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The cytokine TNFα can be tumoricidal; however, it upregulates inhibitor of apoptosis proteins (IAPs) that restrict caspase-induced apoptosis. This work proposes targeted delivery of TNFα via an inactive adoptive cell combined with an IAP antagonist to enable strong cancer cell apoptosis while avoiding broad cytokine release.",{"@graph":69,"@context":122},[70,84,105],{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/chimeric-antigen-receptor-dendritic-cells-targeted-delivery-of-a-single-tumoricidal-factor-for-cancer-immunotherapy/332315/",{"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/chimeric-antigen-receptor-dendritic-cells-targeted-delivery-of-a-single-tumoricidal-factor-for-cancer-immunotherapy/332315.png","ImageObject",300,407,{"name":92,"@type":93},"Liam","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are CAR-T cells less effective for solid cancers?","Question",{"text":112,"@type":113},"They have difficulty achieving sufficient therapeutic impact in solid tumor settings and can also cause severe toxicities. The document notes CAR-T therapies are approved for blood cancers but are not effective for solid cancers.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What role do IAP proteins play in TNFα-mediated cancer cell death?",{"text":117,"@type":113},"TNFα increases cIAP1 and cIAP2 levels, which limit caspase-induced apoptosis. The document states that simply degrading IAP proteins with an IAP antagonist is not sufficient to kill cancer cells effectively unless TNFα can strongly induce apoptosis.",{"name":119,"@type":110,"acceptedAnswer":120},"How were the engineered dendritic cells tested and what was the key therapeutic finding?",{"text":121,"@type":113},"Human dendritic cells were engineered to express TNFα and a membrane-anchored Mucin1 antibody scFv (M-DCsTNF). M-DCsTNF plus the IAP antagonist SM-164 markedly induced apoptosis in a breast cancer model and inhibited growth of patient-derived xenograft tumors in NSG mice.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},332315,1790830992,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":41,"preview_page_count":4},8796095461564,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Cancer Immunology, Immunotherapy (2024) 73:203 [https://doi.org/10.1007/s00262-024-03788-1](https://doi.org/10.1007/s00262-024-03788-1)  \nChimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy  \nRong Duan1 · Philip Milton1,2 · Chutamath Sittplangkoon1 · Xin Liu1,4 · Zhining Sui3 · Brendan F. Boyce1 · Zhenqiang Yao1  \nReceived: 23 February 2024 / Accepted: 19 July 2024 / Published online: 6 August 2024 © The Author(s) 2024  \nAbstract  \nBackground Chimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist.  \nMethods Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membraneanchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCsTNF) . The efficacy of M-DCsTNFin recognizing and treating breast cancer was tested in vitro and in vivo.  \nResults Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCsTNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCsTNF plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCsTNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice. Conclusion An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.  \nKeywords Breast cancer · Dendritic cell (DC) · Tumor necrosis factor-α (TNF) · Chimeric antigen receptor (CAR) cell therapy · Mucin1 · Inhibitor of apoptosis proteins (IAPs) · IAP antagonist · Patient-derived xenograft (PDX) model  \n* Zhenqiang Yao [zhenqiang_yao@urmc.rochester.edu](zhenqiang_yao@urmc.rochester.edu)  \n1 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA  \n2 School of Engineering, University of Rochester, Rochester, NY 14627, USA  \n3 Department of Biostatistics and Computational Biology, University of Rochester Medical Center, 601 Elmwood Ave, Rochester, NY 14642, USA  \n4 Present Address: Department of Orthopedics, Tianjin Hospital, Tianjin 30021, People’s Republic of China  \nAbbreviations  \nACT Adoptive cell therapies  \nBIRC Baculoviral IAP repeat-containing protein  \nBLI Bioluminescence imaging  \nCAR Chimeric antigen receptor  \nCD66b Cluster of differentiation 66b, carcinoembryonic antigen-related cell adhesion molecule 8  \n(CEACAM8) CLD Clodronate  \nDC Dendritic cell  \nEGFR Epidermal growth factor receptor  \nELISA Enzyme-linked immunosorbent assay ER Estrogen receptor  \nFACS Fluorescence-activated cell sorting  \nGFP Green fluorescent protein  \nGM-CSF Granulocyte macrophage-colony stimulating factor,  \nHer-2 Human epidermal growth factor receptor 2  \nIAP Inhibitor of apoptosis proteins  \nIL Interleukin  \nM-DCsTNF Mucin 1 directed DCs expressing TNFα M-CSF Macrophage-colony stimulating factor, PBMCs Peripheral blood mono","cbCaid8GZGInswGq","https://ap.wps.com/l/cbCaid8GZGInswGq","pdf",1914832,12,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusion\n# Introduction\n## Adoptive cell therapies and CAR-T limitations\n## Cytokine engineering and toxicity concerns","[{\"question\":\"Why are CAR-T cells less effective for solid cancers?\",\"answer\":\"They have difficulty achieving sufficient therapeutic impact in solid tumor settings and can also cause severe toxicities. The document notes CAR-T therapies are approved for blood cancers but are not effective for solid cancers.\"},{\"question\":\"What role do IAP proteins play in TNFα-mediated cancer cell death?\",\"answer\":\"TNFα increases cIAP1 and cIAP2 levels, which limit caspase-induced apoptosis. The document states that simply degrading IAP proteins with an IAP antagonist is not sufficient to kill cancer cells effectively unless TNFα can strongly induce apoptosis.\"},{\"question\":\"How were the engineered dendritic cells tested and what was the key therapeutic finding?\",\"answer\":\"Human dendritic cells were engineered to express TNFα and a membrane-anchored Mucin1 antibody scFv (M-DCsTNF). M-DCsTNF plus the IAP antagonist SM-164 markedly induced apoptosis in a breast cancer model and inhibited growth of patient-derived xenograft tumors in NSG mice.\"}]","Chimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy | PDF",1789997682]