{"id":8794,"date":"2023-10-12T10:58:46","date_gmt":"2023-10-12T10:58:46","guid":{"rendered":"https:\/\/www.caltagmedsystems.co.uk\/information\/?p=8794"},"modified":"2023-10-12T10:58:47","modified_gmt":"2023-10-12T10:58:47","slug":"chimeric-antigen-receptor-car-t-cell-therapy","status":"publish","type":"post","link":"https:\/\/www.caltagmedsystems.co.uk\/information\/chimeric-antigen-receptor-car-t-cell-therapy\/","title":{"rendered":"Chimeric Antigen Receptor (CAR) T Cell Therapy"},"content":{"rendered":"\n<h2 class=\"wp-block-heading\">Introduction<\/h2>\n\n\n\n<p>Chimeric Antigen Receptor (CAR) T cell therapy is a revolutionary approach in the field of cancer immunotherapy. This innovative treatment involves genetically engineering a patient&#8217;s own T cells to express chimeric antigen receptors, which are artificial receptors designed to target specific cancer-associated antigens. CAR-T cells combine the antigen recognition capability of antibodies with the potent cytotoxic activity of T cells, enabling them to recognise and eliminate cancer cells with remarkable precision. Over the past decade, CAR-T therapy has demonstrated exceptional success in treating certain hematologic malignancies, such as acute lymphoblastic leukaemia and non-Hodgkin lymphoma. The ability to reprogram a patient&#8217;s own immune cells to effectively combat cancer marks a paradigm shift in cancer treatment strategies, offering new hope for patients with otherwise refractory or relapsed diseases. As research continues to advance, CAR-T therapy holds promise for broader applications and improvements, paving the way for a new era of personalised and targeted cancer therapies.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\">CAR Structure<\/h2>\n\n\n\n<p>Chimeric antigen receptor (CAR) consists of three parts: an extracellular domain, a transmembrane domain, and an intracellular signalling domain.<\/p>\n\n\n\n<ul class=\"wp-block-list\" style=\"font-size:16px\">\n<li>The extracellular domain contains a single-chain variable fragment (scFv) molecule derived from an antibody to recognise specific cancer cell antigens and a hinge region provides flexibility to the receptor, aiding in optimal antigen binding.<\/li>\n\n\n\n<li>The transmembrane domain anchors the CAR within the T cell&#8217;s membrane, ensuring stability.<\/li>\n\n\n\n<li>The intracellular signalling domain is composed of one or more costimulatory molecules, such as a cluster of differentiation CD28 and 4-1BB, and a stimulatory molecule, CD3 \u03b6, transmitting activation signals to the T cell&#8217;s interior, initiating a robust immune response against targeted cancer cells.<\/li>\n<\/ul>\n\n\n\n<figure class=\"wp-block-image aligncenter size-full is-resized\"><a href=\"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-81.png\"><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-81.png\" alt=\"\" class=\"wp-image-8799\" style=\"width:402px;height:258px\" width=\"402\" height=\"258\" srcset=\"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-81.png 612w, https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-81-300x193.png 300w\" sizes=\"auto, (max-width: 402px) 100vw, 402px\" \/><\/a><\/figure>\n\n\n\n<p class=\"has-text-align-right clear\">Xin et al., (2022)<\/p>\n\n\n\n<h2 class=\"wp-block-heading clear\">CAR Evolution<\/h2>\n\n\n\n<p>There are five generations of chimeric antigen receptors (CARs), each building upon the previous to enhance CAR-T cell therapy&#8217;s effectiveness.<\/p>\n\n\n\n<ul class=\"wp-block-list\" style=\"font-size:16px\">\n<li>The first generation only contained the CD3\u03b6 derived signalling modules. While functional, these CARs had limited efficacy and persistence.<\/li>\n\n\n\n<li>The second generation contained CD3\u03b6 and a costimulatory molecular domain. like CD28 or 4-1BB, alongside the signalling domain. These additions improved CAR-T cell activation, proliferation, and persistence, resulting in more potent anti-cancer responses.<\/li>\n\n\n\n<li>The third generation contained CD3\u03b6 and multiple costimulatory molecular domains, including CD28, 4 1BB, OX40 or ICOS, etc, aiming to amplify T cell activity.<\/li>\n\n\n\n<li>The fourth generation is called TRUCKs (T cells redirected for antigen-unrestricted cytokine-initiated killing), engineered to secrete immune-stimulating molecules upon antigen recognition. This design aims to recruit and activate other immune cells against the tumour.<\/li>\n\n\n\n<li>The fifth generation included simultaneous activation of TCR, costimulatory molecular domain, and cytokine triple signalling to stimulate cell proliferation and enhance its persistence.