YouCART Enhances CAR-T Anti-Tumor Efficacy via PD-1 Knockdown for Multiple Myeloma Treatment

Recently, the research team of SHANGHAI UNICAR-THERAPY BIOMED-PHAMACEUTICAL TECHNOLOGY CO., LTD ("UNICAR-THERAPY") and the team led by Director Miao Jianqing of the Hematology Department at Ruijin Hospital published an article in "Journal for ImmunoTherapy of Cancer》 magazine published an article titled "PD-1 downregulation enhances CAR-T cell antitumor efficiency by preserving a cell memory phenotype and reducing exhaustion.）”Innovative research results.

CAR-TTherapy has become a promising immunotherapy in the treatment of hematological malignancies. TargetedBCMATheCAR-TCell therapy shows significant efficacy in patients with relapsed and refractory multiple myeloma, but a considerable proportion of patients still experience recurrence. One of the reasons isCAR-TDysfunction of cells, characterized by suppressed function, cell exhaustion, or limited persistence in vivo. In the tumor immune microenvironment,CAR-TCellularPD-1Receptors and Ligands of Tumor CellsPD-L1Combination inhibitionCAR-TEarly and late cell activationCAR-TEffector functions of cells. Therefore, it can be achieved byBlockadePD-1/PD-L1Signal pathway to relieve the immunosuppressive state,DepletedTCell reactivation, thereby reversingCAR-TAntitumor effect of cells.

In the research project in collaboration with Ruijin Hospital, UNICAR-THERAPY innovativelyshRNAAnti-PD-1The silent fragment is integrated into the containingOX-40Co-stimulatory domainBCMA-CARIn the vector, it plays a role in one aspectOX40Co-stimulatory Molecules Anti-apoptosis, RetentionTThe advantage of cell memory phenotype,On the other hand, throughshRNAAchievePD-1Stable and lasting knockdown, while ensuring the safety of its clinical application.

In vitro study results show that,PD-1Silence can enhanceBCMA CAR-TThe Anti-Tumor and Proliferation Ability of Cells.InCAR-TThe early stage of cell activation,PD-1The silence helpsBCMA CAR-TCell proliferation and cytokine secretion; inCAR-TAfter cells receive repeated antigen stimulation, their central memoryTThe proportion of cells increased, and cell exhaustion decreased.

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Given its promising anti-tumor effects in preclinical studies, SHANGHAI UNICAR-THERAPY BIOMED-PHAMACEUTICAL TECHNOLOGY CO., LTD, in collaboration with Ruijin Hospital, has conducted the first clinical trial of this novel therapy in patients with relapsed or refractory multiple myeloma.BCMATargetedCAR-TCellⅠPhase clinical trials, preliminary clinical research results have demonstrated its safety and clinical efficacy in vivo. As of now, a total of7ExampleR/R MMThe subject receivedPD-1SilenceBCMA CAR-TCell Reinfusion Therapy, wherein4The subject has at least one extramedullary lesion (4/7，57.1%），4The subject had high-risk cytogenetic characteristics (4/7，57.1%). ViaPD-1SilenceBCMA CAR-TAfter treatment,ORRFor85.7%（6/7），sCRFor57.1%（4/7），CRFor14.3%（1/7). In terms of safety, only1Example (14.3%) Appear3LevelCRS，No neurotoxicity was observed.

UNICAR-THERAPY Innovatively Engineers CAR-T to Create a More Powerful and Comprehensive CAR-T Therapy

Although CAR-T therapy, as a revolutionary treatment, has significantly improved the survival rate of patients with relapsed or refractory multiple myeloma, some patients still face the risk of recurrence due to the suppression of CAR-T cell function caused by tumor immune escape. Against the backdrop of the current crowded field of CAR-T therapies in the hematological malignancies space, the question remains: how can we develop truly...Innovative drugs with differentiated advantagesParticularly important. SHANGHAI UNICAR-THERAPY BIOMED-PHAMACEUTICAL TECHNOLOGY CO., LTD deeply understands the challenges of clinical CAR-T therapy, focuses on the pain points of clinical CAR-T therapy, and is committed to optimizing this therapy to more practically solve patient problems.Unlike other optimization methods that enable CAR-T cells to secrete anti-PD-1 antibodies autonomously, UNICAR-THERAPYInnovatively adoptedKnockdown of PD-1 Expression in CAR-T Cells Using RNAi Technology, thereby directlyReduceThe opportunity for CAR-T to "shake hands" with PD-L1 on tumor cells. Both preclinical and clinical data suggest,This strategy of knocking down PD-1 can significantly enhance the anti-tumor ability of CAR-T cells. Additionally,This innovative CAR-T engineering modification has also been validated in CAR-T cells targeting CD19 and CLL-1, laying the foundation for application promotion in other tumors.In the future, we are hopeful to witness a more powerful and comprehensive CAR-T therapy.

About UNICAR-THERAPY

SHANGHAI UNICAR-THERAPY BIOMED-PHAMACEUTICAL TECHNOLOGY CO., LTD ("UNICAR-THERAPY" for short), established in February 2015 in the Zhangjiang Bio-HighTech Incubation Center in Shanghai, is a biopharmaceutical company dedicated to the innovation and translation of global cell therapy technologies, with multiple First-in-class products currently in clinical trial stages.

UNICAR-THERAPY possesses several original core technology platforms, including the SMART small nucleotide gene regulation empowerment technology platform, the MADDS antibody innovation drugability technology platform, the 6H production quality control platform, and more. Additionally, the company has implemented a closed CAR-T production system in Baoshan, with a construction area of approximately 10,000 square meters, dedicated to building an internationally advanced billion-level research, industrialization, and commercialization center for gene and cell therapy. This will establish a world-class immunotherapy tumor innovation technology transformation center as well as an advanced, high-end genetic engineering immune cell industry chain center, mainly encompassing the industrial production of CAR-T products and CDMO services for plasmids, viruses, and CAR-T cells.

UNICAR-THERAPY's product pipeline is widely laid out, including products for the treatment of hematological tumors, solid tumors, and autoimmune diseases. In September 2020, the company’s ssCART-19 injection received clinical trial approval in China and is being used as a breakthrough treatment for CAR-T contraindicated central nervous system leukemia (commonly known as "brain leukemia"). Phase II clinical trials are currently underway and are expected to be completed by the end of 2024, entering the application stage for market approval. UNICAR-THERAPY has collaborated with the hematology departments of several top-tier tertiary hospitals in China, such as Ruijin Hospital and Renji Hospital, successfully treating over 1,000 patients with advanced-stage cancer. The longest survival time among the trial participants with late-stage tumors has exceeded 8 years.

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