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This study targets the TGFβR2(-1) frameshift neoantigen from recurrent microsatellite mutations in colorectal and gastric cancers. Methods used ABabDR4 mice to isolate TGFβR2(-1)-specific CD4+ TCRs and assess potency, processing, presentation, potency, and safety in vitro and in tumor cell line contexts.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/generation-of-tgfr2-1-neoantigen-specific-hla-dr4-restricted-t-cell-receptors-for-cancer-therapy-read-online-free/406674/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/generation-of-tgfr2-1-neoantigen-specific-hla-dr4-restricted-t-cell-receptors-for-cancer-therapy-read-online-free/406674.png","ImageObject",300,407,{"name":92,"@type":93},"anakgang17","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is choosing the target antigen critical for engineered TCR-based cancer therapy?","Question",{"text":113,"@type":114},"The therapy depends on whether the epitope is efficiently processed and binds with high affinity to MHC molecules, ensuring reliable recognition by engineered T cells.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How was the TGFβR2(-1) neoantigen-specific CD4+ TCR generated and evaluated?",{"text":118,"@type":114},"ABabDR4 mice expressing a diverse human TCR repertoire restricted to HLA-DR4 were immunized with the TGFβR2(-1) peptide, and TGFβR2(-1)-specific TCRs were isolated from responding CD4+ T cells. Their potency and safety were tested using cocultures and other functional assays.",{"name":120,"@type":111,"acceptedAnswer":121},"What safety signals were reported for the HLA-DR4-restricted TGFβR2(-1)-specific TCRs?",{"text":122,"@type":114},"The study reports no MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif, supporting a favorable safety profile.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},406674,1790785597,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},962090883568,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Open access Original research  \n Generation of TGFβR2(-1) neoantigen  \nspecific HLA-DR4-restricted T cell receptors for cancer therapy  \nNatalia Plewa  , Lucia Poncette, Thomas Blankenstein  \nTo cite: Plewa N, Poncette L, Blankenstein T. Generation of TGFβR2(-1) neoantigen-specific HLA-DR4-restricted T cell receptors for cancer therapy. Journal for ImmunoTherapy of Cancer 2023;11:e006001 . doi:10.1136/jitc-2022-006001  \n► Additional supplemental material is published online only. To view, please visit the journal online ([http://dx.doi.org/10](http://dx.doi.org/10) . 1136/jitc-2022-006001) .  \nAccepted 06 February 2023  \n© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.  \nMax Delbruck Centre for Molecular Medicine, Berlin, Germany  \nCorrespondence to  \nProfessor Thomas Blankenstein; [tblanke@mdc-berlin.de](tblanke@mdc-berlin.de)  \nABSTRACT  \nBackground Adoptive transfer of patient’s T cells, engineered to express a T cell receptor (TCR) with defined novel antigen specificity, is a convenient form of cancer therapy. In most cases, major histocompatibility complex (MHC) I-restricted TCRs are expressed in CD8+ T cells and the development of CD4+ T cells engineered to express an MHC II-restricted TCR lacks behind. Critical is the choice of the target antigen, whether the epitope is efficiently processed and binds with high affinity to MHC molecules. A mutation in the transforming growth factor β receptor 2 (TGFβR2(-1)) gene creates a frameshift peptide caused by the deletion of one adenine (-1) within a microsatellite sequence. This somatic mutation is recurrent in microsatellite instable colorectal and gastric cancers and, therefore, is a truly tumor-specific antigen detected in many patients.  \nMethods ABabDR4 mice, which express a diverse human TCR repertoire restricted to human MHC II molecule HLADRA/DRB1*0401 (HLA-DR4), were immunized with the TGFβR2(-1) peptide and TGFβR2(-1)-specific TCRs were isolated from responding CD4+ T cells. The TGFβR2(-1) -specific TCRs were expressed in human CD4+ T cells and their potency and safety profile were assessed by cocultures and other functional assays.  \nResults We demonstrated that TGFβR2(-1) neoantigen is immunogenic and elicited CD4+ T cell responses in ABabDR4 mice. When expressed in human CD4+ T cells, the HLA-DR4 restricted TGFβR2(-1)-specific TCRs induced IFNy expression at low TGFβR2(-1) peptide amounts. The TGFβR2(-1)-specific TCRs recognized HLA-DR4+ lymphoblastoid cells, which endogenously processed and presented the neoantigen, and colorectal cancer cell lines SW48 and HCT116 naturally expressing the TGFβR2(-1) mutation. No MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif were observed, indicating the safety of the TCRs.  \nConclusions The data suggest that HLA-DR4-restricted TCRs specific for the TGFβR2(-1) recurrent neoantigen can be valuable candidates for adoptive T cell therapy of a sizeable number of patients with cancer.  \nBACKGROUND  \nAdoptive T cell therapy (ATT) with T cell receptor (TCR)-engineered T cells has become a promising option for cancer treatment. Clinical trials with TCR-engineered T cells showed objective responses1 but also  \nWHAT IS ALREADY KNOWN ON THIS TOPIC  \n\n| ⇒ Recurrent somatic mutations leading to targetable neoantigens are rare. The few described are presented by major histocompatibility complex (MHC) I molecules to CD8+ T cells. Case studies showed tumor regression with tumor-infiltrating lymphocytes containing neoantigen-specific CD4+ T cells. The TGFβR2(-1) mutation is recurrent in colorectal cancer (CRC) with microsatellite instability. CD8+ T cell responses specific for the TGFβR2(-1) neoantigen have been shown. No MHC II-restricted T cell receptor (TCRs) specific for TGFβR2(-1) have been described.\u003Cbr>WHAT THIS STUDY ADDS |\n| --- |\n| ⇒ We demonstrated that TGFβR2(-1) neoantigen is immunogenic and processe","cbCaidKeaqQvK3ta","https://ap.wps.com/l/cbCaidKeaqQvK3ta","pdf",4849569,13,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# What is already known on this topic\n# What this study adds\n# How this study might affect research, practice or policy","[{\"question\":\"Why is choosing the target antigen critical for engineered TCR-based cancer therapy?\",\"answer\":\"The therapy depends on whether the epitope is efficiently processed and binds with high affinity to MHC molecules, ensuring reliable recognition by engineered T cells.\"},{\"question\":\"How was the TGFβR2(-1) neoantigen-specific CD4+ TCR generated and evaluated?\",\"answer\":\"ABabDR4 mice expressing a diverse human TCR repertoire restricted to HLA-DR4 were immunized with the TGFβR2(-1) peptide, and TGFβR2(-1)-specific TCRs were isolated from responding CD4+ T cells. Their potency and safety were tested using cocultures and other functional assays.\"},{\"question\":\"What safety signals were reported for the HLA-DR4-restricted TGFβR2(-1)-specific TCRs?\",\"answer\":\"The study reports no MHC II alloreactivity or cross-reactivity to peptides with a similar TCR-recognition motif, supporting a favorable safety profile.\"}]","Generation of TGFβR2(-1) neoantigen specific HLA-DR4 restricted T cell receptors for cancer therapy - read online free | PDF",1790567207,33]