<\/li>\n<\/ul>\n\n\n\n<figure class=\"wp-block-image aligncenter size-large is-resized\"><a href=\"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-82.png\"><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-82-1024x372.png\" alt=\"\" class=\"wp-image-8800\" style=\"width:648px;height:235px\" width=\"648\" height=\"235\" srcset=\"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-82-1024x372.png 1024w, https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-82-300x109.png 300w, https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-82-768x279.png 768w, https:\/\/www.caltagmedsystems.co.uk\/information\/wp-content\/uploads\/image-82.png 1193w\" sizes=\"auto, (max-width: 648px) 100vw, 648px\" \/><\/a><\/figure>\n\n\n\n<p class=\"has-text-align-right clear\">Xin et al., (2022)<\/p>\n\n\n\n<h2 class=\"wp-block-heading clear\">In-Vitro CAR-T Cell<\/h2>\n\n\n\n<p>In this method, T cells are extracted from the patient and engineered outside the body. The extracted T cells are modified to express the CARs, then expanded and cultured to create a large population of CAR-T cells. Once their numbers are sufficient, these cells are infused back into the patient. In-Vitro CAR-T allows for precise CAR design, rigorous quality control, and optimal expansion of modified cells before treatment, but it involves complex cell manipulation processes.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\">Six FDA Approved CAR-T Cell Products<\/h3>\n\n\n\n<figure class=\"wp-block-table is-style-stripes\"><table><thead><tr><th>Product Name<\/th><th>Targets<\/th><th>Target Diseases<\/th><th>Time of Approval<\/th><\/tr><\/thead><tbody><tr><td>Kymriah\u00ae (tisagenlecleucel)<\/td><td>CD19<\/td><td>B-ALL ; DLBCL<\/td><td>August 2017<\/td><\/tr><tr><td>Yescarta\u00ae (axicabtagene ciloleucel)<\/td><td>CD19<\/td><td>DLBCL ; RRFL<\/td><td>October 2017<\/td><\/tr><tr><td>Tecartus\u00ae (brexucabtagene autoleucal)<\/td><td>CD19<\/td><td>R\/R MCL<\/td><td>July 2020<\/td><\/tr><tr><td>Breyanzi\u00ae (lisocabtagene maraleucel)<\/td><td>CD19<\/td><td>DLBCL<\/td><td>February 2021<\/td><\/tr><tr><td>Abecma\u00ae (idecabtagene vicleucel)<\/td><td>BCMA<\/td><td>R\/R MM<\/td><td>March 2021<\/td><\/tr><tr><td>Carvykti\u00ae (ciltacabtagene autoleucel)<\/td><td>BCMA<\/td><td>R\/R MM<\/td><td>February 2022<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p class=\"has-text-align-right clear\">Chen et al., (2022)<\/p>\n\n\n\n<p class=\"clear\">B-ALL, B-cell acute lymphoblastic leukaemia; DLBCL, Diffuse large B-cell lymphoma; R\/R FL, relapsed or refractory follicular lymphoma; R\/R MCL, relapsed or refractory mantle cell lymphoma; R\/R MM, relapsed or refractory multiple myeloma.<\/p>\n\n\n\n<h2 class=\"wp-block-heading\">In-Vivo CAR-T Cell<\/h2>\n\n\n\n<p>In this approach, CAR-T cells induced by nanocarriers loaded with CAR genes and gene editing tools are generated within the patient&#8217;s body. Once inside the body, these modified T cells start expressing the CAR receptor and target cancer cells. In-Vivo CAR-T offers simplicity and avoids the need for cell collection, engineering, and reinfusion, but controlling the modification process can be challenging.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\">In-Vivo CAR-T Cell Gene Delivery Systems<\/h3>\n\n\n\n<figure class=\"wp-block-table\"><table><thead><tr><th class=\"has-text-align-center\" data-align=\"center\">Viral Vectors<\/th><\/tr><\/thead><tbody><tr><td class=\"has-text-align-center\" data-align=\"center\"><strong>Viral vectors<\/strong> have good transfection efficiency and are widely used to deliver genes in<br>various applications, but they suffer from immunogenicity and cellular toxicity.<br><strong>Example<\/strong>: Lentiviral vector (LV) and Adeno-associated virus vector (AAV)<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<figure class=\"wp-block-table\"><table><thead><tr><th class=\"has-text-align-center\" data-align=\"center\">Non-Viral Delivery Systems<\/th><\/tr><\/thead><tbody><tr><td class=\"has-text-align-center\" data-align=\"center\"><strong>Physical delivery systems<\/strong> have low immunogenicity but cannot target internal organs.<br><strong>Example<\/strong>: electroporation, needle injection, laser irradiation, and gene guns.<\/td><\/tr><tr><td class=\"has-text-align-center\" data-align=\"center\"><strong>Chemical delivery systems<\/strong> have recently gained worldwide attention. Lipid-based nanoparticles are one of the most attractive non-viral vectors for gene delivery as several formulations of these carriers have been approved to use in the clinic. Some T cell-targeted lipid nanoparticles (LNPs) with plasmid DNA or in vitro-transcribed (IVT) mRNA have been reported.<br><strong>Example<\/strong>: cationic lipids or polymer-based nanoparticles, gold nanoparticles, silica<br>nanoparticles, and exosomes.