sequences or mutations, the very low T cell frequency in the blood has limited TCR discovery efforts. (akampion.com)
  • TScan plans to file INDs for three additional TCR-T candidates by year end, including a TCR-T that targets the tumor-associated antigen PRAME. (financialcontent.com)
  • Future work must focus on identifying primary and acquired mechanisms of resistance to these therapies, and extend T-cell receptor discovery to other tumor-associated antigens. (jnccn.org)
  • Analysis of the X-ray structures of the two peptides bound to HLA-B*15:01 reveals drastically different conformations with measurable changes in the stability of the protein complexes, while the self-epitope is excluded from binding due to steric hindrance in the MHC groove. (frontiersin.org)
  • Methods A vaccine consisting of 9 MHC class I-restricted breast cancer-associated peptides (from MAGE-A1, −A3, and -A10, CEA, NY-ESO-1, and HER2 proteins) was combined with a TLR3 agonist, poly-ICLC, along with a helper peptide derived from tetanus toxoid. (bmj.com)
  • For instance, targeting inhibitory molecules on the surface of activated T cells (e.g., cytotoxic T-lymphocyte-associated antigen-4) represents an emerging strategy to elicit (without specificity) the immune response against a tumor. (medscape.com)
  • 9. Lysis of human chondrosarcoma cells by cytolytic T lymphocytes recognizing a MAGE-A3 antigen presented by HLA-A1 molecules. (nih.gov)
  • 14. Lack of tumor recognition by cytolytic T lymphocyte clones recognizing peptide 195-203 encoded by gene MAGE-A3 and presented by HLA-A24 molecules. (nih.gov)
  • Cancer immunotherapy harnesses a patient's CD4+ and CD8+ T cell responses toward peptide neoantigens, which are displayed on the surface of tumor cells by major histocompatibility complex molecules [MHC, termed human leukocyte antigen (HLA) in humans] ( 1 ). (frontiersin.org)
  • We show here that FS human chondrosarcoma (FS) cells express MAGE-A3 gene and HLA-A1 molecules. (dc-research.eu)
  • Incubation of FS cells with 50 U/mL interferon-gamma increased surface expression of HLA class-I molecules, increased their susceptibility to lysis, and had no effect on MAGE-A3 gene expression. (dc-research.eu)
  • Previously, we have shown that the mechanism underlying the power of TLR-L SLP conjugates is improved delivery of the antigen together with a dendritic cell activation signal. (sb-peptide.com)
  • This work provides a rational approach toward high-throughput identification and further optimization of putative neoantigen/HLA targets with desired recognition features for cancer immunotherapy. (frontiersin.org)
  • With regards to the solid tumor program, we continue to focus our efforts on populating the ImmunoBank with TCR-Ts that address different targets and diverse HLA types to enable tailored, multiplexed TCR-T therapies. (financialcontent.com)
  • TScan announced the U.S. Food and Drug Administration (FDA) clearance of its investigational new drug (IND) application for TSC-101, which targets minor histocompatibility antigen HA-2 for the prevention of relapse following hematopoietic cell transplantation (HCT) in hematologic malignancies. (tscan.com)
  • Finally, MHC tetramer staining of peripheral blood mononuclear cells from HLA-matched donors shows that the two neoepitopes are recognized by CD8+ T cells. (frontiersin.org)
  • For immuno-monitoring we established methods and protocols for detection of antigen-specific T cell populations in human and mice. (dc-research.eu)
  • Indeed, it has been demonstrated that Ovalbumin contains B-cell epitopes which are recognized by specific IgE antibodies and CD4 T cell epitopes restricted by the MHC I-Ad molecule in mice and by HLA-D molecule in human. (sb-peptide.com)
  • To evaluate the range of HLA alleles that could display the ALK neoepitopes, we used structure-based Rosetta comparative modeling calculations, which accurately predict several additional high affinity interactions and compare our results with commonly used prediction tools. (frontiersin.org)
  • 2. Differential expression of MAGE-1, -2, and -3 messenger RNA in transformed and normal human cell lines. (nih.gov)
  • In particular embodiments, the genes that are knocked out or knocked down are Signaling Threshold Regulating Transmembrane Adaptor 1 (SIT1), Bone Marrow Stromal Cell Antigen 2 (BST2), and Programmed cell death protein 1 (PD-1). (justia.com)
  • For non-self tumor antigens, such as those derived from viral sequences or mutations, the very low T cell frequency in the blood has limited TCR discovery efforts. (t-knife.com)
  • The aim of adjuvants being to catalyze innate immune response by stimulating the interactions between antigens and TLR proteins, new TLR agonists based on bacterial material appeared as natural candidate. (sb-peptide.com)