<?xml version="1.0" encoding="UTF-8"?><rss version="2.0" xmlns:content="http://purl.org/rss/1.0/modules/content/" xmlns:wfw="http://wellformedweb.org/CommentAPI/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:atom="http://www.w3.org/2005/Atom" xmlns:sy="http://purl.org/rss/1.0/modules/syndication/" xmlns:slash="http://purl.org/rss/1.0/modules/slash/" > <channel> <title>Creative Biolabs CAR-T Blog</title> <atom:link href="https://www.creative-biolabs.com/blog/car-t/feed/" rel="self" type="application/rss+xml" /> <link>https://www.creative-biolabs.com/blog/car-t</link> <description>CellRapeutics™ CAR-T/NK, TCR services and products</description> <lastBuildDate>Tue, 02 Jul 2024 06:51:56 +0000</lastBuildDate> <language>en-US</language> <sy:updatePeriod> hourly </sy:updatePeriod> <sy:updateFrequency> 1 </sy:updateFrequency> <generator>https://wordpress.org/?v=6.3.1</generator> <image> <url>https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2020/02/cropped-favicon-32x32.png</url> <title>Creative Biolabs CAR-T Blog</title> <link>https://www.creative-biolabs.com/blog/car-t</link> <width>32</width> <height>32</height> </image> <item> <title>CAR-T Cells Targeting PSCA Show Promise in Treating Metastatic Castration-Resistant Prostate Cancer</title> <link>https://www.creative-biolabs.com/blog/car-t/car-t-cells-targeting-psca-show-promise-in-treating-metastatic-castration-resistant-prostate-cancer/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Tue, 02 Jul 2024 06:51:56 +0000</pubDate> <category><![CDATA[Cancer Immunotherapy]]></category> <category><![CDATA[Chimeric Antigen Receptor Research]]></category> <category><![CDATA[News]]></category> <category><![CDATA[CAR-T Cells]]></category> <category><![CDATA[Prostate Cancer]]></category> <category><![CDATA[PSCA-targeted CAR-T cells]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=919</guid> <description><![CDATA[Treating prostate cancer with immunotherapy remains challenging. However, researchers at City of Hope have developed a chimeric antigen receptor (CAR) T cell (CAR-T) therapy, and the initial results of the first-in-human Phase<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/car-t-cells-targeting-psca-show-promise-in-treating-metastatic-castration-resistant-prostate-cancer/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Treating prostate cancer with immunotherapy remains challenging. However, researchers at City of Hope have developed a chimeric antigen receptor (CAR) T cell (CAR-T) therapy, and the initial results of the first-in-human Phase I trial indicate that advanced prostate cancer patients can safely receive this cellular immunotherapy with promising therapeutic activity. The findings were published in the June 2024 issue of Nature Medicine, titled “PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial.”</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41591_2024_2979_Fig4_HTML.png"><img decoding="async" fetchpriority="high" class="aligncenter wp-image-921" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41591_2024_2979_Fig4_HTML.png" alt="" width="600" height="964" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41591_2024_2979_Fig4_HTML.png 1557w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41591_2024_2979_Fig4_HTML-187x300.png 187w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41591_2024_2979_Fig4_HTML-638x1024.png 638w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41591_2024_2979_Fig4_HTML-768x1233.png 768w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41591_2024_2979_Fig4_HTML-957x1536.png 957w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41591_2024_2979_Fig4_HTML-1275x2048.png 1275w" sizes="(max-width: 600px) 100vw, 600px" /></a></p> <p><span style="font-size: 15px;">This clinical trial treated 14 patients with metastatic castration-resistant prostate cancer (mCRPC) positive for prostate stem cell antigen (PSCA). These patients’ cancer cells had spread beyond the prostate and no longer responded to hormone therapy. In the United States, over 34,000 men die annually from this type of prostate cancer.</span></p> <p><span style="font-size: 15px;">Dr. Saul Priceman, co-corresponding author of the study and Associate Professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, and his team developed CAR-T cells targeting PSCA, which is highly expressed in prostate cancer. This therapy involves extracting immune cells (T cells) from the patient’s blood and reprogramming them in the laboratory with CAR to recognize and attack the PSCA protein on cancer cells. These reprogrammed CAR-T cells are then infused back into the patient to eliminate the cancer cells.</span></p> <p><span style="font-size: 15px;">Dr. Tanya Dorff, co-corresponding author and first author of the paper, and Professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, stated, “Prostate cancer is known as an immune desert – its tumor microenvironment is difficult to treat with immunotherapy because there are not many T cells in the tumor. Something very potent is needed to overcome this. Our study shows that City of Hope’s CAR-T cell therapy for prostate cancer may be a step closer to that goal.”</span></p> <p><span style="font-size: 15px;">Priceman added, “The primary finding of our clinical trial is that <a href="/car-t/target-psca-75.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>PSCA-targeted CAR-T cells</strong></span></a> are safe and indeed effective against mCRPC. This provides an opportunity to continue developing this cellular immunotherapy for these patients, who currently have no other effective treatment options.”</span></p> <p><span style="font-size: 15px;">The trial aimed to assess the safety and dose-limiting toxicity (side effects that limit the treatment dose) of the therapy, as well as preliminary data on its efficacy for patients. The clinical trial results are as follows:</span></p> <p><span style="font-size: 15px;">1. Patients who did not undergo lymphodepletion chemotherapy beforehand received a single infusion of 100 million CAR-T cells. Lymphodepletion chemotherapy is a standard method in blood cancer treatment to enhance CAR-T cell efficacy. Since this was the first human CAR-T cell trial, it was necessary to assess the safety of using CAR-T cells alone.</span></p> <p><span style="font-size: 15px;">2. Dose-limiting toxicities such as cystitis or bladder irritation were observed at the same CAR-T cell dose and lymphodepletion. Dorff explained that PSCA is also present in the bladder, so CAR-T cells likely attacked bladder cells, causing inflammation. The researchers subsequently added a new cohort to the clinical study using reduced lymphodepletion to mitigate this toxicity.</span></p> <p><span style="font-size: 15px;">3. Four out of 14 patients showed a decrease in prostate-specific antigen (PSA) levels, a serum marker of disease progression in prostate cancer patients. One patient had a significant PSA level drop. Imaging results indicated a treatment response in some patients.</span></p> <p><span style="font-size: 15px;">4. Five out of 14 patients experienced mild to moderate cytokine release syndrome (CRS), a common side effect of CAR-T cell therapy caused by the rapid release of cytokines into the blood by immune cells. CRS is a treatable side effect.</span></p> <p><span style="font-size: 15px;">5. CAR-T cells did not maintain high levels after the 28-day monitoring period, limiting the therapy’s effectiveness. This is a common challenge in the CAR-T cell field for solid tumors, and the researchers plan to address this in follow-up clinical trials currently open for recruitment at City of Hope.</span></p> <p><span style="font-size: 15px;">One patient who had undergone multiple treatments responded well to this CAR-T cell therapy. His PSA level decreased by 95%, and there was a reduction in cancer in his bones and soft tissue. This positive response lasted about eight months.</span></p> <p><span style="font-size: 15px;">Dorff remarked, “The results for this patient are very encouraging, and we are very grateful to him and other patients and their families for participating in our research. We hope to continue using this therapy, increasing the number of CAR-T cells, and carefully monitoring for any health issues, as we believe this can enhance the therapy’s effectiveness.”</span></p> <p><span style="font-size: 15px;"><strong>Creative Biolabs</strong> masters the most advanced CAR/TCR technology. With state-of-art TCR development platforms and advanced technologies, Creative Biolabs is capable of offering a broad range of <a href="/car-t/one-stop-car-t-therapy-development-services.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>CAR-T therapy development</strong></span></a> services, including TCR engineered T cell biomarker identification and selection, design, construction, and analysis. To support the development of <span style="color: #0000ff;"><a style="color: #0000ff;" href="/car-t/target-psca-75.htm" target="_blank" rel="noopener"><strong>PSCA-targeted CAR therapy</strong></a></span>, Creative Biolabs has developed a comprehensive series of PSCA molecular-related products, such as CAR-T/CAR-NK/CAR-Macrophage Vectors and Cells, AbTCR/TriCAR Vectors, CAR Viral Particles, TCR-Like CAR, CAR Animal Cells, CAR mRNA Lipid Nanoparticles</span></p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1</span><span style="color: #808080; font-size: 14px;">. Dorff, Tanya B., et al. “PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial.” Nature Medicine (2024): 1-9.</span></p> ]]></content:encoded> </item> <item> <title>Advancements and Challenges in CAR-Macrophage Therapy: A New Frontier in Cancer Immunotherapy</title> <link>https://www.creative-biolabs.com/blog/car-t/advancements-and-challenges-in-car-macrophage-therapy-a-new-frontier-in-cancer-immunotherapy/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Thu, 20 Jun 2024 06:13:58 +0000</pubDate> <category><![CDATA[Cancer Immunotherapy]]></category> <category><![CDATA[Chimeric Antigen Receptor Research]]></category> <category><![CDATA[CAR-macrophage therapy]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=915</guid> <description><![CDATA[In recent years, Chimeric Antigen Receptor (CAR) technology has made significant progress in the treatment of hematologic malignancies, particularly in acute lymphoblastic leukemia (ALL), lymphoma, and plasma cell myeloma (PCM). However, the<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/advancements-and-challenges-in-car-macrophage-therapy-a-new-frontier-in-cancer-immunotherapy/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">In recent years, Chimeric Antigen Receptor (CAR) technology has made significant progress in the treatment of hematologic malignancies, particularly in acute lymphoblastic leukemia (ALL), lymphoma, and plasma cell myeloma (PCM). However, the effectiveness of <span style="color: #0000ff;"><a style="color: #0000ff;" href="/car-t/one-stop-car-t-therapy-development-services.htm" target="_blank" rel="noopener"><strong>CAR-T cell therapy</strong></a></span> in treating solid tumors remains suboptimal. This has prompted researchers to explore alternative immunotherapy methods to overcome the major challenges faced by current CAR-T cell therapies. Macrophages, with their strong phagocytic ability, antigen-presenting function, and ability to modulate the tumor microenvironment and stimulate adaptive responses, have emerged as a promising option.