Human’s First Line of Defense Against Cancer Cells and Viruses – NK Cells

Cell therapy is a hot direction in research and development and clinical transformation in recent years, among which the innovative therapy of chimeric antigen receptor (CAR) modified T cells (CAR-T) has been approved as a drug for clinical treatment. However, CAR-T therapy is not perfect, and has many shortcomings such as large side effects, high production costs, and the temporary inability to overcome solid tumors. Because of this, pharmaceutical companies have never stopped exploring cell therapy. Researchers followed the engineering technology similar to CAR-T to explore the possibility of clinical transformation of other immune cells, such as tumor infiltrating lymphocytes (TIL), natural killer cells (NK), regulatory T cells (Treg), tree dendritic cells (DC), etc.

Among them, NK cells, as a type of lymphocytes that can non-specifically kill tumor cells and virus-infected cells without prior sensitization, have attracted the attention of researchers. Many entrepreneurial teams have begun to enter the NK cell therapy track, especially CAR-NK cells therapy . According to Market Research Guru, the global NK cell therapy market will reach US$340 million in 2021, and is expected to grow to US$1.009 billion in 2028, with a compound annual growth rate (CAGR) of 16.8%.

With the commercial launch of CAR-T cell therapy and the gradual enlargement of the market size, NK cell therapy, as a branch of cell therapy, has also gathered more and more heat. Many entrepreneurial teams and investment institutions have entered this track. NK Cell therapy promises to create the next wealth creation myth.

Human's first line of defense against cancer cells and viruses - NK cells

NK cells are a kind of innate lymphoid cells, which are different from T and B cells. They can spontaneously kill tumor cells and pathogens without prior sensitization, and participate in the body's anti-tumor immune surveillance and immune response . kill" . At the same time, NK cells are the first line of defense of the human body against cancer cells and viral infections, and are mainly distributed in the blood, liver, spleen, bone marrow and other parts of the human body.

Distribution of NK cells in the body:

As the body's first line of defense against cancer, the role of NK cells in the line of defense mainly includes: 1. Secrete perforin, granzyme, granulysin and other cytotoxic soluble particles to induce apoptosis of target cells; 2. By secreting a large number of cytokines (IFN-γ, TNF-α, TNF-β, etc.) , recruiting macrophages, T cells, etc. to cooperate; 3. Express FC receptors, which mediate antibody-dependent cell-mediated cytotoxicity (ADCC).

NK cell function

In fact, as early as the 1970s, American scientist Professor Ronald Herberman first discovered NK cells, but it was not until the past 15 years that people gradually understood the potential of NK cells in anti-tumor and other diseases. The use of NK cells for treatment can generally be divided into two major paths, one is to use unmodified NK cells as cancer therapy; the other is to use genetic engineering modification, plus CAR-NK cell therapy with a specific CAR structure . In this way, NK cells can reduce the damage to normal cells when they target and kill cancer cells. Currently, CAR-NK cell therapy is the mainstream.

Compared with CAR-T: What are the advantages of CAR-NK

T cell therapy is relatively mature among various cell therapies. At present, FDA has approved 6 CAR-T cell immunotherapy products for the treatment of lymphoma and myeloma, and 2 CAR-T cell therapy products have been approved in China . However, in the clinical application of CAR-T products, there are challenges such as long production cycle, cytokine storm and neurotoxic side effects, which limit their wide application. In addition, CAR-T products have not yet achieved breakthroughs in the field of solid tumors. The CAR-NK products developed based on NK cells are considered to have the potential to solve the above challenges.

Compared with CAR-T therapy, CAR-NK cell therapy has the following advantages:

01  /  better security

The safety of unmodified NK cells and CAR-NK cells is high. For example, allogeneic NK cells will not cause graft-versus-host disease (GvHD) ; since CAR-NK cells do not secrete inflammatory factors, they generally do not induce cytokine storms, etc.; Due to the short survival period of NK cells in vivo, it is not easy to produce long-term toxicity.

02  /  Multiple tumor killing mechanisms

In addition to CAR-mediated targeted killing, CAR-NK cells can also use NK cells' own anti-tumor properties, such as increasing their cytotoxicity and cytokine release through two other co-stimulatory molecules, namely NKG2D and CD244, And through ADCC and other functions to identify and kill tumor cells with down-regulated or missing CAR targets, so as to improve the effect of immunotherapy. In addition, CAR-NK therapy is expected to break through the bottleneck of solid tumors.

03  /  The source of NK cells is wider

Most of the CAR-T cells are derived from the patient's own or healthy human donor cells, while NK cells can be derived from peripheral blood, CD34+ hematopoietic progenitor cells, umbilical cord blood, induced pluripotent stem cells ( iPSC) , NK-92 and other cell lines. This makes the allogeneic CAR-NK more convenient to obtain, and the quality is relatively uniform and efficient.

04  /  Can be developed into a general-purpose CAR-NK

Due to the high safety of NK cells, CAR-NK can be developed as a general-purpose product, thereby improving production efficiency and reducing production costs and selling prices.

Domestic and foreign pharmaceutical companies are actively entering the CAR-NK therapy track

Based on the various advantages of CAR-NK cell therapy, in recent years, the research and development of CAR-NK therapy worldwide has embarked on the road that CAR-T has gone, many companies have quit, and the popularity of NK cell therapy has continued to rise.

In 2019, Takeda Pharmaceuticals cooperated with the University of Texas MD Anderson Cancer Center to obtain CAR-NK technology and four CAR-NK products, and has since continued to increase investment in CAR-NK cell therapy.