<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p class=\"has-text-align-right clear\">Wakao et al., (2023)<\/p>\n\n\n\n<h2 class=\"wp-block-heading\">Challenges &amp; Potential Strategies in CAR-T Cell Therapy<\/h2>\n\n\n\n<figure class=\"wp-block-table is-style-stripes\"><table><thead><tr><th class=\"has-text-align-left\" data-align=\"left\">Limitations of CAR-T Cell Therapy<\/th><th class=\"has-text-align-left\" data-align=\"left\">Potential Strategies<\/th><\/tr><\/thead><tbody><tr><td class=\"has-text-align-left\" data-align=\"left\">Antigen escape<\/td><td class=\"has-text-align-left\" data-align=\"left\">&#8211; Targeting multiple antigens (dual or tandem CARs)<\/td><\/tr><tr><td class=\"has-text-align-left\" data-align=\"left\">On-target off-tumour effects<\/td><td class=\"has-text-align-left\" data-align=\"left\">&#8211; Targeting tumour-restricted post-translational modifications<\/td><\/tr><tr><td class=\"has-text-align-left\" data-align=\"left\">CAR-T cell trafficking and tumoir infiltration<\/td><td class=\"has-text-align-left\" data-align=\"left\">&#8211; Local administration vs systemic delivery<br>&#8211; Engineering CAR-T cells to enhance penetration through physical barriers (tumour stroma)<\/td><\/tr><tr><td class=\"has-text-align-left\" data-align=\"left\">Immunosuppressive microenvironment<\/td><td class=\"has-text-align-left\" data-align=\"left\">&#8211; Combination immunotherapy with CAR-T cells and checkpoint blockade<br>&#8211; Engineering CAR-T cells to provide immunostimulatory signals in the form of cytokines or CARs resistant to immunosuppressive factors.<\/td><\/tr><tr><td class=\"has-text-align-left\" data-align=\"left\">CAR-T cell-associated toxicities<\/td><td class=\"has-text-align-left\" data-align=\"left\">&#8211; Altering CAR structure to ameliorate toxicity<br>&#8211; Modifying CAR transduced T cells and neurotoxicity<br>&#8211; CAR \u201coff-switches\u201d<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<p class=\"has-text-align-right clear\">Sterner et al., (2021)<\/p>\n\n\n\n<div class=\"wp-block-buttons is-content-justification-center is-layout-flex wp-container-core-buttons-is-layout-a89b3969 wp-block-buttons-is-layout-flex\">\n<div class=\"wp-block-button\"><a class=\"wp-block-button__link has-text-color has-background wp-element-button\" href=\"https:\/\/www.caltagmedsystems.co.uk\/docs\/Tumor_Associated_Antigens_of_CAR_T_Cell_Therapy_Abnova_January_2023.pdf\" style=\"color:#fbc100;background-color:#21318f\"><strong>Tumour-Associated Antigens of CAR T Cell Therapy<\/strong><\/a><\/div>\n<\/div>\n\n\n\n<p class=\"clear\"> <\/p>\n\n\n\n<hr class=\"wp-block-separator has-text-color has-alpha-channel-opacity has-background\" style=\"background-color:#21318f;color:#21318f\"\/>\n\n\n\n<p>Originally posted by <a href=\"https:\/\/www.caltagmedsystems.co.uk\/abnova\/\">Abnova <\/a>on <a href=\"https:\/\/www.abnova.com\/en-global\/newsletter\/newsletter\/content\/newsletter2023-09-01\">https:\/\/www.abnova.com\/en-global\/newsletter\/newsletter\/content\/newsletter2023-09-01<\/a><\/p>\n\n\n\n<p><a href=\"https:\/\/www.caltagmedsystems.co.uk\/\">Caltag Medsystems <\/a>is the distributor of <a href=\"https:\/\/www.caltagmedsystems.co.uk\/abnova\/\">Abnova <\/a>products in the UK and Ireland. If you have any questions about these products, please <a href=\"https:\/\/www.caltagmedsystems.co.uk\/contact.php\">contact us<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Chimeric Antigen Receptor (CAR) T cell therapy is a revolutionary approach in the field of cancer immunotherapy. <\/p>\n","protected":false},"author":13,"featured_media":8825,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10,722,1],"tags":[203,7,475,644,158],"class_list":["post-8794","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-cancer","category-cell-and-gene-therapy","category-general-information","tag-abnova","tag-cancer","tag-car-t","tag-cell-and-gene-therapy","tag-immunotherapy"],"_links":{"self":[{"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/posts\/8794","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/users\/13"}],"replies":[{"embeddable":true,"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/comments?post=8794"}],"version-history":[{"count":26,"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/posts\/8794\/revisions"}],"predecessor-version":[{"id":8826,"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/posts\/8794\/revisions\/8826"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/media\/8825"}],"wp:attachment":[{"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/media?parent=8794"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/categories?post=8794"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.caltagmedsystems.co.uk\/information\/wp-json\/wp\/v2\/tags?post=8794"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}