CAR-NK治疗 z-bo 2020-09-30 305

　　Recently, Fate Therapeutics, which is committed to the development of cellular immunotherapy, announced that the US FDA has approved the investigational new drug (IND) application for its investigational therapy FT596. FT596 is derived from the clone master induced pluripotent stem cell (ipsC) line and is the company's first ready-made CAR-NK cell immunotherapy, which targets a variety of tumor-related antigens.

　　Fate plans to initiate clinical studies of FT596 single-drug and combined CD20 monoclonal antibody in the treatment of B-cell lymphoma and chronic lymphocytic leukemia.

　　"FT596 is a breakthrough product candidate that has the potential to replace current patient-specific and allogeneic CD19 CAR-T cell immunotherapy. This immunotherapy only recognizes one antigen and fails to solve the relapse caused by antigen escape. Significant risks," said Scott Wolchko, President and CEO of Fate Therapeutics. "FT596's strong clinical development strategy is aimed at targeting multiple tumor-associated antigens for the treatment of B-cell lymphoma and leukemia. We believe that compared with single antigen targeting CD19 CAR-T cells, the engineering functions of the candidate product and its advantages The cost-effectiveness of multiple treatment cycles will provide patients with a deeper and longer-lasting response."

　　FT596 is the third off-the-shelf, ipsC-derived NK cell product candidate on the company’s proprietary iPSC product platform, and was approved by the FDA for clinical research in less than a year. The company is conducting the first human clinical trials of FT516 and FT500: FT516 is an off-the-shelf NK cell therapy engineered to express hnCD16 for the treatment of acute myeloid leukemia and B-cell lymphoma; FT500 is an off-the-shelf NK cell therapy, For the treatment of advanced solid tumors.

　　is expected to solve the problem of recurrence and cost

　　Although CD19 CAR-T cell therapy has shown profound clinical responses in some B-cell malignancies, not all patients have responded to the treatment. Even for those patients who initially responded, the durability of the response is still a key challenge. The down-regulation of tumor cell surface target antigen CD19 has been clinically proven to be one of the important drug resistance mechanisms.

　　FT596 is a cell therapy containing three active anti-tumor components, and its unique design aims to overcome the escape of CD19 antigen:

　　Proprietary CD19 CAR optimized for NK cell biology, including NKG2D transmembrane domain, 2B4 costimulatory domain and CD3-zeta signaling domain;

　　In addition to the patented CAR targeting CD19, FT596 also expresses a new non-cleavable CD16 (hnCD16) Fc receptor that has been modified to enhance antibody-dependent cellular cytotoxicity (ADCC), allowing CD19 and other antigens (such as CD20) can be targeted simultaneously;

　　FT596 also expresses interleukin-15 receptor fusion protein (IL-15RF), which is an effective cytokine complex that can promote the survival, proliferation and transactivation of NK cells and CD8 T cells without the need for a system Cytokine support.

　　In short, these features of FT596 are designed to maximize the effectiveness of treatment and minimize toxicity.

　　In the preclinical study of FT596, the company has demonstrated that the simultaneous activation of CAR and hnCD16 targeting modes combined with IL-15RF signaling can produce synergistic anti-tumor activity. Compared with the activation of the receptor alone, increased degranulation and cytokine release were observed when the receptor was simultaneously activated in lymphoma cancer cells, indicating that dual antigen binding can cause a deeper and longer-lasting response. In addition, in the cytotoxicity assay of a mixed cell composition composed of CD19+ and CD19- tumor cells, the combination of FT596 and rituximab (CD20 monoclonal antibody) effectively eliminated the heterogeneous population of tumor cells, which is a single antigen Targeting unachieved results in CD19 CAR-T cells.

　　"On the other hand, FT596 is derived from the clone master induced pluripotent stem cell (iPSC) line. At present, Fate’s ipsC product platform has been supported by an IP portfolio of more than 100 issued patents and more than 100 pending patent applications for mass production of general-purpose NK cell and T cell products.

　　In a new study published in the authoritative journal Cell Stem Cell in June last year, researchers from the University of California San Diego School of Medicine (UCSD) and the University of Minnesota reported that in mouse ovarian cancer models, CAR-NK derived from ipsC The cells show similar activity to CAR-T cells but are less toxic. The main leader of the research is Dr. Dan Kaufman, and related patents have been submitted. He cooperates with scientists from Fate Therapeutics to promote the clinical transformation of the technology.

　　CAR-NK

　　CAR-NK cells can significantly improve the specificity of NK cell curative effects. The principle is to chimeric tumor-specific antigen receptors on the surface of NK cells, so that NK cells can target and destroy tumor cells. Studies have shown that CAR-NK exhibits stronger cytotoxicity than ADCC. In the application of CAR, NK cells have advantages over T cells:

　　Many clinical studies have confirmed that allogeneic NK cells will not cause graft versus host response (GVHD);

　　NK cells do not secrete inflammatory factors that cause cytokine release syndrome (CRS), such as IL-1 and IL-6;

　　In addition to CAR-mediated targeted killing, CAR-NK cells can also identify and kill tumor cells whose CAR targets are down-regulated or missing through the anti-tumor properties of NK cells, thereby improving the effect of immunotherapy;

　　Allogeneic NK cells have a wide range of sources: including peripheral blood, NK cell lines, cord blood, induced pluripotent stem cells, NK-92 and other cell lines.