</span></p> <p><span style="font-size: 15px;">CAR-M therapy (CAR-Macrophage therapy) leverages the properties of macrophages, endowing them with specific antitumor abilities through genetic engineering. Macrophages play key roles in tumors by phagocytosing cancer cells, secreting cytokines and chemokines, infiltrating dense tissues, and accumulating in tumors. These characteristics make macrophages an operable candidate in CAR immunotherapy. Since Biglari et al. first engineered <strong><a href="/car-t/target-cea-29.htm" target="_blank" rel="noopener"><span style="color: #0000ff;">CEA-targeted CAR</span></a></strong> molecules into human monocytes in 2006, the development and optimization of CAR-macrophages have been ongoing. Currently, two CAR-M therapies (CT-0508 and MCY-M11) have received FDA approval to enter clinical trials.</span></p> <p><span style="font-size: 15px;">Despite some progress, CAR-M therapy is still in its infancy and faces significant issues, including limited cell resources, resistance to gene transfer, and potential inflammatory pathology. With the combination of human induced pluripotent stem cell (iPSC) preparation, gene editing technologies, and biomaterial delivery technologies, a new generation of CAR-M therapy is expected to possess specific tumor antigen recognition abilities, feasible gene modifications, improved expansion capabilities, and controllable safety. The June 1 issue of Molecular Cancer, “A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy,” reviewed the latest advancements in CAR-M therapy, covering basic scientific research and clinical trials, and discussed major obstacles hindering the full potential of CAR-M therapy and their solutions.</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/12943_2024_2032_Fig6_HTML.png"><img decoding="async" class="aligncenter wp-image-916" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/12943_2024_2032_Fig6_HTML.png" alt="" width="603" height="425" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/12943_2024_2032_Fig6_HTML.png 3543w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/12943_2024_2032_Fig6_HTML-300x212.png 300w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/12943_2024_2032_Fig6_HTML-1024x723.png 1024w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/12943_2024_2032_Fig6_HTML-768x542.png 768w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/12943_2024_2032_Fig6_HTML-1536x1084.png 1536w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/12943_2024_2032_Fig6_HTML-2048x1446.png 2048w" sizes="(max-width: 603px) 100vw, 603px" /></a></p> <p><span style="font-size: 15px;">With the advent of revolutionary technologies such as gene editing, synthetic biology, and biomaterial-supported gene transfer, the integration of these advanced methods will bring about a new generation of CAR-M therapy, enhancing its efficacy, safety, and accessibility. CAR-M therapy not only shows potential in combating hematologic and non-hematologic tumors but also indicates broad future applications in cancer immunotherapy.</span></p> <p><span style="font-size: 15px;">In recent years, Chimeric Antigen Receptor (CAR) technology has achieved breakthrough progress in the field of cancer treatment, especially in the treatment of hematologic malignancies. However, the effectiveness of CAR-T cells in treating solid tumors remains limited, prompting researchers to explore new immunotherapy approaches. Macrophages, as the main cells of the innate immune system, have become emerging candidates for CAR therapy due to their multifunctionality and important roles in the tumor microenvironment.</span></p> <p><span style="font-size: 15px;">Macrophages are the primary phagocytic cells in the body, capable of engulfing and digesting pathogens such as bacteria, viruses, and cancer cells. Besides their strong phagocytic ability, macrophages have an antigen-presenting function, which can activate adaptive immune responses. Additionally, macrophages play crucial roles in tissue repair, inflammatory responses, and immune regulation. Based on these characteristics, researchers have begun exploring the application of CAR technology to macrophages to develop new cancer immunotherapy methods.</span></p> <h4><span style="font-size: 15px;">Research Progress in CAR-M Therapy</span></h4> <h5><span style="font-size: 15px;">Basic Principles of CAR-M</span></h5> <p><span style="font-size: 15px;">CAR is an artificially designed transmembrane receptor typically comprising a single-chain variable fragment (scFv) that recognizes tumor antigens, a hinge domain, a transmembrane domain, and an intracellular signaling domain. By genetically engineering macrophages to introduce CARs, these cells can specifically recognize and kill cancer cells expressing the corresponding antigens.</span></p> <p><span style="font-size: 15px;">CARs typically consist of the following parts:</span></p> <p><span style="font-size: 15px;">Single-chain Variable Fragment (scFv): The scFv, located on the surface of the CAR cell, connects the heavy chain variable region (VH) and light chain variable region (VL) of the tumor antigen-targeting antibody via a linker sequence.</span></p> <p><span style="font-size: 15px;">Hinge Region: The hinge region, usually derived from CD8 or CD28 sequences, provides flexibility to the CAR molecule, enabling appropriate conformational changes when recognizing antigens.</span></p> <p><span style="font-size: 15px;">Transmembrane Region: The transmembrane region is responsible for embedding the CAR molecule into the cell membrane and is also typically derived from CD8 or CD28 sequences.</span></p> <p><span style="font-size: 15px;">Intracellular Activation Domain: The intracellular activation domain of most CAR molecules consists of CD3ζ and 4-1BB or CD28 regions, responsible for transducing antigen recognition signals into the cell and activating the immune response.</span></p> <p><span style="font-size: 15px;">Different Intracellular Activation Domains in CAR-M Design</span></p> <p><span style="font-size: 15px;">In CAR-M design, researchers have explored various intracellular activation domains to endow CAR-M with different antitumor capabilities:</span></p> <p><span style="font-size: 15px;">Phagocytosis Domains: Integrating phagocytosis domains such as FcRγ, CD3ζ, or Megf10 into CARs enables macrophages to phagocytose antigen-specific target cells and inhibit tumor progression.</span></p> <p><span style="font-size: 15px;">PI3K Recruiting Domain: The tandem of FcRγ and the PI3K recruiting domain can achieve whole-cell phagocytosis.</span></p> <p><span style="font-size: 15px;">Transmembrane and Intracellular Domain: The transmembrane and intracellular domains of CD147 are used in CAR-M design to secrete matrix metalloproteinases, aiding immune cells in penetrating tumor tissue.</span></p> <p><span style="font-size: 15px;">Inflammatory Signaling Domains: Incorporating the intracellular signaling domains of TLR4 or TLR2 into the CAR framework can induce macrophage polarization towards the M1 type, exhibiting antitumor effects.</span></p> <p><span style="font-size: 15px;">Costimulatory Domain and Inflammatory Cytokine: A tandem CAR molecule containing the CD28 costimulatory domain, CD3ζ phagocytosis domain, and M1-type cytokine IFN-γ, released through cleavage sites, can inhibit tumor progression through phagocytosis and pro-inflammatory antitumor effects.</span></p> <p><span style="font-size: 15px;">Co-expression of CD3ζ and TLR4 Intracellular Domains: Enhances macrophage phagocytosis of target cells and promotes M1 polarization.</span></p> <h5><span style="font-size: 15px;">Early Research on CAR-M</span></h5> <p><span style="font-size: 15px;">As early as 2006, Biglari et al. successfully introduced CEA (carcinoembryonic antigen)-targeted CAR molecules into human monocytes, demonstrating the feasibility and safety of this therapy. Since then, researchers have been committed to developing and optimizing CAR-macrophage therapy. Preliminary studies indicate that CAR-M therapy has potential in managing both hematologic and non-hematologic tumors.</span></p> <p><span style="font-size: 15px;">Currently, two CAR-M therapies (CT-0508 and MCY-M11) have received FDA approval to enter clinical trials, marking an important step towards the practical clinical application of CAR-M therapy.</span></p> <h5><span style="font-size: 15px;">Challenges of CAR-M in Solid Tumor Treatment</span></h5> <p><span style="font-size: 15px;">Despite the potential of CAR-M therapy in treating hematologic malignancies, its application in solid tumors faces many challenges. Firstly, the dense tissue structure and complex tumor microenvironment of solid tumors limit the infiltration and killing effects of CAR-M cells. Secondly, macrophages in the tumor microenvironment are easily “educated” into M2-type macrophages that support tumor growth, weakening their antitumor function. To overcome these problems, researchers are exploring various strategies such as optimizing CAR structure, combining other immunotherapies, and using biomaterials to aid CAR molecule delivery.</span></p> <h4><span style="font-size: 15px;">Advantages and Potential of CAR-M Therapy</span></h4> <h5><span style="font-size: 15px;">Multifunctionality of Macrophages</span></h5> <p><span style="font-size: 15px;">Macrophages play multiple roles in the immune system, including phagocytosing pathogens and cancer cells, secreting cytokines and chemokines, and regulating immune responses. These characteristics make macrophages ideal candidates for CAR immunotherapy. Studies have shown that CAR-M cells not only have the ability to directly phagocytose cancer cells but also can activate adaptive immune responses such as T cells through their antigen-presenting function, further enhancing antitumor effects.</span></p> <h5><span style="font-size: 15px;">Optimization Strategies for CAR-M Therapy</span></h5> <p><span style="font-size: 15px;">To improve the effectiveness of CAR-M therapy, researchers are continuously optimizing CAR design and the genetic modification of macrophages. For example, introducing different intracellular signaling domains such as CD3ζ and FcRγ can enhance the phagocytic ability and antitumor activity of macrophages. Additionally, combining advanced technologies such as in situ gene editing, synthetic biology, and biomaterial-assisted gene delivery can further enhance the safety and efficacy of CAR-M therapy.