"Parallel" CAR-T is coming!

Recent popular reports from Yimaike★Over 1.
3 billion US dollars! Yang Sen bets heavily on the next generation of bispecific antibody therapyYi Mai Meng broke the news ★Treat rare diseases! AAV new gene therapy results in positive results in pre-clinical dataMedClub broke the news October 23, 2021/eMedClub News/--Recently (October 21, 2021), Leucid Bio announced the completion of approximately US$16 million In the A round of financing, the funds will be used to initiate a phase 1 clinical trial of its ongoing CAR-T cell therapy LEU-011 for the treatment of platinum-based chemotherapy-resistant ovarian cancer
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LEU-011 is an autologous CAR-T therapy targeting NKG2D ligand, and is undergoing preclinical development for solid tumors and hematomas
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Leucid Bio's CAR-T cell therapy is based on a novel CAR structure called "Parallel CAR" (pCAR) T cells, which simultaneously express two CARs: one is a second-generation CAR with a single costimulatory domain; the other One has a different costimulatory domain
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▲Image source: Leucid and NKG2D receptor is a transmembrane protein, NKG2D ligand is expressed on more than 80% of human tumor cells
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In addition to Leucid Bio, a number of clinical phase projects in the pipeline of Celyad also target NKG2D
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In addition, NKG2D CAR-NK from Nkarta has also entered clinical research
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Recommended reading: New shRNA platform helps CAR-T, Celyad's next-generation targeted NKG2D CAR-T therapy IND is approved by the FDA Leucid’s method of breaking through the difficulties of solid tumors one by one integrates a new parallel CAR-T platform and CAR-T cell “armor” technology, aiming to overcome the key challenges of CAR-T cell therapy for solid tumors, including: lack of suitable targets: Solid tumors and healthy cells share many surface proteins
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Leucid is investigating a set of highly specific and broad targets that can identify 80% of cancers with minimal toxicity
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Tumor microenvironment: The immunosuppressive tumor microenvironment makes it difficult for immune cells to survive, and Leucid's parallel CAR technology can overcome this by improving efficacy and continuous killing of tumor cells
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Poor transport and tumor invasion: CAR-T cells must be able to survive in the blood long enough to reach the tumor tissue
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Leucid's parallel CAR technology improves the persistence of CAR-T cells.
At the same time, "armor" technology will enable CAR-T cells to target tumor sites more accurately
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The continuous development of CAR structure The chimeric antigen receptor (CAR) is mainly composed of extracellular tumor antigens, antibodies, and intracellular stimulating molecules, and the structure of CAR is constantly iteratively updated
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The first generation of CAR-T cells: The structure has only one intracellular signal transduction domain (mainly CD-3ζ or FcRγ), which only express single-chain antibodies on T cells, and target tumor cell surface antigen molecules, but the survival time is short and limited To make it work
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Second-generation CAR-T cells: The introduction of costimulatory domains (such as single co-excitation zone CD28 or 4-1BB) allows CAR-T cells to continue to proliferate and release cytokines to enhance anti-tumor activity
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The costimulatory domain of Novartis Kymriah is 4-1BB, and the costimulatory domain of Yescarta from Gilead is CD28
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The third-generation CAR-T cells: contain two costimulatory domains (such as CD28+4-1BB), which can make T cells continue to activate and proliferate, and enhance the effect of killing tumor cells
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The evolution of CAR-T has been seen that the addition of costimulatory domains may have the effect of increasing activity
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However, Dr.
John Maher, the developer of Leucid's core technology, believes that these third-generation CARs with a linear arrangement of custom fields have limited impact on the basis of the second-generation.
Perhaps the third-generation technology has not been properly enabled because of these two co-stimulatory domains.
It is not physically close to the plasma membrane of T cells
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This is also the reason why Dr.
John Maher has been working hard on the structural transformation of CAR
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Overall, in view of the limitations of CAR-T cells, the transformation strategy is still evolving
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In terms of optimizing therapeutic effects and limiting toxicity, careful consideration of the modular structure of CAR is necessary
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Reference materials: 1.
https:// -to-develop-next-generation-of-innovative-chimeric-antigen-receptor-t-cell-car-t-therapies-301404851.
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https:// -to-trial-car-t-twist-ovarian-cancer-patients