{"id":171608,"date":"2023-09-08T16:23:25","date_gmt":"2023-09-08T21:23:25","guid":{"rendered":"https:\/\/lifeboat.com\/blog\/2023\/09\/novel-modular-chimeric-antigen-receptor-spacer-for-t-cells-derived-from-signal-regulatory-protein-alpha-ig-like-domains"},"modified":"2023-09-08T16:23:25","modified_gmt":"2023-09-08T21:23:25","slug":"novel-modular-chimeric-antigen-receptor-spacer-for-t-cells-derived-from-signal-regulatory-protein-alpha-ig-like-domains","status":"publish","type":"post","link":"https:\/\/lifeboat.com\/blog\/2023\/09\/novel-modular-chimeric-antigen-receptor-spacer-for-t-cells-derived-from-signal-regulatory-protein-alpha-ig-like-domains","title":{"rendered":"Novel modular chimeric antigen receptor spacer for T cells derived from signal regulatory protein alpha Ig-like domains"},"content":{"rendered":"<p style=\"padding-right: 20px\"><a class=\"aligncenter blog-photo\" href=\"https:\/\/lifeboat.com\/blog.images\/novel-modular-chimeric-antigen-receptor-spacer-for-t-cells-derived-from-signal-regulatory-protein-alpha-ig-like-domains.jpg\"><\/a><\/p>\n<p><b>Background:<\/b> T cells equipped with chimeric antigen receptors (CAR) have shown remarkable efficacy in targeting B lineage malignancies. Improvement of the CAR structure is needed, however, with a view to developing flexibly modifiable spacers that are inert in interactions with unwanted cells. Specifically, binding to cells carrying receptors for IgG\u2019s crystallizable fragment (FcR), that recognize IgG-derived domains in CARs is to be avoided.<\/p>\n<p><b>Methods:<\/b> Two novel CARs targeting the CD19 antigen where the IgG1-CH2 and-CH3 domains were replaced with Ig-like domains from signal-regulatory protein \u03b1 (SIRP\u03b1) were designed <em>in silico<\/em>. An IgG1-based CAR and a CAR lacking both SIRP\u03b1 and IgG1 domains were used as comparators. The phenotype and memory phenotype of the expanded cells were analyzed by flow cytometry, and CAR T cell activation and cytotoxic efficacy were assessed in co-culture experiments in response to CD19<sup>+<\/sup> target cells. Unwanted interactions with FcR-expressing myeloid cells were interrogated in co-culture assays with THP-1 monocytic cells.<\/p>\n<p><b>Results:<\/b> T cells carrying the novel SIRP\u03b1-based CARs enacted potent <em>in vitro<\/em> cytotoxicity against CD19 positive B-lineage leukemia cells, comparable to traditional IgG1-based CAR T cells. Co-culture of IgG1-based CAR T cells with FcR-expressing THP-1 monocytic cells led to prominent cell surface expression of CD69 on T cells together with production of Interleukin (IL)-2 and Interferon-\u03b3, and production of IL-1\u03b2, indicating activation of the T cells and monocytes, respectively. Longer co-culture led to killing of the monocytes. No signs of T cell nor monocyte activation were detected in co-cultures of SIRP\u03b1-based CAR T cells with THP-1 cells. Arming T cells with the SIRP\u03b1-based CARs favored differentiation towards CD4<sup>+<\/sup> phenotype during expansion, while the effects on memory phenotype of the T cells were equivalent between the SIRP\u03b1- and IgG1-based CARs. In a pilot experiment, T cells modified with one of the SIRP\u03b1-based CARs showed dose dependent leukemia cell control.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Background: T cells equipped with chimeric antigen receptors (CAR) have shown remarkable efficacy in targeting B lineage malignancies. Improvement of the CAR structure is needed, however, with a view to developing flexibly modifiable spacers that are inert in interactions with unwanted cells. Specifically, binding to cells carrying receptors for IgG\u2019s crystallizable fragment (FcR), that recognize [\u2026]<\/p>\n","protected":false},"author":662,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[20],"tags":[],"class_list":["post-171608","post","type-post","status-publish","format-standard","hentry","category-futurism"],"_links":{"self":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/171608","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/users\/662"}],"replies":[{"embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/comments?post=171608"}],"version-history":[{"count":0,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/posts\/171608\/revisions"}],"wp:attachment":[{"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/media?parent=171608"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/categories?post=171608"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/lifeboat.com\/blog\/wp-json\/wp\/v2\/tags?post=171608"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}