</span></p> <p><span style="font-size: 15px;">This system is mainly to improve the efficiency of gene editing, enabling these immune cells to efficiently express CAR molecules, thereby enhancing their antitumor activity. LNPs (lipid nanoparticles) are an advanced gene delivery tool whose use in mRNA vaccines (such as COVID-19 vaccines) has garnered widespread attention. The advantages of LNPs include high delivery efficiency, low toxicity, and good biocompatibility. Researchers use LNPs to deliver CAR-encoding mRNA to macrophages and T cells, enabling these cells to specifically recognize and kill tumor cells.</span></p> <p><span style="font-size: 15px;">In their research, researchers first optimized the composition of LNPs and the modification of mRNA to improve transfection efficiency in macrophages and T cells. Specifically, they screened a set of lipids and mRNAs and found that incorporating phosphatidylethanolamine (DOPE) into LNPs was crucial for nucleic acid delivery. In vitro experiments showed that this optimized LNP-mRNA system could effectively deliver CAR mRNA to mouse macrophages and human CD8+ T cells, enabling these cells to express CAR molecules and exhibit significant cytotoxic effects, effectively killing B-cell lymphoma cells.</span></p> <h5><span style="font-size: 15px;">Combining with Other Immunotherapies</span></h5> <p><span style="font-size: 15px;">In addition to optimizing CAR-M cells themselves, researchers are also exploring combining CAR-M therapy with other immunotherapies to achieve synergistic antitumor effects. For example, combining CAR-M cells with CAR-T cells can leverage the tumor infiltration ability of macrophages and the potent killing ability of T cells, forming complementary advantages. Additionally, combining checkpoint inhibitors such as anti-PD-1 antibody Pembrolizumab (Keytruda) can further release the immunosuppressive tumor microenvironment and enhance therapeutic effects.</span></p> <h5><span style="font-size: 15px;">Clinical Application Prospects </span><span style="font-size: 15px;">of CAR-M Therapy</span></h5> <p><span style="font-size: 15px;">As CAR-M therapy continues to develop, an increasing number of clinical trials are underway to evaluate its efficacy and safety in various types of cancer. CT-0508 and MCY-M11 are currently the fastest-progressing CAR-M therapies, both approved by the FDA to enter clinical trials for treating HER2-expressing recurrent or metastatic solid tumors and recurrent/refractory ovarian cancer and peritoneal mesothelioma.</span></p> <p><span style="font-size: 15px;">Preliminary clinical data show that CT-0508 exhibits good safety and tolerability in patients, with no significant dose-related toxicity. Additionally, CAR-M therapy shows better tumor suppression effects when delivered locally, providing new insights for future solid tumor treatments.</span></p> <p><span style="font-size: 15px;">Despite the immense potential of CAR-M therapy in cancer treatment, its clinical application still faces many challenges. Future research needs to continue optimizing CAR-M cell design, enhancing antitumor efficacy, and reducing potential side effects. Furthermore, exploring more efficient gene delivery systems and combination therapy strategies will help promote the widespread clinical application of CAR-M therapy.</span></p> <p><span style="font-size: 15px;">With the continuous advancement of gene editing technology, synthetic biology, and biomaterials science, there is reason to believe that CAR-M therapy will bring new hope and better treatment options for cancer patients in the near future. Through ongoing research and clinical validation, CAR-M therapy is expected to become an important component of cancer immunotherapy, providing a powerful weapon for tackling the challenge of solid tumors.</span></p> <p><span style="font-size: 15px;">CAR-macrophage therapy, as an emerging cancer immunotherapy method, has shown great application potential. Despite facing many challenges, through the tireless efforts of researchers and continuous technological advancements, there is reason to believe that CAR-M therapy will play an increasingly important role in future cancer treatment, bringing hope to more patients.</span></p> <p><span style="font-size: 15px;"><strong>Creative Biolabs</strong> masters the most advanced CAR/TCR technology. With state-of-art TCR development platforms and advanced technologies, Creative Biolabs is capable of offering a broad range of <a href="/car-t/one-stop-car-ma-therapy-development.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>CAR-MA therapy development</strong></span></a> services, from biomarker identification and selection, CAR design and construction, to CAR-MA preparation, and in vitro/in vivo assessments.</span></p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1</span><span style="color: #808080; font-size: 14px;">. Li, Na, et al. “A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy.” Molecular Cancer 23.1 (2024): 117.</span></p> ]]></content:encoded> </item> <item> <title>NK Cell Surveillance Limits T Cell Responses: Implications for Cancer Immunotherapy</title> <link>https://www.creative-biolabs.com/blog/car-t/nk-cell-surveillance-limits-t-cell-responses-implications-for-cancer-immunotherapy/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Fri, 10 May 2024 05:58:20 +0000</pubDate> <category><![CDATA[Cancer Immunotherapy]]></category> <category><![CDATA[News]]></category> <category><![CDATA[B7H6]]></category> <category><![CDATA[NK cell]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=912</guid> <description><![CDATA[Activated T cells with certain surface markers, such as checkpoint inhibitor proteins, are regulated by another type of immune system cell—natural killer (NK) cells. In this way, the body likely suppresses destructive<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/nk-cell-surveillance-limits-t-cell-responses-implications-for-cancer-immunotherapy/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Activated T cells with certain surface markers, such as checkpoint inhibitor proteins, are regulated by another type of immune system cell—natural killer (NK) cells. In this way, the body likely suppresses destructive immune responses. Researchers from the German Cancer Research Center and Mannheim University Medical Center have now discovered that NK cells can impair the effectiveness of immune checkpoint inhibitor (ICI) cancer therapies in this manner. They may also contribute to the rapid reduction of therapeutic CAR-T cells. Interventions targeting this mechanism could potentially enhance the efficacy of these cellular immunotherapies for cancer. The findings were published in the May 2024 issue of Science Immunology under the title “The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance”.</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/sciimmunol.adj7970-f5-scaled.jpg"><img decoding="async" class="aligncenter wp-image-913" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/sciimmunol.adj7970-f5-scaled.jpg" alt="" width="609" height="350" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/sciimmunol.adj7970-f5-scaled.jpg 2560w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/sciimmunol.adj7970-f5-300x172.jpg 300w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/sciimmunol.adj7970-f5-1024x588.jpg 1024w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/sciimmunol.adj7970-f5-768x441.jpg 768w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/sciimmunol.adj7970-f5-1536x882.jpg 1536w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/sciimmunol.adj7970-f5-2048x1176.jpg 2048w" sizes="(max-width: 609px) 100vw, 609px" /></a></p> <p><span style="font-size: 15px;">T cells in the immune system play a critical role in combating viral infections and tumor cells. However, they can also attack healthy tissues in autoimmune reactions, potentially with fatal consequences. Therefore, the body tightly controls the activity of T cells.</span></p> <p><span style="font-size: 15px;">A myriad of molecules and messengers are involved in the highly complex regulation of T cell activity. Recently, scientists have discovered that another type of immune cell is also involved in controlling T cell activity. <a href="/car-t/category-nk-cells-80.htm" target="_blank" rel="noopener"><strong><span style="color: #0000ff;">NK cells</span></strong></a> are part of innate immunity, acting as a rapid response force capable of swiftly detecting and eliminating infected or malignant cells.</span></p> <p><span style="font-size: 15px;">Michael Platten, co-corresponding author and head of the department at the German Cancer Research Center, stated, “Previous studies have shown that NK cells can kill activated T cells, thereby limiting their proliferation. However, it was not known what characteristics of T cells make them targets for NK cell action.”</span></p> <p><span style="font-size: 15px;">In this new study, the team led by Platten screened activated T cells from healthy donors and identified the protein <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/car-t/target-b7-h6-6.htm" target="_blank" rel="noopener">B7H6</a></span></strong> as a recognition molecule targeted by NK cells. Activated T cells from patients with autoimmune diseases, cancer, or viral infections showed significant surface expression of B7H6. Co-culture experiments conducted in petri dishes demonstrated that NK cells recognize activated T cells through the expression of B7H6. In contrast, T cells with the B7H6 gene disrupted by CRISPR-Cas did not undergo lethal attack by NK cells.</span></p> <p><span style="font-size: 15px;">Michael Kilian, co-corresponding author and first author of the paper, explained, “NK cells eliminate T cells through mechanisms intrinsic to T cells themselves. Activated T cells temporarily identify themselves as targets for NK-induced cell lysis,” and added, “This could potentially limit excessive activation and expansion of T cells as a control mechanism against destructive immune responses.”</span></p> <p><span style="font-size: 15px;">Platten elaborated, “We now know that certain immune checkpoint molecules can either diminish or enhance T cell activation, thus modulating the immune response process. B7H6 can now be classified as another inhibitory immune checkpoint on the surface of T cells.”</span></p> <p><span style="font-size: 15px;">Some widely used cancer therapies utilize immune checkpoint inhibitors (ICI) that target specific inhibitory immune checkpoint molecules. They work by releasing the immune system’s brakes to activate immune responses against tumors. Could the clearance of tumor-reactive T cells mediated by B7H6 counteract the efficacy of ICI cancer immunotherapies? The authors tested tissue samples from esophageal cancer patients who had undergone ICI therapy. Patients who did not respond to ICI treatment had more NK cells in their tumor tissues and shorter progression-free survival.