　　There have been a number of clinical trials on CAR-NK. These clinical trials are mostly focused on hematological tumors and trying to solve the research that CAR-T failed to solve solid tumors.

　　→Boshengji Medical Technology (Suzhou) currently has at least 4 CAR-NK clinical studies that target CD19, CD7, CD33 and MUC1, respectively.

　　→MD Anderson Cancer Center researchers are studying CAR-NK cell therapy, using cord blood-derived NK cells, and genetically modified to insert a CAR that recognizes CD19. The clinical trial (NCT03056339) that started in 2017 is currently underway. The subject has recurrent disease and is paying attention to B lymphoid malignancies, non-Hodgkin's lymphoma, and acute and chronic lymphocytic leukemia.

　　→ At the end of 2017, Keji Biosciences, together with Shanghai Cancer Institute and Renji Hospital affiliated to Shanghai Jiaotong University, published the first research paper on GPC3-targeted CAR-NK treatment of hepatocellular carcinoma in the authoritative medical journal Molecular Therapy.

　　The results show that the GPC3-CAR-NK cell line (NK-92/9.28.z) prepared by Keji Biosciences and Shanghai Cancer Research Institute using independent intellectual property rights antibodies can specifically target and kill GPC3 in vivo and in vitro. Hepatocellular carcinoma of the liver, and is not affected by serum levels of soluble GPC3, hypoxic environment of solid tumors and TGF-β. Compared with the current CAR-T cell therapy, the CAR-GPC3-NK treatment program saves a lot of cost.

　　Cell therapy 3.0: ipsC source

　　Fate believes that the current mainstream patient-derived (autologous) or healthy donor-derived cell therapies are "batch-to-batch" engineering, which is costly and time-consuming, and results in significant product heterogeneity-each production batch All consist of millions of variable engineering events in primary T cells.

　　Then, based on the early success, how to transition from an allogeneic process to a cost-effective and optimized cell product? The answer may be a renewable master cell line like ipsC.

　　Through the selection, characterization and regeneration of single cells, ipsC-derived cell therapy may change the rules of the game for cellular cancer immunotherapy.

　　As early as 2013, Dr. Dan Kaufman (Director of Medicine, Department of Regenerative Medicine and Cell Therapy, University of California, San Diego School of Medicine) and his team developed a method of massively expanding NK cells from human ipsC for use in cancer treatment. Related results were published in Stem Cells Translational Medicine.

　　After a large number of pre-clinical trials, the FDA approved Dr. Kaufman and Fate in November last year to conduct a phase I clinical trial to test the efficacy of the ipsC-derived allogeneic NK cell therapy FT500 on patients with advanced solid tumors.

　　In February 2019, Fate announced that the FDA approved the IND application for another NK cell therapy, FT516. The preliminary study will evaluate its safety and tolerability for the treatment of certain advanced blood cancers.

　　CAR-T therapy

　　In May last year, Mesoblast and Cartherics announced the establishment of a partnership to develop ready-made CAR-T cells with multiple target receptors for the treatment of solid tumors. The combination of the two technology platforms aims to promote the large-scale production of allogeneic CAR-T cells derived from iPSCs. Clinical-grade manufacturing and storage methods will be used to transform gene-edited ipsC into a potentially unlimited number of killer T cells, thereby eliminating the expensive resources required to produce autologous CAR-T cells, and providing a large number of cancer patients with cost-effective" Ready-made CAR-T cell therapy.

　　In July 2019, Takeda Pharmaceuticals and the CiRA (iPS Cell Research and Application Center) of Kyoto University announced that the university’s first ipsC-based CAR-T therapy (iCART) was licensed to Takeda. Takeda will carry out clinical development of the therapy and has the exclusive right to develop and commercialize iCART products. CiRA will receive milestone payments for the clinical development and application of the therapy. It is expected that iCART will conduct its first human test in 2021.

　　In addition, Century Therapeutics, which recently received US$250 million in financing, focuses on the development of ipsC allogeneic cell therapy for blood and solid tumors. Its platform is a stem cell platform that can be generated from adult stem cells, with unlimited self-renewal capabilities, and can carry out multiple rounds of cell engineering. These engineering modifications will produce a master cell bank of modified cells, which can expand and differentiate into immune effector cells, providing a large number of allogeneic and homogeneous therapeutic products.

　　Conclusion

　　ipsC-based cell therapy has become a new protagonist under the spotlight. In terms of cost, it may be a huge leap from hundreds of thousands of dollars to thousands of dollars!