TIRAP

HANGZHOU, China, Dec. 20, 2023 /PRNewswire/ -- Recently, a CAR-macrophage therapy product (CAR-M) SY001 from CellOrigin Biotechnology (Hangzhou) Co., Ltd. was dosed to the first patient in a hospital in China. "A single center, single-arm, dose-escalation, exploratory clinical trial to examine the safety, tolerability, pharmacokinetics and preliminary efficacy of SY001 from CellOrigin Biotechnology in patients with advanced solid tumors" is the first investigator-initiated clinical study of CAR-M cell therapy product in China. The successful completion of the first patient dosing of SY001 demonstrates the advanced technology of the company's R&D platform and the maturity of the CMC platform. Currently, the clinical study is actively recruiting patients. SY001 was well tolerated and no dose-limiting toxicity (DLT) was observed (n=2). Only 2 grade 3 adverse events occurred; Common grade 1 - 2 adverse events included fever, elevated C-reactive protein, etc. No cytokine release syndrome or neurotoxicity related to cell infusion occurred in any patients. The clinical data of CAR-M products up to now suggest the excellent safety and certain clinical benefits of macrophage immunotherapy. CellOrigin expects that this innovative product will prove its safety and effectiveness in clinical trials, bringing new hope for the treatment of solid tumors, thereby improving patients' quality of life and prolonging their life span. Besides, in November 2023, CellOrigin collaborated with Zhejiang University to publish a paper entitled "A second generation M1-polarized CAR macrophage with antitumor efficacy" in Nature immunology, designing an exclusive CAR with antigen-dependent polarization and activation of macrophage function (TIR-CAR or M-CAR) by introducing the TIR signal transduction domain. Based on M-CAR, a functionally enhanced second generation CAR-iMAC has been developed to enhance the effectiveness of the therapy for solid tumors. The mechanism of antigen-dependent activation and polarization of the second generation CAR-iMAC and the mechanisms of solid tumor cell killing were also revealed. In November 2020, the team published a paper in J Hematol Oncol entitled "Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions." It opens the door for human iPSC-derived CAR-macrophage (CAR-iMAC) and its applications in targeted anti-tumor research. The first generation CAR-iMAC was designed, and was capable of carrying out the antigen-dependent killing of tumor cells. On September 11, 2023, the team collaborated with Dr. Wang Ben's Research Group of Zhejiang University to publish a paper entitled "Targeted glycan degradation potentials cellular immunotherapy for solid tumors" in Proceedings of the National Academy of Sciences (PNAS). The collaboration found that simultaneous deletion of sialidase-binding immune checkpoints Siglec-5 and Siglec-10 (DKO-CAR-iMac) on macrophages significantly enhanced CAR-iMAC's anti-solid tumor function. Almost the same time, the team published another paper entitled "Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophases in solid tumors" in Nature communications. A CRISPR Screen method was used to find the key metabolic genes related to CAR-iMAC polarization in tumor microenvironment. It was discovered that knockout of ACOD1 (or IRG1) could improve macrophage proinflammatory polarization, phagocytic capacity and tumor-killing activity. Furthermore, the study also found that the anti-tumor effect of ACOD1-/- MSLN-CAR-iMAC can be further enhanced by combining immune checkpoint inhibitors. These findings offer fresh concepts for remodeling macrophages based on metabolic reprogramming or editing the immune checkpoints. Based on these research results, CellOrigin is conducting a series of pre-clinical and clinical studies of CAR-macrophage therapies for solid tumors in an effort to provide patients with safe and effective treatment choices as soon as possible. About CellOrigin: CellOrigin is committed to the development and clinical translation of their proprietary CAR-expressing iPSC-derived immune cells such as CAR-iMAC. They have obtained engineered immune cells derived from iPSC using cutting-edge technologies including gene editing and synthetic biology. CellOrigin takes advantage of the unique characteristics of macrophages that can infiltrate the solid tumor microenvironment (TME), and is developing CAR-M products mainly for relapsed/refractory solid tumors. They have completed the establishment of a clinical-grade iPSC cell bank, independently developed the CMC process of CAR-iMAC cells that can be produced in large scale to meet the amount for off-the-shelf products, and established a complete GMP quality system and corresponding quality control methods. They are collaborating with domestic and international hospitals for clinical trials, and also seeking for opportunities of licensing of the technology platform and certain pipelines. For more information,please contact Yaoyao Li, [email protected]. SOURCE CellOrigin