</span></p> <p><span style="font-size: 15px;">Cellular immunotherapy is becoming increasingly important in cancer medicine. For example, certain forms of blood cancers now often use <a href="/car-t/one-stop-car-t-therapy-development-services.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>CAR-T cells</strong></span></a>, which carry customized receptors targeting cancer cells. However, the success of these therapies is often limited by the rapid depletion of therapeutic CAR-T cells in patients.</span></p> <p><span style="font-size: 15px;">These therapeutic CAR-T cells also express B7H6 on their cell surfaces. Could NK cells lead to their rapid depletion following treatment initiation? Experiments in humanized mouse models suggest this possibility: the addition of NK cells during CAR-T cell therapy for leukemia led to a reduction in therapeutic CAR-T cell numbers and an increase in tumor burden.</span></p> <p><span style="font-size: 15px;">Platten explained, “NK cell control of T cells could interfere with various forms of cancer immunotherapy. By specifically intervening in this process, it may be possible in the future to modulate immune responses of T cells.” With the help of CRISPR-Cas gene scissors, they now hope to collaborate with the Department of Hematology and Oncology at Heidelberg University Hospital in clinical trials to protect CAR-T cells from NK cell elimination, thereby enhancing the efficacy of cellular immunotherapy.</span></p> <p><span style="font-size: 15px;"><strong>Creative Biolabs</strong> masters the most advanced CAR/TCR technology. With state-of-art TCR development platforms and advanced technologies, Creative Biolabs is capable of offering a broad range of <a href="/car-t/one-stop-car-nk-therapy-development.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>CAR-NK therapy development</strong></span></a> services, including biomarker identification and selection, CAR-NK vector design and construction, and in vitro/in vivo assays.</span></p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1</span><span style="color: #808080; font-size: 14px;">. Kilian, Michael, et al. “The immunoglobulin superfamily ligand B7H6 subjects T cell responses to NK cell surveillance.” Science Immunology 9.95 (2024): eadj7970.</span></p> ]]></content:encoded> </item> <item> <title>High-throughput Discovery of Tumor-Reactive T Cell Receptors: Advancing Personalized Cellular Immunotherapy</title> <link>https://www.creative-biolabs.com/blog/car-t/high-throughput-discovery-of-tumor-reactive-t-cell-receptors-advancing-personalized-cellular-immunotherapy/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Fri, 26 Apr 2024 05:49:37 +0000</pubDate> <category><![CDATA[Cancer Immunotherapy]]></category> <category><![CDATA[TCR Research]]></category> <category><![CDATA[Personalized Cellular Immunotherapy]]></category> <category><![CDATA[TCR engineered T cell]]></category> <category><![CDATA[Tumor-Reactive T Cell Receptor]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=907</guid> <description><![CDATA[T-cell receptor (TCR) gene therapy is a form of cellular immunotherapy where peripheral blood T cells from cancer patients are genetically engineered ex vivo to express tumor-specific TCRs before being reintroduced into<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/high-throughput-discovery-of-tumor-reactive-t-cell-receptors-advancing-personalized-cellular-immunotherapy/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">T-cell receptor (TCR) gene therapy is a form of cellular immunotherapy where peripheral blood T cells from cancer patients are genetically engineered ex vivo to express tumor-specific TCRs before being reintroduced into the patient’s body. Compared to other immunotherapies like immune checkpoint blockade or tumor-infiltrating lymphocyte therapy, therapeutic TCR gene transfer allows precise control over the engineered T cells’ specificity, which strictly depends on the selected TCR. Furthermore, <a href="/car-t/tcr-engineered-t-cell-development.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>TCR-engineered T cells</strong></span></a> constructed ex vivo permit additional genetic modifications to maximize their activity and persistence in vivo.</span></p> <p><span style="font-size: 15px;"><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41587_2024_2210_Fig3_HTML.png"><img decoding="async" loading="lazy" class="aligncenter wp-image-909" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41587_2024_2210_Fig3_HTML.png" alt="" width="600" height="602" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41587_2024_2210_Fig3_HTML.png 1200w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41587_2024_2210_Fig3_HTML-300x300.png 300w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41587_2024_2210_Fig3_HTML-1021x1024.png 1021w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41587_2024_2210_Fig3_HTML-150x150.png 150w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/07/41587_2024_2210_Fig3_HTML-768x770.png 768w" sizes="(max-width: 600px) 100vw, 600px" /></a></span></p> <p><span style="font-size: 15px;">However, in many patients, tumor-specific TCRs represent only a small fraction of the peripheral or tumor-infiltrating TCR repertoire, complicating the identification of relevant therapeutic TCRs from patient sources. Additionally, many highly immunogenic tumor antigens, such as cancer neoantigens generated by patient-specific tumor mutations, are unique to individual patients, highlighting the need for truly personalized approaches in discovering therapeutic TCRs.</span></p> <p><span style="font-size: 15px;">While the role of major histocompatibility complex (MHC) class I-restricted CD4+ T cells in anti-tumor immunity is well-established, recent data emphasize the importance of MHC class II-restricted CD4+ T cells in direct anti-tumor cytotoxicity and enhancing the activity of tumor-specific CD8+ T cells, crucial for tumor control and immune therapy responsiveness. Thus, there is a need for new technologies capable of high-throughput discovery of both MHC class I and class II-restricted TCRs at the individual patient level.</span></p> <p><span style="font-size: 15px;">On April 23, 2024, Ely Porter from RootPath, and Wouter Scheper from the Netherlands Cancer Institute published a study titled “Discovery of tumor-reactive T cell receptors by massively parallel library synthesis and screening” in the journal Nature Biotechnology. This research developed a high-throughput, personalized technology for discovering T-cell receptors (TCRs), combining the assembly of large-scale synthetic TCR libraries with high-throughput genetic screening to screen and discover tumor-reactive TCRs in a single experiment, significantly reducing the time required for TCR discovery and promising to be a powerful tool for designing cellular immunotherapies.</span></p> <p><span style="font-size: 15px;">In this study, the research team developed a high-throughput, personalized TCR discovery technology that integrates the assembly of large-scale synthetic TCR libraries with high-throughput genetic screening, enabling functional analysis of specificity for thousands of individual TCRs in a single experiment. Importantly, by generating patient-derived synthetic TCR libraries, this method allows evaluation of TCR specificity independent of patient T-cell phenotypic adaptability and clonal abundance.</span></p> <p><span style="font-size: 15px;">Using this technology, the research team screened thousands of TCRs derived from tumor-infiltrating lymphocytes (TILs) from multiple cancer patients and identified dozens of potent tumor-reactive TCRs sourced from CD4+ and CD8+ T cells, including those recognizing patient-specific neoantigens.</span></p> <p><span style="font-size: 15px;">The researchers indicate that this method facilitates the identification of tumor antigen-specific TCRs for next-generation personalized TCR gene therapy. By employing a meticulously optimized workflow compliant with good laboratory practice (GLP), the discovery of therapeutic TCRs using this technology is expected to be achieved within 4-5 weeks (from patient tissue sampling to TCR validation), whereas discovery of existing TCRs or tumor antigens could typically take 3-5 months. Thus, the approach proposed by this study represents a potent tool for future design of cellular immunotherapies.</span></p> <p><span style="font-size: 15px;"><strong>Creative Biolabs</strong> masters the most advanced CAR/TCR technology. With state-of-art TCR development platforms and advanced technologies, Creative Biolabs is capable of offering a broad range of <a href="/car-t/tcr-engineered-t-cell-development.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>TCR-T therapy development</strong></span></a> services, including TCR engineered T cell biomarker identification and selection, design, construction, and analysis.</span></p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1</span><span style="color: #808080; font-size: 14px;">. Moravec, Ziva, et al. “Discovery of tumor-reactive T cell receptors by massively parallel library synthesis and screening.” Nature Biotechnology (2024): 1-9.</span></p> ]]></content:encoded> </item> <item> <title>Overcoming Resistance: Enhancing CAR-T Therapy for AML with TP53 Mutations</title> <link>https://www.creative-biolabs.com/blog/car-t/overcoming-resistance-enhancing-car-t-therapy-for-aml-with-tp53-mutations/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Wed, 27 Mar 2024 05:48:35 +0000</pubDate> <category><![CDATA[Chimeric Antigen Receptor Research]]></category> <category><![CDATA[News]]></category> <category><![CDATA[CAR-T therapy]]></category> <category><![CDATA[TP53]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=900</guid> <description><![CDATA[Acute myeloid leukemia (AML) is an aggressive blood cancer caused by a plethora of genetic mutations acquired throughout one’s lifetime. One of these genes, the tumor suppressor gene TP53, plays a crucial<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/overcoming-resistance-enhancing-car-t-therapy-for-aml-with-tp53-mutations/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">Acute myeloid leukemia (AML) is an aggressive blood cancer caused by a plethora of genetic mutations acquired throughout one’s lifetime. One of these genes, the tumor suppressor gene TP53, plays a crucial role. Normally, TP53 helps prevent tumor formation. However, if this gene mutates in leukemia patients, their prognosis becomes very poor because their genes develop resistance to conventional chemotherapy drugs. Therefore, there is currently intensive research into new treatment methods such as CAR-T cell therapy. <span style="color: #0000ff;"><a style="color: #0000ff;" href="/car-t/one-stop-car-t-therapy-development-services.htm" target="_blank" rel="noopener"><strong>CAR-T cell therapy</strong></a></span> has already been successfully used for other blood cancers.