{"id":36302,"date":"2025-06-26T18:48:41","date_gmt":"2025-06-26T16:48:41","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2025\/06\/26\/gpc2-targeted-car-t-cells-engineered-with-nfat-inducible-membrane-tethered-il-15-il-21-exhibit-enhanced-activity-against-neuroblastoma\/"},"modified":"2025-06-26T18:48:41","modified_gmt":"2025-06-26T16:48:41","slug":"gpc2-targeted-car-t-cells-engineered-with-nfat-inducible-membrane-tethered-il-15-il-21-exhibit-enhanced-activity-against-neuroblastoma","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2025\/06\/26\/gpc2-targeted-car-t-cells-engineered-with-nfat-inducible-membrane-tethered-il-15-il-21-exhibit-enhanced-activity-against-neuroblastoma\/","title":{"rendered":"GPC2-targeted CAR T cells engineered with NFAT-inducible membrane-tethered IL-15\/IL-21 exhibit enhanced activity against neuroblastoma"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2025 Jun 26. doi: 10.1158\/2326-6066.CIR-24-0975. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Neuroblastoma (NB) is a highly aggressive childhood solid tumor with poor outcomes. Chimeric antigen receptor (CAR) T cells have shown limited efficacy in NB, with the best outcomes reported in patients with a low tumor burden, highlighting the need for further CAR optimization. One approach to addressing the high tumor burden involves engineering CAR T cells to release or express transgenic cytokines. However, its systemic toxicity remains an important therapeutic challenge. Here, we evaluated the efficacy of interleukin (IL)-15- and IL-21-enhanced glypican-2 (GPC2)-targeted CAR T cells (GPC2-CAR T cells) in targeting high-burden NB. Three strategies for expressing the cytokines were evaluated: constitutive secretion (GPC2-CAR+sol.IL15.IL21), constitutive membrane-tethered expression (GPC2-CAR+teth.IL15.IL21), and NFAT-inducible membrane-tethered expression (GPC2-CAR+NFAT.IL15.IL21). Engineered GPC2-CAR T cells were tested in vitro and in vivo using high NB-burden xenograft models. Additionally, single-cell RNA sequencing was used to profile the effector cells in the tumor microenvironment. All three versions of GPC2-CAR T cells significantly enhanced killing against a high NB burden, both in vitro and in vivo, relative to control GPC2-CAR T cells. Mice treated with GPC2-CAR+NFAT.IL15.IL21 exhibited significantly lower anorexia-associated morbidity\/mortality. Supporting these data, tumor-infiltrating GPC2-CAR+NFAT.IL15.IL21 developed an immunosuppressive transcriptional profile upon tumor regression, leading to prolonged survival in treated mice. In contrast, GPC2-CAR+teth.IL15.IL21 maintained a pro-inflammatory transcriptional signature despite near tumor clearance, resulting in hypercytokinemia and death. NFAT-inducible co-expression of tethered IL-15\/IL-21 enhanced GPC2-CAR T-cell function against a high NB burden with acceptable tolerability in mice. Further studies are required to validate these findings.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/40569285\/?utm_source=WordPress&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20250626124839&amp;v=2.18.0.post9+e462414\">40569285<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-24-0975\">10.1158\/2326-6066.CIR-24-0975<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2025 Jun 26. doi: 10.1158\/2326-6066.CIR-24-0975. Online ahead of print. ABSTRACT Neuroblastoma (NB) is a highly aggressive childhood solid tumor with poor outcomes. Chimeric antigen receptor (CAR) T cells have shown limited efficacy in NB, with the best outcomes reported in patients with a low tumor burden, highlighting the need for further CAR &#8230; <a title=\"GPC2-targeted CAR T cells engineered with NFAT-inducible membrane-tethered IL-15\/IL-21 exhibit enhanced activity against neuroblastoma\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2025\/06\/26\/gpc2-targeted-car-t-cells-engineered-with-nfat-inducible-membrane-tethered-il-15-il-21-exhibit-enhanced-activity-against-neuroblastoma\/\" aria-label=\"Read more about GPC2-targeted CAR T cells engineered with NFAT-inducible membrane-tethered IL-15\/IL-21 exhibit enhanced activity against neuroblastoma\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[55,42],"tags":[],"class_list":["post-36302","post","type-post","status-publish","format-standard","hentry","category-cancer-immunology-reserch","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/36302","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=36302"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/36302\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=36302"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=36302"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=36302"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}