Researchers have discovered natural cellular molecules that drive critical plant immune responses. These compounds have all the hallmarks of being small messengers tailored by plants to turn on key defense-control hubs. Harnessing these insights may allow scientists and plant breeders to design molecules that make plants, including many important crop species, more resistant to disease. Two studies published in the journal Science by researchers at the Max Planck Institute for Plant Breeding Research in Cologne, Germany in collaboration with colleagues in China have discovered natural cellular molecules that drive critical plant immune responses. These compounds have all the hallmarks of being small messengers tailored by plants to turn on key defense-control hubs. Harnessing these insights may allow scientists and plant breeders to design molecules that make plants, including many important crop species, more resistant to disease. World food production must double by 2050 in order to feed the anticipated extra 2 billion people living on earth by then. Boosting food production requires increases in the yields of many of our staple crops. To do so, strategies need to be in place to ensure that we can make plants more resistant to microscopic infectious agents, whilst also ensuring that food production is environmentally safe. Achieving this, in turn, requires a detailed understanding of the plant immune system -- the defenses that plants mount when confronted with invading microorganisms. Now, in two landmark studies, scientists led by Jijie Chai and Jane Parker from the Max Planck Institute for Plant Breeding Research in Cologne and the University of Cologne, Germany, collaborating with Junbiao Chang's group at Zhengzhou University in Zhengzhou and Zhifu Han and colleagues at Tsinghua University in Beijing, China, have identified two classes of molecules and determined their modes of action in mediating immune responses inside plant cells. Their findings pave the way for the design of bioactive small molecules that could allow researchers and plant growers to manipulate -- and thereby boost -- plant resistance against harmful microbes. At a molecular level, a main immune strategy employed by plants involves proteins called nucleotide-binding leucine-rich repeat receptors, or NLRs for short. NLRs are activated by invading microorganisms and set in motion protective immune responses. These immune responses culminate in the so-called hypersensitive response, which involves restriction of pathogen growth and often strictly demarcated death of cells at the site of infection -- akin to amputating a toe to ensure survival of the body. One class of NLR proteins, those with so-called toll/interleukin-1 receptor (TIR) domains, which are termed TIR-NLRs (or TNLs), have been shown to relay signals to the downstream immune protein Enhanced Disease Susceptibility 1 (EDS1). Smaller TIR-containing proteins also feed signals into EDS1 to potentiate disease resistance. EDS1 functions as a control hub which, depending on the types of other proteins it interacts with, pushes plant cells to restrict pathogen growth or commit to cell death. Earlier work showed that TNL receptors and TIR proteins are actually pathogen-induced enzymes. Evidence suggested that these TIR enzymes produce a small messenger or messenger(s) that signal to EDS1 inside cells. However, the identities of the precise molecules generated by TNLs or TIRs that stimulate the different immune responses have remained elusive. Parker and colleagues established that the two functional EDS1 modules leading to immunity or cell death can be triggered by pathogen-activated TNL enzymes inside plant cells. To identify the small molecules produced by TNLs or TIRs and that act upon EDS1, the Chai group reconstituted key components of the signaling pathway in insect cells, a system that allows production and purification of high amounts of molecules which can then be isolated and characterized. Using this approach, the authors discovered two different classes of modified nucleotide molecules produced by TNLs and TIRs. These compounds preferentially bound to and activated differentEDS1 sub-complexes. Hence, the authors demonstrate that different EDS1 sub-complexes recognize particular TIR-produced molecules, which function as information-carrying chemicals, to promote immune responses. The TIR immune receptors and EDS1 hub proteins exist in many important crop species, such as rice and wheat, and Jijie Chai points out that "the identified TIR-catalyzed small molecules could be employed as general and natural immunostimulants to control crop diseases." Jane Parker further remarks that "knowing the biochemical modes of action of these small molecules opens a whole new chapter on plant immunity signaling and disease management."