</span></p> <p><span style="font-size: 15px;">In a recent study, researchers from institutions including the University of Zurich and Zurich University Hospital in Switzerland discovered a specific mutation in cancer cells of an aggressive blood cancer that hinders the effectiveness of novel immunotherapies like CAR-T cell therapy. Their research also elucidated the reasons for cancer cells developing resistance and how to overcome this resistance: by simultaneously using drug therapy or genetically modified CAR-T cells. The related research findings were published in the EMBO Molecular Medicine journal on March 14, 2024, titled “Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.”</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/04/44321_2024_24_figa_html.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-901" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/04/44321_2024_24_figa_html.jpg" alt="" width="528" height="484" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/04/44321_2024_24_figa_html.jpg 550w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/04/44321_2024_24_figa_html-300x275.jpg 300w" sizes="(max-width: 528px) 100vw, 528px" /></a></p> <p><span style="font-size: 15px;">An international research group led by Professor Markus Manz and Professor Steffen Boettcher from the Department of Oncology and Hematology at the University of Zurich and Zurich University Hospital has now confirmed that AML cells carrying TP53 mutations exhibit significantly higher resistance to a novel immunotherapy, CAR-T cell therapy, compared to AML cells without this mutation.</span></p> <p><span style="font-size: 15px;">Boettcher stated, “The reason for the poor effectiveness of CAR-T cells with mutated TP53 genes is that these immune cells exhaust more quickly, thus exhibiting lower activity against cancer cells.”</span></p> <p><span style="font-size: 15px;">In CAR-T cell therapy, specific immune cells called T cells are extracted from the patient’s blood. These immune cells are then genetically modified in the laboratory to form numerous new contact points on their surface, known as chimeric antigen receptors (CARs). Once reintroduced into the patient’s body, these CAR-T cells can recognize certain surface structures of tumor cells, enabling them to identify and selectively eliminate cancer cells. Currently, various <a href="https://www.creative-biolabs.com/car-t/pl-car-cell-products-108.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>CAR cell products</strong></span></a> are undergoing early clinical trials for testing against AML.</span></p> <p><span style="font-size: 15px;">In this new study, the authors not only explored the mechanisms by which AML cells with mutated TP53 genes develop resistance to CAR-T cell immunotherapy but also discovered how to enhance the endurance of CAR-T cells and exploit the weaknesses of AML cells with mutated <a href="/car-t/target-p53-170.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>TP53</strong></span></a> genes to overcome this resistance.</span></p> <p><span style="font-size: 15px;">Through additional drug-assisted therapy or further genetic improvements to CAR-T cells, they were able to significantly enhance the efficacy of CAR-T cells against AML cells with mutated TP53 genes, to the point where there was no longer any treatment difference compared to AML cells without TP53 gene mutations.</span></p> <p><span style="font-size: 15px;">Manz said, “This proof-of-concept study suggests that the simultaneous use of drug therapy and genetically modified CAR-T cells is an effective strategy for developing more effective and tolerable immunotherapies for AML patients with mutated TP53 genes.”</span></p> <h5>What We Do</h5> <p><span style="font-size: 15px;">As the leading cell therapeutics biotech that provides CAR-T cell therapy related services, Creative Biolabs masters the most advanced technology and has a very rich extensive experience and thus, can offer the best CAR products and CAR design & construction services.Our anti-TP53 products ranging from TCR vectors, TCR viral particles, TriCAR cectors, to TCR-like CAR products.</span></p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1. Mueller, Jan, <em>et al</em>. “Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.” EMBO Molecular Medicine (2024): 1-30.</span></p> ]]></content:encoded> </item> <item> <title>Prospects of TCR-T Cell Therapy in Cancer Treatment</title> <link>https://www.creative-biolabs.com/blog/car-t/prospects-of-tcr-t-immunotherapy-in-cancer-treatment/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Sun, 18 Feb 2024 08:22:07 +0000</pubDate> <category><![CDATA[Cancer Immunotherapy]]></category> <category><![CDATA[Chimeric Antigen Receptor Research]]></category> <category><![CDATA[TCR-T cell therapy]]></category> <category><![CDATA[TCR-T Therapy]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=892</guid> <description><![CDATA[T-cell receptor-engineered T cells (TCR-T) represent a form of cellular immunotherapy and a subtype of adoptive cell transfer (ACT). It involves the identification and selection of TCR sequences capable of specifically binding<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/prospects-of-tcr-t-immunotherapy-in-cancer-treatment/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">T-cell receptor-engineered T cells (TCR-T) represent a form of cellular immunotherapy and a subtype of adoptive cell transfer (ACT). It involves the identification and selection of TCR sequences capable of specifically binding target antigens, genetically engineering T cells from the patient’s peripheral blood to express these selected TCRs, and then reinfusing these modified T cells back into the patient. This enables the T cells to selectively recognize and eliminate tumor cells expressing the target antigens, thereby achieving therapeutic goals in cancer treatment.</span></p> <h5><span style="font-size: 15px;">Comparison between TCR-T and CAR-T</span></h5> <p><span style="font-size: 15px;">Some TCR-T products have been utilized domestically and internationally for treating patients with refractory/recurrent melanoma, synovial sarcoma, multiple myeloma, lung cancer, among others, showing promising safety profiles and efficacy in certain clinical trial settings. Compared to <span style="color: #0000ff;"><a style="color: #0000ff;" href="/car-t/one-stop-car-t-therapy-development-services.htm" target="_blank" rel="noopener"><strong>CAR-T therapy</strong></a></span>, TCR-T demonstrates superior penetration into solid tumors, enhanced specificity towards tumor cells, and a lower risk of immune rejection and antibody generation.</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g003.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-895" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g003.jpg" alt="" width="599" height="367" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g003.jpg 2362w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g003-300x184.jpg 300w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g003-1024x628.jpg 1024w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g003-768x471.jpg 768w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g003-1536x942.jpg 1536w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g003-2048x1256.jpg 2048w" sizes="(max-width: 599px) 100vw, 599px" /></a></p> <p><span style="font-size: 15px;">The primary distinction between CAR-T and TCR-T lies in how they recognize tumor cells. CAR-T involves the genetic engineering of T cells to express chimeric antigen receptors (CARs), allowing them to recognize non-MHC (major histocompatibility complex) restricted antigens on the surface of tumor cells. Conversely, TCR-T modifies the natural T cell receptors on T cells to recognize MHC-restricted antigens on the surface of tumor cells.</span></p> <p><span style="font-size: 15px;">A key advantage of TCR-T therapy lies in its ability to target MHC-restricted antigens on tumor cells, which are often highly expressed on the surface of tumor cells, enabling TCR-T cells to more accurately identify and attack tumor cells. Additionally, TCR-T therapy exhibits lower immunogenicity since it utilizes naturally occurring T cell receptors rather than artificially synthesized CARs, thus less likely to elicit immune responses.</span></p> <p><strong><span style="font-size: 15px;">TCR-T Technologies</span></strong></p> <p><span style="font-size: 15px;">In recent years, numerous innovations have emerged in T-cell receptor (TCR) engineering technologies aimed at improving T cell recognition of specific tumor antigens and treatment efficacy. For instance: </span><span style="font-size: 15px;">Immune mobilizing monoclonal TCRs Against Cancer (ImmTAC) are fusion proteins combining engineered TCRs with single-chain antibody fragments to enhance T cell persistence and anti-tumor activity. Unlike antibodies targeting surface or secreted proteins alone, ImmTACs’ TCRs can recognize intracellular target peptides presented by HLA.</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g004.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-894" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g004.jpg" alt="" width="630" height="336" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g004.jpg 2362w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g004-300x160.jpg 300w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g004-1024x547.jpg 1024w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g004-768x410.jpg 768w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g004-1536x820.jpg 1536w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/03/fimmu-12-658753-g004-2048x1093.jpg 2048w" sizes="(max-width: 630px) 100vw, 630px" /></a></p> <p><span style="font-size: 15px;">T-cell Receptor Fusion Constructs (TRuCs) fuse antibody-based binding domains with TCR subunits, presenting novel target specificity and HLA-independent capabilities, thereby precisely identifying tumor surface antigens. TRuCs integrate into T cell surface TCR complexes, retaining their activation and effector functions, with superior anti-tumor effects compared to second-generation CAR-T cells. Additionally, TRuCs predominantly utilize TCR signaling while CARs employ limited CD3z signaling.