The new "revolution" of cell therapy, NK therapy a number of giant companies joined hands to layout

Source: Yaozhi Network/Yi

Recently, Celularity announced that the FDA has granted its orphan drug certification for the treatment of natural killer (NK) cell therapy CYNK-101 for the treatment of gastric/gastroesophageal junction cancer. Prior to this, CYNK-101 was identified by the FDA in January 2022 as a fast-track candidate for advanced HER2/neu positive gastric or gastroesophageal junction (GEJ) adenocarcinomas with standard first-line chemotherapy, herceptizumab and pembolizumab (Keytruda).

Image source: the company's official website

CYNK-101 is an NK cell therapy derived from placental hematopoietic stem cells that is genetically modified to express high affinity and anti-cleavage CD16 (FCGRIIIA) variants to drive antibody-dependent cell-mediated cytotoxicity. Preclinical studies have shown that CYNK-101 shows a powerful killer activity against lymphoma cells in vitro.

In addition, Celularity has an NK cell therapy, CYNK-001. CYNK-001 is a cryopreserved allogeneic NK cell therapy, unproducted, containing CD56+/CD3-NK cells derived from the expansion of human placental CD34+ cells, and is intended to be developed for the treatment of hematologic malignancies, solid tumors and infectious diseases. Previously, CYNK-001 had been awarded a fast-track designation for the treatment of polyglioma and leukemia by the FDA, as well as an orphan drug for the treatment of malignant glioma.

Natural killer (NK) cell therapy is on the rise

Natural killer (NK) cells are the third type of lymphocytes in the human body, also known as the core cells of natural immunity, accounting for about 5%-15% of the number of lymphocyte circulation, and their surface lacks specific markers of T cells and B cells such as TCR and Smlg. The study found that NK cells are not only related to anti-tumor, antiviral infection and immunomodulation, but also participate in the occurrence of hypersensitivity reactions and autoimmune diseases in some cases, and can identify target cells and kill mediators.

It is worth mentioning that compared with other anti-cancer immune cells, NK cells kill tumors and virus-infected cells more effectively, and their activation does not depend on tumor cell surface antigens, nor does it need to be like T cells, through the immune system's antigen recognition response to determine the "attack" target. NK cells exercise immune monitoring functions in blood vessels throughout the body, can detect and activate immune defense functions at the first time, quickly kill diseased and cancerous cells, and are recognized by the medical community as the first line of defense against cancer.

Currently, immunotherapy based on NK cells is in full swing, including monoclonal antibodies against NK cell inhibitory or activated receptors, immune factor-related therapies, and NK cell adoptive immunotherapy. NK cell adoptive immunotherapy is to achieve the purpose of treating tumors by infusing NK cells that have been induced and cultured in vitro to tumor patients, so that they can play a direct or indirect role in killing tumor cells in the body.

There are two main types of NK cell adoptive immunotherapy: one is autologous or allogeneic NK cell infusion, and the other is CAR-NK cell therapy. Among them, the adoptive transmission of autologous or allogeneic NK cells is the transfusion of NK cells from peripheral blood sources, stem cell sources and iPS induction sources into patients to increase the number and activity of NK cells in patients. Car-NK cell therapy modifies NK cells in a similar way to CAR-T cells, enhancing cell targeting and improving the efficiency of tumor suppression.

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Several models have entered clinical research

At present, NK cell therapies are mostly in the early stages of research. According to incomplete statistics, there have been a number of autologous or allogeneic NK cell therapies in the world, as detailed in the following table:

SNK01 is an autologous NK cell therapy that fights cancer by harvesting a small amount of NK immune cells from a patient and transfusing the activated NK cells back into the patient after in vitro expansion. In November 2021, a Phase 1/2a clinical trial of its combination with the PD-1 inhibitor perbolizumab (Keytruda) for the treatment of non-small cell lung cancer (NSCLC) showed that the progression-free survival period (PFS) of patients treated with combination therapy was significantly longer compared with the pambolizumab monotherapy.

FC21-NK is a haploid, FC21 amplified allogeneic NK cell therapy. Data from a Phase 1 clinical trial conducted in 13 patients with relapsed/refractory acute myeloid leukemia (r/rAML) showed that FC21-NK cell therapy was well tolerated and controllable. The complete response and overall response rates were 50% and 78.6%, respectively, and the median overall and disease-free survival after treatment were 231 and 186 days, respectively.

FT500 is an iPSC-derived allogeneic NK cell therapy immunotherapy from a clone master that provides a large population of homologous NK cells and clearly demonstrates potent activity and the ability to work synergistically with T cells. The latest preclinical data data show that in the in vitro three-dimensional tumor spheroid model, the combination of FT500 with activated T cells and anti-PD-1 antibodies can significantly enhance the elimination effect of cancer cells compared with FT500 or activated T cells alone.

