AGA Journal: Incorporating IL-15, "off-the-shelf" CAR-NK therapy significantly inhibits pancreatic cancer growth

January 22, 2022 / eMedClub News/--Recently, CytoImmune announced that its “off-the-shelf” CAR-NK therapy targeting prostate stem cell antigen (PSCA), developed in collaboration with City of Hope, can significantly inhibit Pancreatic cancer, the research results were published in Gastroenterology, an international authoritative journal in the field of gastroenterology
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Pancreatic cancer (PC) is one of the deadliest cancers with a 5-year overall survival rate of 9% and is generally difficult to cure
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PC is usually detected at an advanced stage, has only a modest response to standard chemotherapy, and is the third leading cause of cancer-related death
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As research progressed, it was found that approximately 60-80% of PCs expressed prostate stem cell antigen (PSCA), also in gastric, bladder, prostate and some other lung cancer settings
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In search of more effective and innovative solid tumor treatments, CytoImmune partnered with City of Hope to develop a PSCA-targeted chimeric antigen receptor (CAR) for transduction into human natural killer (NK) cells
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NK cells spontaneously kill both liquid and solid tumors regardless of MHC (major histocompatibility complex) autoantigen expression
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In humans, NK cells utilize endogenous IL-15 to develop, survive, expand and activate against tumor cells
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Therefore, the investigators incorporated a soluble, secretable form of IL-15 into the PSCA CAR construct itself, which was then transduced into NK cells obtained from umbilical cord blood with approximately 50% transduction efficiency
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Transduced NK cells express a CAR against PSCA and secrete measurable amounts of human IL-15 protein in vitro
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PSCA CAR-NK cells can expand more than 1,000-fold in vitro in approximately 16 days and retain their expression and their ability to specifically kill PSCA(+) tumor cell targets in vitro
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The results showed that PSCA CAR-NK cells produced more TNFα, IFNγ and CD107a when targeting the PSCA(+) human pancreatic tumor cell line (Capan-1), demonstrating the interaction of sIL-15 with PSCA CAR-NK cells.
Co-expression significantly enhanced their cytotoxic function against pancreatic tumor cells
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In an animal model of metastatic human pancreatic cancer, repeated infusions of human PSCA CAR-NK cells from viable cryopreservation were able to defend against pancreatic tumor cells without more pronounced side effects, resulting in prolonged survival
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Dr.
Christina Coughlin, CEO of CytoImmune, said: "We are excited to share data on our CAR-NK drug candidate in pancreatic cancer
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We are encouraged by these findings based on the strong anti-tumor activity of CYTO NK-203, which is based on Looking forward to continuing to work with City of Hope to continue advancing this project into the clinic
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" Opportunities to engineer NK cells to treat cancer Natural Killer cells (NK cells) cells play an important role in the body's innate immune system , they were described by researchers in the 1970s, but only in the last 15 years has the complexity and therapeutic potential of NK cells been gradually understood in helping fight cancer and other diseases
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Different from other immune cells, NK cells are a type of lymphocytes that can non-specifically kill tumor cells and virus-infected cells without prior sensitization, and have broad-spectrum anti-tumor effects.

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The specificity of NK cell surface markers is relative, expressing a random combination of activating and inhibitory receptors
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The balance of stimulatory and inhibitory signals expressed by different receptors enables NK cells to express response or tolerance to target cells
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This is a major advantage of NK cells different from T cell-related tumor immunotherapy
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Another advantage is that NK cells can target major histocompatibility complex (MHC)-deficient tumor cells and induce tumor cell apoptosis by releasing cytotoxic perforin and granzyme; they can also secrete a series of cytokines.
, such as interferon gamma (IFN-γ) and tumor necrosis factor (TNF), etc.
, regulate the immune response and indirectly kill tumor cells
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Therefore, NK cells have great potential in anti-tumor immune cell therapy
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Preclinical studies on NK cells and cancer immunotherapy have also shown that NK cells show high safety in clinical applications
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For example, CAR-NK cells did not develop severe graft-versus-host disease (GVHD) and high-grade cytokine storms
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At the same time, the level of PD-1 secreted by NK cells is lower, and the immunosuppressive effect is less, which makes NK cells an ideal candidate cell against solid tumors
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At present, many companies are involved in the research and development of NK cells, and various ways to improve the effector function of NK cells have been developed
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NK cell therapy has now become a hot field
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FateFate is an early company in the development of NK cells in the world, and there are a variety of iPSC-derived NK cell candidate products in the pipeline
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The investigational new drug (IND) application for its "off-the-shelf", iPSC-derived CAR-NK product candidate FT536 has been approved by the FDA
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Recommended reading: "Super Soldiers" with multifunctional grooming! Another iPSC CAR-NK therapy from Fate has entered the clinicYimai Meng broke the news that NkartaNkarta is a clinical-stage biopharmaceutical company with a variety of NK cell candidate products, among which the faster progress is the treatment of relapsed/refractory acute myeloid leukemia NKX101, and NKX019, a CAR-NK product that has just received IND approval from the U.
S.
Food and Drug Administration (FDA) for clinical trials, for the treatment of relapsed/refractory B-cell malignancies
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Recommended reading: Donor-derived “off-the-shelf” CAR-NK drug receives IND application from FDA Dosing
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 Recommended reading: The NK cell therapy developed by the company founded by "the world's richest doctor" Huang Xinxiang welcomes its 100th patientYimai Meng revealed that with the deepening of research and the accumulation of technology, NK cells have also attracted many domestic developers.
layout and investment
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 Guojianchengnuo Guojianchengnuo is a technology platform with gene and cell therapy and artificial intelligence as its core technology, focusing on the research and development of tumor therapy, especially CAR-NK cell therapy for solid tumors
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At present, its clinical trial application for "targeted mesothelin (MSLN) chimeric antigen receptor NK cell (CAR-NK) injection" for the treatment of advanced epithelial ovarian cancer has been accepted by CDE
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 Recommended reading: The first case in China, the clinical application of Guojian's allogeneic "spot-type" CAR-NK cell injection for the treatment of solid tumors was accepted by the State Food and Drug AdministrationYimai Meng broke the news that BeiGene BeiGene is a global, commercial The staged biotech company is currently developing and commercializing a portfolio of NK cell therapy-based products with iPSC-derived NK cell therapy company Shoreline for the treatment of various malignancies
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 Primis Biotech and Aika Biotech Primis and Aika Biotech recently formally reached a global strategic cooperation to jointly develop two iPSCs targeting solid tumors using Aika's iPSC NK cell therapy technology and Primis' preclinical R&D and clinical capabilities - CAB-NK cell therapy products
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At present, the leaders of the international NK cell therapy track include Fate, Celularity, Cellectis and other companies.
There are also many domestic companies participating, most of which are NK therapies derived from iPSCs, such as Xingion, Zhongshengsuyuan, Aike Bio, Sai Yuanbi, Jiakesi, BeiGene,
etc.

Reference: 1.
https:// -natural-killer-nk-cell-based-therapy-against-pancreatic-cancer/,