</span></p> <p><span style="font-size: 15px;">T cell Antigen Couplers (TACs) constitute an MHC-independent platform enhancing anti-tumor responses and reducing toxicity by combining CD3 domain with TCR. TAC activity relies on the selection of CD3 binding domains, where subtle differences may lead to significant functional outcomes. Compared to second-generation CARs, TAC-engineered T cells demonstrate advantages in solid tumor infiltration, reduced expansion of healthy tissue-resident T cells, and off-tumor toxicity reduction.</span></p> <h5><span style="font-size: 15px;">Advancements in TCR-T Research</span></h5> <p><span style="font-size: 15px;">Reducing TCR mispairing to enhance expression and functionality</span><br /> <span style="font-size: 15px;">TCR-T therapy relies on introducing TCR genes with tumor reactivity into T cells via mRNA or viral transduction to redirect T cells specifically towards tumor cells. However, the presence of endogenous TCR genes may lead to mispairing, posing safety risks such as graft-versus-host disease (GvHD). Several strategies have been explored to reduce mispairing, including introducing inter-chain disulfide bonds, substituting human TCR constant domains with mouse sequences, manipulating TCR constant domains, generating single-chain TCRs (scTCRs), and genetically editing out endogenous TCRs. Furthermore, gene editing technologies like CRISPR/Cas9 hold potential in TCR-T therapy but need to address challenges such as off-target toxicity.</span></p> <ul> <li><strong><span style="font-size: 15px;">Enhancing T cell persistence</span></strong></li> </ul> <p><span style="font-size: 15px;">T cell persistence is crucial for immune surveillance, yet tumor-specific T cells infused into non-responding patients often lack persistence. To enhance T cell persistence, researchers are actively exploring combinations of various cytokines, some of which have entered clinical trial stages. Additionally, preconditioning regimens such as lymphodepletion can conserve limited cytokines, eliminate immunosuppressive cells like Tregs and MDSCs, and enhance T cell engraftment and expansion. Moreover, selecting less differentiated T cell subsets like Tscm and Tcm cells, modified with CARs to produce antigen-specific T cells, can also enhance persistence and functionality, mediating strong and enduring anti-tumor responses.</span></p> <ul> <li><strong><span style="font-size: 15px;">Optimizing T cell migration</span></strong></li> </ul> <p><span style="font-size: 15px;">Effective migration and infiltration of tumor-specific T cells into solid tumors rely on the interaction between tumor-secreted chemokines and chemokine receptor expression on T cells. Designing T cells to express specific chemokine receptors is crucial for enhancing this process’s efficiency. By expressing receptors like CCR2, CXCR2, CCR4, and CXCR4 on Tc cells, significant improvement in T cell homing and localization to tumors can be achieved, thereby enhancing their anti-tumor activity. These strategies demonstrate immense potential and clinical prospects in the field of tumor immunotherapy. Additionally, combining with radiotherapy and chemotherapy can further promote T cell homing and infiltration. While approved cancer chemokine immunotherapy strategies are yet to be established, multiple studies show promising clinical potential.</span></p> <ul> <li><strong><span style="font-size: 15px;">Overcoming the tumor immune microenvironment</span></strong></li> </ul> <p><span style="font-size: 15px;">Tumor cells reside in a complex microenvironment consisting of various immunosuppressive cells, factors, and stroma, collectively supporting tumor growth, migration, metastasis, and evasion from immune system attacks. To improve this immunosuppressive environment, various strategies have been explored. Direct use of immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies can enhance immune responses, although challenges of resistance and toxicity remain.</span><br /> <span style="font-size: 15px;">To overcome these challenges, researchers utilize chimeric switch receptors (CSRs) to convert immune inhibitory signals within T cells into stimulatory signals, such as PD-1:CD28 combinations, enhancing T cell anti-tumor effects. Meanwhile, blockade of immune inhibitory factors such as TGF-β also enhances immunotherapy efficacy. These strategies demonstrate the potential to convert immune suppression into stimulatory signals, providing new directions for tumor immunotherapy.</span></p> <ul> <li><strong><span style="font-size: 15px;">Developing new targets</span></strong></li> </ul> <p><span style="font-size: 15px;">The application of TCR-T cell therapy in cancer is limited by effective and safe antigen targets. Currently, tumor-associated antigens are predominantly used, but they may lead to autoimmune toxicity. Truly tumor-specific antigens and novel antigens present safer alternatives. Personalization and heterogeneity of novel antigens pose challenges in clinical development. With advancements in sequencing technologies, personalized TCR-T immunotherapy targeting novel antigens may become mainstream in the future. “Hot” tumors with higher TIL content are sensitive to checkpoint blockade therapy, and combining therapies can enhance the efficacy of TCR-T cell therapy. Newly identified tumor-associated antigens also offer potential targets for future TCR-T therapy.</span></p> <p><strong>Creative Biolabs</strong> masters the most advanced CAR/TCR technology. With state-of-art TCR development platforms and advanced technologies, Creative Biolabs is capable of offering a broad range of <a href="/car-t/tcr-engineered-t-cell-development.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>TCR-T therapy development</strong></span></a> services, including TCR engineered T cell biomarker identification and selection, design, construction, and analysis.</p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1</span><span style="color: #808080; font-size: 14px;">. </span><span style="color: #808080; font-size: 14px;">Zhao, Qijie, et al. “Engineered TCR-T cell immunotherapy in anticancer precision medicine: pros and cons.” Frontiers in immunology 12 (2021): 658753.</span></p> <p> </p> ]]></content:encoded> </item> <item> <title>Positive Outcomes in Clinical Trial of Cord Blood-Derived CAR-NK Cell Therapy for B Cell Malignancies</title> <link>https://www.creative-biolabs.com/blog/car-t/positive-outcomes-in-clinical-trial-of-cord-blood-derived-car-nk-cell-therapy-for-b-cell-malignancies/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Fri, 26 Jan 2024 05:26:46 +0000</pubDate> <category><![CDATA[Chimeric Antigen Receptor Research]]></category> <category><![CDATA[News]]></category> <category><![CDATA[B Cell Malignancies]]></category> <category><![CDATA[CAR-NK]]></category> <category><![CDATA[CD19]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=889</guid> <description><![CDATA[In a recent study, researchers from the University of Texas MD Anderson Cancer Center in the United States reported favorable results from a Phase I/II clinical trial involving 37 patients with relapsed<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/positive-outcomes-in-clinical-trial-of-cord-blood-derived-car-nk-cell-therapy-for-b-cell-malignancies/">Read More...</a>]]></description> <content:encoded><![CDATA[<p>In a recent study, researchers from the University of Texas MD Anderson Cancer Center in the United States reported favorable results from a Phase I/II clinical trial involving 37 patients with relapsed or refractory B cell malignancies. The patients received targeted <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/car-t/target-cd19-12.htm" target="_blank" rel="noopener">CD19</a></span></strong>-specific cord blood-derived chimeric antigen receptor (CAR) natural killer (NK) cell therapy. The results showed an overall response rate of 48.6% after 100 days of treatment, with one-year progression-free survival and overall survival rates of 32% and 68%, respectively. The clinical trial, emphasizing excellent safety with no severe cytokine release syndrome, neurotoxicity, or graft-versus-host disease, was published online in the Nature Medicine journal on January 18, 2024, titled “Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial.”</p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41591_2023_2785_Fig1_HTML.png"><img decoding="async" loading="lazy" class="aligncenter wp-image-890" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41591_2023_2785_Fig1_HTML.png" alt="" width="619" height="694" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41591_2023_2785_Fig1_HTML.png 1725w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41591_2023_2785_Fig1_HTML-268x300.png 268w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41591_2023_2785_Fig1_HTML-913x1024.png 913w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41591_2023_2785_Fig1_HTML-768x861.png 768w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41591_2023_2785_Fig1_HTML-1370x1536.png 1370w" sizes="(max-width: 619px) 100vw, 619px" /></a></p> <p>Another crucial finding from the clinical trial was the significance of donor selection criteria for allogeneic cord blood-derived CAR-NK cell manufacturing. Cord blood units frozen within 24 hours of collection and units with low nucleated red cell content were associated with significantly better outcomes. CAR-NK cells derived from these units demonstrated a one-year progression-free survival rate of 69% and an overall survival rate of 94%. In contrast, CAR-NK cells produced from units with higher nucleated red cell content or longer collection-to-freezing times had a one-year progression-free survival rate of 5% and an overall survival rate of 48%.</p> <p>Dr. Katy Rezvani, the corresponding author and professor of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center, stated, “The responses observed in these patients are very encouraging as we continue to evaluate the long-term efficacy of <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/car-t/one-stop-car-nk-therapy-development.htm" target="_blank" rel="noopener">CAR-NK cell therapy</a></span></strong> for these malignancies. To achieve successful allogeneic cell therapy, we must also identify characteristics of the optimal cord blood donor for CAR-NK cell manufacturing. We were able to identify two key factors associated with cord blood units most likely to yield a positive clinical response and uncover the biological mechanisms behind this phenomenon.”</p> <p>The study also highlighted encouraging response rates for different types of B cell malignancies. Patients with low-grade non-Hodgkin lymphoma achieved a 100% overall response rate 30 days post-treatment, while those with untreated chronic lymphocytic leukemia had a 67% overall response rate, and diffuse large B-cell lymphoma (DLBCL) patients had a 41% overall response rate.