FT516 is FateTherapeutics' "ready-to-use" NK cell therapy derived from the differentiation of a clone-induced pluripotent stem cell (iPSC) line, using an innovative high-affinity, non-lysed CD16Fc receptor designed to maximize antibody-dependent cell-mediated cytotoxicity (ADCC). Data from the published Phase 1 clinical trial of the drug combined with ritriximab for relapsed/refractory B-cell lymphoma showed that 8 of the 11 patients achieved objective remission, including 6 achieved complete remission, and these patients had previously received an average of 3 pre-treatments, of which 4 had previously received autologous CD19CAR-T cell therapy. In terms of safety, no dose-limiting toxicity was found in the trial, no FT516-related serious adverse events and FT516-related adverse events of grade 3 or above were found.

FT536 is a multi-engineered, induced pluripotent stem cell (iPSC)-derived ready-to-use CAR-NK cell therapy. In addition to expressing a novel CAR that specifically targets the class I major histocompatibility complex (MHC) related proteins A and B (MICA/MICB) α3 domains, the drug also expresses a novel high-affinity, non-lysatable CD16 (hnCD16) Fc receptor, enhancing antibody-mediated cytotoxicity. In January 2022, the drug was approved for clinical trials in the United States.

CAT-248 is an allogeneic CD70-targeted CAR-NK cell therapy developed by Catamaran through its TAILWIND™ platform.

CAR19-CYNK was produced by Cellularity using anti-CD19CAR (Sorrento Therapeutics' CD19scFv-CD28CD3ζ) retroviral transfusion of human placental CD34+ cells and cultured under cytokine conditions.

The prospect is promising, and a number of pharmaceutical companies have joined hands to lay out

Baekje, Merck, Gilead...

FateTherapeutics, NkartaTherapeutics, InnatePharma, GlycostemTherapeutics, NantKwest and other companies are the leading players in the field of NK cell therapy. Among them, Nkarta Theraeutics focuses on CAR-NK therapy, and GlycostemTherapeutics focuses on developing stem cell-derived NK cell therapies. NantKwest focuses on the treatment of cancer and virus-induced infectious diseases through NK cell therapy, and its main products include haNK cell products with high affinity cd16 receptors, taNK cell products with high expression specific CAR, and t-haNK cell products that combine the advantages of the two.

In recent years, more and more companies have valued NK cell therapy and joined hands with other companies to lay out this market:

In February 2022, Intellia Theraeutics and ONK Therapeutics reached a partnership of up to $920 million. Under the agreement, Intellia will grant ONK a non-exclusive patent license for in vitro gene editing and LNP delivery technology, as well as an exclusive patent license for part of the gRNA for the development of allogeneic NK cell therapies for 5 CRISPR gene editing.

In February 2022, Boya Jiyin and Xingyi Ang Bio reached a cooperation agreement to develop a new generation of immune cell therapies based on Boya Jiyin's technology and resource advantages in high-throughput genome editing and screening, as well as Xingyi Ang Bio's technology and resources in induced pluripotent stem cell (iPSC) and natural killer cell (NK) cell function and production process.

In June 2021, BeiGene announced a partnership agreement with ShorelineBiosciences. BeiGene will pay an advance of $45 million to introduce allogeneic NK cell therapies with 4 targets developed by Shoreline technology. BeiGene has global commercialization rights, while Shoreline reserves the right to commercialize up to 2 targets in the U.S. and Canada.

In January 2021, Merck signed a global exclusive partnership and licensing agreement with ArtivaBiotherapeutics totaling more than US$1.8 billion to develop novel CAR-NK cell therapies for solid tumor-related antigens using Artiva's off-the-shelf allogeneic NK cell manufacturing platform and proprietary CAR-NK technology.

In April 2020, Gilead subsidiary KitePharma and biotech company oNKo-innate entered into a three-year cancer immunotherapy research collaboration to support the discovery and development of next-generation drugs and cell therapies focused on natural killer (NK) cells.

In December 2018, FateTherapeutics reached an agreement with Max DelbrückCenter (MDC) to acquire an exclusive selection of the novel humanized antibody BCMA-CAR construct for the development of iPSC-derived cell products, including CAR-NK cells and T cell products derived from iPSCs.

In October 2018, DragonflyTherapeutics entered into a $695 million partnership agreement with Merck to jointly develop and market solid tumor cancer immunotherapies developed through Dragonfly's proprietary technology platform, TriNKET.

summary

NK cells have been in clinical trials for more than ten years, but due to factors such as few sources, difficult expansion, large differences in transduction technology, and low transduction efficiency, NK cell therapy has developed slowly, and the future market prospects are still very clear. However, with the development of science and technology, many technical problems will be overcome, and some institutions predict that the global NK cell therapy market sales will reach 350 million US dollars in 2021 and is expected to reach 1 billion US dollars in 2028.

Responsible editor: Three seven

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