In July 2020, Nkarta, an NK cell therapy company with four pipelines, landed on NASDAQ with a market value of over US$1.4 billion. In April this year, Nkarta announced the positive phase I clinical data of its two CAR-NK therapies, and its stock price finally closed up 140.93% that day.

Nkarta's technical route

In November 2020, Sanofi acquired Dutch cell therapy company Kiadis for a total of US$358 million , thereby owning the latter's NK cell platform and products. There are 5 products under research in the company's pipeline, and the fastest-growing one is in Phase II clinical stage. On September 28, 2022, Sanofi cooperated with Scribe Therapeutics to obtain non-exclusive rights to Scribe's proprietary CRISPR platform, using its CRISPR gene editing technology to achieve genetic modification of NK cell therapy. Under the agreement, Scribe will receive an upfront payment of $25 million and is eligible to receive potential payments in excess of $1 billion based on development and commercial milestones, as well as sales royalties on net sales of development products.

In January 2021, Merck spent US$1.8 billion to cooperate with NK cell therapy company Artiva Biotherapeutics . Artiva has three NK cell therapy pipelines, the fastest of which is in Phase I clinical stage.

In February 2021, Cytovia , which develops induced pluripotent stem cell therapy, and Cellectis , a cellular immunotherapy company, reached a $760 million strategic partnership to jointly develop CAR-NK cell therapy, with the goal of entering clinical trials around 2022.

In June 2021, Gilead's Kite Pharma and Shoreline Biosciences reached a cooperation with a total of more than 2.3 billion US dollars to jointly develop iPSC-derived NK cell therapy.

There are also more and more NK cell therapies in China, but they are basically in the early clinical stage, mainly in phase I/II, mainly hematological tumors, and only a few solid tumors, mainly involving hepatocellular carcinoma, gastric cancer, pancreas cancer etc. Relevant companies include Ascoli, Guojian Chengnuo, Enbry Biology, Jingda Biology, Jinyin Biology, Xinchuan Biology, Kelun Botai, etc.

At present, the domestic progress of CAR-NK therapy includes Ascoli, Guojian Chengnuo and Inbary .

Ascoli is an early entrant to CAR-NK. The CAR-NK product developed by it targets the nerve axon guidance molecule ROBO1 , which is suitable for more than 80% of solid tumors and more than 90% of blood tumors. In a phase I clinical trial, the clinical data of 17 patients with relapsed/refractory advanced solid tumors (11 cases of breast cancer, 3 cases of bowel cancer, 1 case of lung cancer, 1 case of pancreatic cancer, and 1 case of liver cancer) showed that the disease control rate Reached 76.5%, the overall survival time of the patients was more than 20 months, and no major adverse event occurred. It has remarkable anticancer effect and good safety.

Guojian promises to focus on the research and development of new drugs for the treatment of solid tumors with CAR-NK. The company has six technology platforms: CAR-NK R&D platform, antibody screening platform, iPSC technology development platform, gene detection platform, intelligent manufacturing production platform and exosome development platform, and has deployed multiple CAR-NK product lines. Its self-developed CAR-NK injection uses lentiviral transfection technology to transduce the CAR structure that recognizes MSLN into NK, making CAR-NK cells an immune cell product with the ability to specifically recognize and kill epithelial ovarian tumors.

Enbry has independently developed the world's leading tiNK, CAR-raNK cell technology platform and a number of general-purpose allogeneic NK and CAR-NK cell therapy products. At present, a number of new drugs for solid tumors and hematological tumors are being promoted into the clinic stage. Its CAR-NK product IBR854 injection is a ready-to-use allogeneic CAR-raNK product targeting carcinoembryonic antigen 5T4. 5T4 carcinoembryonic antigen is a highly glycosylated cell surface protein, which is found in various solid tumors such as non-small cell lung cancer, breast cancer, pancreatic cancer, ovarian epithelial cancer, cervical cancer, prostate cancer, and colorectal cancer. Higher expression rate.

In terms of financing for domestic companies, since 2022, Enbry, Jingda, Jinyin, and Xinchuan Biotech have all received financing.

Embry Bio has received 230 million yuan in Series A financing, and now has 11 CAR-NK immune cell product pipelines and 4 original antibody new drugs in the preclinical and clinical stages.

Jingda Biotech received 10 million yuan in angel round financing. The company has rich experience in large-scale NK cell culture and virus transduction, and realizes the full closed-loop development process of CAR-NK cell drugs from screening, construction, amplification, transduction, and detection .

Jiyin Biotechnology has received tens of millions of yuan in seed round financing, which was used for the early development of iCAR-NK pipeline series products, the optimization and upgrading of the core technology platform, and external cooperation.

Xinchuan Biotech has received nearly 100 million yuan in seed round financing for the development and production of iPSC-CAR-NK immune cell therapy.

With the breakthrough of technology and the influx of capital, NK cell therapy has obviously become the next outlet of cellular immunotherapy, and is expected to become the "main force" for the development of next-generation cancer immunotherapy. However, under the background of thriving investment and financing, we still cannot ignore the problems to be overcome in NK cell therapy, such as the expansion of NK cells, the short duration of NK cell therapy, the pollution in the transduction process of NK cell therapy, and the homing of NK cells The efficiency of reaching the tumor site needs to be further improved. For pharmaceutical companies, the speed of solving these problems is the key to success or failure, and it also requires more patience from capital.