</p> <p>The researchers observed durable responses to CAR-NK cell therapy. One year after treatment, 83% of low-grade non-Hodgkin lymphoma patients, 50% of chronic lymphocytic leukemia patients, and 29% of DLBCL patients achieved a complete response. Patients who responded 30 days after treatment had significantly increased chances of progression-free survival one year later.</p> <p>Rezvani commented, “Our research underscores the importance of identifying predictive indicators of response after donor-specific allogeneic cell therapy, particularly as one donor may be used to treat hundreds of patients. CAR-NK cells have the potential for advanced manufacturing and storage for immediate use, increasing patients’ chances to access these cell therapies, reducing treatment time, and lowering treatment costs.”</p> <p>The selection criteria identified in this study are being applied in clinical trials at the University of Texas MD Anderson Cancer Center, where genetically modified cord blood NK cells are used to target other antigens and malignancies, including solid tumors.</p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1. Marin, David, et al. “Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial.” Nature Medicine (2024): 1-13.</span></p> ]]></content:encoded> </item> <item> <title>Enhancing CAR-T Cell Therapy: Modular Cytokine Receptors Boost Anti-Tumor Activity in Solid Tumors</title> <link>https://www.creative-biolabs.com/blog/car-t/enhancing-car-t-cell-therapy-modular-cytokine-receptors-boost-anti-tumor-activity-in-solid-tumors/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Wed, 06 Dec 2023 09:18:22 +0000</pubDate> <category><![CDATA[Cancer Immunotherapy]]></category> <category><![CDATA[Chimeric Antigen Receptor Research]]></category> <category><![CDATA[CAR-T cell therapy]]></category> <category><![CDATA[Solid Tumors]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=886</guid> <description><![CDATA[The use of modified chimeric antigen receptor (CAR) T cells (CAR-T) in immunotherapy has significantly improved the survival rates of pediatric patients with relapsed leukemia. However, these therapies are not as effective<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/enhancing-car-t-cell-therapy-modular-cytokine-receptors-boost-anti-tumor-activity-in-solid-tumors/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">The use of modified chimeric antigen receptor (CAR) T cells (CAR-T) in immunotherapy has significantly improved the survival rates of pediatric patients with relapsed leukemia. However, these therapies are not as effective in treating solid tumors and may carry substantial toxicity. In a new study, researchers from St. Jude Children’s Research Hospital in the United States found that incorporating a modular chimeric cytokine receptor into CAR-T cells enhances their efficacy in various solid tumor models. The research findings were published online in the Nature Biomedical Engineering journal on November 30, 2023, under the title “Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling.”</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41551_2023_1143_Fig1_HTML.png"><img decoding="async" loading="lazy" class="aligncenter wp-image-887" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41551_2023_1143_Fig1_HTML.png" alt="" width="627" height="719" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41551_2023_1143_Fig1_HTML.png 1828w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41551_2023_1143_Fig1_HTML-262x300.png 262w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41551_2023_1143_Fig1_HTML-893x1024.png 893w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41551_2023_1143_Fig1_HTML-768x881.png 768w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41551_2023_1143_Fig1_HTML-1339x1536.png 1339w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2024/02/41551_2023_1143_Fig1_HTML-1785x2048.png 1785w" sizes="(max-width: 627px) 100vw, 627px" /></a></p> <p><span style="font-size: 15px;">The lead author of the paper, Matthew Bell, stated, “We designed modular chimeric cytokine receptors and demonstrated their ability to improve CAR-T cells. From our models, it appears that this technique has the potential to broadly enhance the effectiveness of <strong><span style="color: #0000ff;"><a style="color: #0000ff;" href="/car-t/one-stop-car-t-therapy-development-services.htm" target="_blank" rel="noopener">CAR-T cell therapy</a></span></strong> for solid tumors and brain tumors.”</span></p> <p><span style="font-size: 15px;">CAR-T cells are modified immune cells from the patient that can target and kill cancer cells. Signals from solid tumors can deactivate CAR-T cells, reducing the efficacy of treatment. To address this issue, scientists combined CAR-T cells with cytokine injections; however, this approach could lead to severe unexpected toxicity. The new method developed by the authors allows the delivery of pro-immune signals from cytokines exclusively to CAR-T cells, eliminating systemic toxicity.</span></p> <p><span style="font-size: 15px;">Bell explained, “Our approach confines the action of cytokine signals solely to the modified CAR-T cells. In turn, this reduces the likelihood of cytokine-related toxicity and provides the signals necessary for these CAR-T cells to effectively function in the inhibitory tumor microenvironment.”</span></p> <p><span style="font-size: 15px;">The corresponding author, Dr. Stephen Gottschalk from St. Jude Children’s Research Hospital’s Bone Marrow Transplantation and Cellular Therapy Division, said, “Our modular chimeric cytokine receptors represent an approach to improve current CAR-T cell therapy for solid tumors, as the effectiveness of this therapy has been somewhat disappointing in early clinical trials. Our preliminary study results suggest an improvement in tumor control in various model systems, which is promising.”</span></p> <p><span style="font-size: 15px;">The authors replaced the extracellular domains of different cytokine receptors with a leucine zipper motif, creating constitutively active receptors. CAR-T cells expressing modular chimeric cytokine receptors demonstrated stronger anti-tumor activity against various cancer types in cell lines and mouse models compared to traditional CAR-T cells. While modular chimeric cytokine receptors provide a sustained “on” signal to CAR-T cells, they do not induce nonspecific proliferation of CAR-T cells.</span></p> <p><span style="font-size: 15px;">Gottschalk explained, “We are pleased to find that modular chimeric cytokine receptors only slightly activate the cytokine pathway. In the absence of tumor cells, these receptors can enhance the survival of CAR-T cells without causing proliferation. To optimize the <a href="/car-t/car-design-construction.htm" target="_blank" rel="noopener"><strong><span style="color: #0000ff;">chimeric cytokine receptor design</span></strong></a> and characterization, we collaborated closely with several researchers from St. Jude Children’s Research Hospital, including Giedre Krenciute, Jiyang Yu, Junmin Peng, Hongbo Chi, and Madan Babu.”</span></p> <p><span style="font-size: 15px;">Bell concluded, “Ultimately, we have identified a method to enhance CAR-T cell anti-tumor activity, which may be more effective and safer than cytokine injections.”</span></p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1. Bell, Matthew, et al. “Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling.” Nature Biomedical Engineering (2023): 1-17.</span></p> ]]></content:encoded> </item> <item> <title>CAR-T Cell Therapy May Lead to HHV-6 Virus Reactivation</title> <link>https://www.creative-biolabs.com/blog/car-t/car-t-cell-therapy-may-lead-to-hhv-6-virus-reactivation/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Fri, 10 Nov 2023 03:22:47 +0000</pubDate> <category><![CDATA[Chimeric Antigen Receptor Research]]></category> <category><![CDATA[News]]></category> <category><![CDATA[CAR-T cell therapy]]></category> <category><![CDATA[HHV-6]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=763</guid> <description><![CDATA[In a recent study, researchers from Stanford University in the United States collected data from previous studies on CAR-T cell therapy to investigate the reactivation of human herpesvirus 6 (HHV-6) in patients<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/car-t-cell-therapy-may-lead-to-hhv-6-virus-reactivation/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">In a recent study, researchers from Stanford University in the United States collected data from previous studies on CAR-T cell therapy to investigate the reactivation of human herpesvirus 6 (HHV-6) in patients undergoing chimeric antigen receptor (CAR) T cell therapy. The study aimed to describe the characteristics of HHV-6 reactivation, especially in the context of CAR-T cell therapy for B-cell lymphoma or leukemia. The researchers found that CAR-T cell therapy could potentially lead to the reactivation of HHV-6 in patients. The relevant research findings were published in the November 16, 2023, issue of the Nature journal under the title “Latent human herpesvirus 6 is reactivated in CAR T cells.”</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/11/41586_2023_6704_Fig1_HTML.png"><img decoding="async" loading="lazy" class="aligncenter wp-image-764" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/11/41586_2023_6704_Fig1_HTML.png" alt="" width="961" height="619" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/11/41586_2023_6704_Fig1_HTML.png 2153w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/11/41586_2023_6704_Fig1_HTML-300x193.png 300w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/11/41586_2023_6704_Fig1_HTML-1024x659.png 1024w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/11/41586_2023_6704_Fig1_HTML-768x494.png 768w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/11/41586_2023_6704_Fig1_HTML-1536x989.png 1536w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/11/41586_2023_6704_Fig1_HTML-2048x1318.png 2048w" sizes="(max-width: 961px) 100vw, 961px" /></a></p> <p><span style="font-size: 15px;">The authors reanalyzed the single-cell RNA sequencing (scRNA-seq) datasets of three groups of patients treated with autologous <a href="/car-t/product.htm" target="_blank" rel="noopener"><strong><span style="color: #0000ff;">CAR-T cell products</span></strong></a>. While HHV-6 virus transcripts were not detected in CAR-T cell products before infusion, a significant increase in HHV-6+ cells was observed in post-infusion samples.</span></p> <p><span style="font-size: 15px;">The authors found that 28 CAR-T cells in post-infusion samples expressed HHV-6B transcripts, with 13 CAR-T cells resembling HHV-6 “super-expressor” cells, a rarity in research-grade allogeneic CAR-T cells. Detailed temporal analysis of two patients with HHV-6 super-expression showed the appearance of HHV-6+ cells one week after treatment, aligning with clinical symptoms of immune effector-related neurotoxicity syndrome. Symptoms such as confusion and decline in neurocognitive abilities matched the presence of HHV-6 virus in the blood, though causation was not established for all patients.</span></p> <p><span style="font-size: 15px;">These findings suggest a connection between T cell activation, proliferation, and culture duration and the reactivation of HHV-6, emphasizing the need for further consideration in the development and monitoring of CAR-T cell therapy.</span><br /> <span style="font-size: 15px;">The new study also identified HHV-6B reactivation events in standard CD4+ T cell cultures, confirming a potential association between cell therapy products and lytic HHV-6 infection, a correlation previously reported in clinical trials of <a href="/car-t/one-stop-car-t-therapy-development-services.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>CAR-T cell therapy</strong></span></a></span><span style="font-size: 15px;">. </span></p> <p><span style="font-size: 15px;">HHV-6B infection occurs in nearly 70% of individuals before the age of three, leading to a common childhood illness—subacute erythematous rash or infantile roseola. By adulthood, approximately 95% of people have been infected with this virus. During the primary infection period, the virus is present in various cell and tissue types, and viral DNA continues to survive in peripheral blood mononuclear cells after infection.</span></p> <p><span style="font-size: 15px;">The authors emphasize the role of comprehensive genomic analysis in identifying cell therapy products as potential sources of virus infection. The correlation between HHV-6 reactivation and CAR-T cell therapy suggests the possibility of other latent viruses reactivating in various cell therapies, prompting the need for further research.</span></p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1. Lareau, Caleb A., et al. “Latent human herpesvirus 6 is reactivated in CAR T cells.” Nature 623.7987 (2023): 608-615.</span></p> ]]></content:encoded> </item> <item> <title>A Lego-Like Gene Editing Tool: ModPoKI, Paving the Way for Enhanced CAR-T Cell Therapy</title> <link>https://www.creative-biolabs.com/blog/car-t/a-lego-like-gene-editing-tool-modpoki-paving-the-way-for-enhanced-car-t-cell-therapy/</link> <dc:creator><![CDATA[biocart]]></dc:creator> <pubDate>Thu, 05 Oct 2023 10:21:57 +0000</pubDate> <category><![CDATA[Chimeric Antigen Receptor Research]]></category> <category><![CDATA[News]]></category> <category><![CDATA[CAR-T cell therapy]]></category> <category><![CDATA[ModPoKI]]></category> <guid isPermaLink="false">https://www.creative-biolabs.com/blog/car-t/?p=756</guid> <description><![CDATA[In recent years, scientists have harnessed the power of gene editing technology to reprogram immune cells into therapies capable of targeting cancer. However, these immunotherapies are not universally effective across all patients<a class="moretag" href="https://www.creative-biolabs.com/blog/car-t/a-lego-like-gene-editing-tool-modpoki-paving-the-way-for-enhanced-car-t-cell-therapy/">Read More...</a>]]></description> <content:encoded><![CDATA[<p><span style="font-size: 15px;">In recent years, scientists have harnessed the power of gene editing technology to reprogram immune cells into therapies capable of targeting cancer. However, these immunotherapies are not universally effective across all patients or types of cancer. Furthermore, identifying the precise combination of genetic changes that can enhance these reprogrammed immune cells is a daunting and time-consuming task.</span></p> <p><span style="font-size: 15px;">Now, in a groundbreaking study, researchers from the Gladstone Institutes and the University of California, San Francisco, have developed a technique that allows them to rapidly “assemble” thousands of different gene editing combinations for testing in immune cells. They have utilized a screening technology known as “Modular Pooled Knockin Screening” (ModPoKI) to identify a novel gene combination that, when introduced into immune cells, prolongs their lifespan and enhances their anti-cancer efficacy. The research findings were published in the September 14, 2023, issue of the journal Cell, titled “Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.”</span></p> <p><a href="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/09/F1.large_.jpg"><img decoding="async" loading="lazy" class="aligncenter wp-image-757" src="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/09/F1.large_.jpg" alt="" width="761" height="349" srcset="https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/09/F1.large_.jpg 1156w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/09/F1.large_-300x138.jpg 300w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/09/F1.large_-1024x470.jpg 1024w, https://www.creative-biolabs.com/blog/car-t/wp-content/uploads/2023/09/F1.large_-768x353.jpg 768w" sizes="(max-width: 761px) 100vw, 761px" /></a></p> <p><span style="font-size: 15px;">Dr. Alexander Marson, co-corresponding author of the study and Director of the Gladstone-UCSF Institute of Genomic Immunology, stated, “This is a significant step forward for us. We now have the capability to pose questions about how to assemble fragments of genetic programs into cells and test how they benefit patients. I believe this will accelerate the development of improved cell therapies.”</span></p> <p><span style="font-size: 15px;">Dr. Ansuman Satpathy, co-author of the study and Assistant Professor in the Department of Pathology at Stanford University School of Medicine, added, “This new research demonstrates the power of using high-throughput genomics to discover and design novel molecular programs in cell therapy, further understanding how these programs impact the T-cell states required to kill cancer.”</span></p> <h5><span style="font-size: 15px;">Mixing and Matching Components</span></h5> <p><span style="font-size: 15px;">T cells of the immune system play a crucial role in the anti-cancer process. When T cells recognize cancer cells as foreign entities through receptors on their surface, they target and destroy the cancer cells. Scientists have found ways to modify these receptors on T cells, often by adding DNA sequences encoding chimeric antigen receptors (CARs), to enable T cells to more easily identify and eliminate cancer cells.</span></p> <p><span style="font-size: 15px;">In CAR-T cell therapy, T cells are extracted from cancer patients’ blood, genetically reprogrammed in the lab to introduce these new CAR receptors, and then infused back into the patient’s bloodstream. However, many <a href="/car-t/one-stop-car-t-therapy-development-services.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>CAR-T cell therapies</strong></span></a> still have limitations: they often prove ineffective against solid tumors, degrade over time, and some CARs may not elicit a strong enough immune response to kill cancer cells.</span></p> <p><span style="font-size: 15px;">Dr. Franziska Blaeschke, the first author of the paper and a postdoctoral researcher in the Marson lab, explained, “CAR-T cells have achieved incredible success in treating blood cancers such as leukemia and lymphoma, but we are still searching for ways to optimize them and apply them to other cancers. Until now, we’ve lacked a systematic approach to discovering which genetic changes in T cells are most effective for improving CAR-T cells.”</span></p> <p><span style="font-size: 15px;">To fill this gap, the authors developed ModPoKI. This technique assembles multiple genes into long DNA segments for use in the CRISPR gene editing platform. Using this tool, they created approximately 10,000 potential combinations by mixing hundreds of genes with the DNA encoding specific CARs. Subsequently, they used CRISPR to insert these spliced DNA sequences into a defined location in T cell genomes.</span></p> <p><span style="font-size: 15px;">Each T cell received a different DNA sequence, and these cells were then pitted against each other to see which T cell performed best in various predictive tests of anti-tumor activity. Each gene combination generated by ModPoKI had an easily readable DNA barcode, allowing researchers to track which gene combinations improved T cell function.</span></p> <p><span style="font-size: 15px;">This Lego-like capability enabled them to quickly discover gene combinations that could enhance CAR-T cells without the need for manual selection and design of each gene combination before introducing them into cells.</span></p> <p><span style="font-size: 15px;">Dr. Theodore Roth, co-corresponding author and former member of the Marson lab, said, “We don’t have to individually guess what can improve cell function and then study them one by one; we can put these fragments together and rapidly test many cells. This is a highly valuable aspect of molecular biology.”</span></p> <h5><span style="font-size: 15px;">Towards Better Therapies</span></h5> <p><span style="font-size: 15px;">In this new study, the genes added to the cells by the Marson team were surface receptors (both natural and engineered receptors designed to send enhanced signals to CAR-T cells) and transcription factors (genes that activate or deactivate other genes). When analyzing the results of testing hundreds of surface receptors and transcription factors, the authors found that different CARs could be optimized through different factors.</span></p> <p><span style="font-size: 15px;">Dr. Blaeschke explained, “It turns out that transcription factors are not one-size-fits-all. Therefore, when scientists are developing new CAR-T cells, it’s essential to check what other factors can optimize CAR-T cells. Our research creates a roadmap that scientists can use to combine different transcription factors with different T cell receptors (TCRs) or CARs.”</span></p> <p><span style="font-size: 15px;">The authors also identified two combinations of transcription factors that seemed to consistently enhance CAR-T cells. These two transcription factors, BATF and <a href="/car-t/target-tfap4-47231.htm" target="_blank" rel="noopener"><span style="color: #0000ff;"><strong>TFAP4</strong></span></a>, improved the adaptability of CAR-T cells previously developed for treating pediatric brain tumors.</span></p> <p><span style="font-size: 15px;">Dr. Marson noted, “In the lab, ModPoKI sequences with BATF and TFAP4 have shown the potential to enhance anti-tumor activity in CAR-T cells. Next, we need to conduct further research to determine whether adding these transcription factors will make CAR-T cells more effective for human cancer patients.”</span></p> <p><span style="color: #808080;">Reference</span></p> <p><span style="color: #808080; font-size: 14px;">1. Blaeschke, Franziska, et al. “Modular pooled discovery of synthetic knockin sequences to program durable cell therapies.” Cell 186.19 (2023): 4216-4234.</span></p> ]]></content:encoded> </item> </channel> </rss>