Recently, at the annual meeting of the American Society of Hematology (ASH), the iPSC-NK clinical data released by Fate Therapeutics (hereinafter referred to as Fate) has attracted widespread attention from all parties. As a pioneer in induced pluripotent stem cells (iPSCs), Fate is committed to developing "spot-type" cell immunotherapies derived from iPSCs.
Compared with the previous ones, the clinical data released by Fate further verified the safety and efficacy of the FT516 and FT596 pipelines, and preliminarily demonstrated the durability of the FT516 and FT596 efficacy. As an observer of the medical industry, Arterial Network has been closely monitoring the progress of global iPSC-based cell therapy clinical research and development. With this curiosity, we had the honor to visit Dr. Liu Xiaodong, founder and chairman of Aikai Biotech, to hear how this industry scientist interpreted Fate's clinical data and the development trend and enlightenment of iPSCs behind them.
Dr. Liu Xiaodong has been engaged in research at Monash University in Australia, francis Crick Institute in the United Kingdom and cambridge university, and has nearly ten years of research experience in iPSC, epigenetics, cell fate regulation, gene editing and human embryo development. His research, which resulted in the world's first successful construction of human blastocyst structures in vitro using somatic reprogramming, was published in Nature magazine in March 2021 as a cover article and was selected as one of the top ten breakthroughs of the year in Science magazine in 2021.
Dr. Liu Xiaodong, Founder & Chairman of Aikai Biotech
Fate's latest ASH data interpretation - safety, effectiveness, durability
Arterial Network: This is the third time since 2019 that Fate has presented clinical trial results at the ASH Annual Meeting. Compared with the previous clinical results shown by Fate, what are the characteristics of the clinical results shown by Fate?
Dr. Liu Xiaodong: In terms of safety, compared with T cell therapy, NK cell drugs have many advantages in terms of mechanism of action. In the FT516 and FT596 clinical trials, a total of 50 subjects were further validated in the clinical trial results of more than 6 months, that is, the safety advantages of NK cell drugs were not subjected, that is, no dose-limiting toxicity, no ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome), GVHD (graft-versus host disease, Graft Versus-Host Disease), only three cases of grade 1-2 CRS (Cytokine Release Syndrome) occurred in the FT596 study, and recovery was achieved with simple treatment.
In terms of effectiveness, FT516 and FT596 continue to show positive signals in larger populations, with high ORR (Objective Response Rate) and similar results to previous outcomes, especially in the treatment of terminal patients who have previously received CAR-T therapy, and another step towards the goal of achieving clinical "Proof Of Concept" (Proof of Concept) for cell drugs.
Arterial Network: What do Fate's data reveal compared to previous results?
Dr. Liu Xiaodong: The results show the clinical trial data of genetically engineered "spot-type" iPSC-NK cell drugs in a larger patient population, which can objectively show the clinical characteristics of FT516 and FT596 in a close-to-real situation, and show early positive signals in terms of the persistence of efficacy. In the future, whether cell drugs such as FT516 and FT596 can continue to function in vivo is the most worthy of our attention at this stage.
In the design of Fate's existing clinical trial protocols, multiple dosing cycles are short (once a week) and repeated preparations are required after every three dosings. Combined with the data presented by Fate before this conference, it shows that there is still room for further improvement in the immunogenicity of Fate's existing iPSC-NK cell drugs.
In this meeting, FT516 and FT596 initially demonstrated more positive observational data on medium- and long-term efficacy, especially in the higher dose group of FT596. Although we have also noticed that some patients have disease progression after the emergence of efficacy (for example, the disease progression occurs after a complete remission of a single treatment of FT596, follow-up of 1.7 months), but overall, the results of this clinical trial show that the immunogenic risk of FT516 and FT596 is relatively controllable, which reduces the previous doubts to a certain extent.
Although the current data on efficacy persistence are incomplete, the industry is encouraged by the positive results and will be further validated in the future with data from PFS (Progression-Free-Survival) and OS (Overall Survival).
Discussion on the future development trend in the field of iPSC
Arterial Network: Taking Fate as an example, what are the current development trends and enlightenments of the global iPSC industry?
Dr. Xiaodong Liu: Fate delivered 3 oral presentations and 5 poster presentations at the ASH Annual Meeting. In addition to the compelling FT516 and FT596-related data, Fate also shared the mass production of FT819, a CAR-T cell product derived from iPSC cells; a spot cell drug development strategy targeted at tumor neoantigens; and the synergistic effects of antitumor mechanisms in overcoming tumor heterogeneity and cancer escape after binding to iPSC-derived T cells.
In addition, iPSC cell drug companies such as Century also released their own results at the ASH Annual Meeting. All this shows that the field of iPSC-based cell therapy is developing rapidly and has great promise for the future. At the same time, the emergence of emerging technologies is inevitably accompanied by continuous optimization and challenges, which mainly include the bottleneck of the industrialization transformation and differentiation potential of iPSC technology itself, the challenge of safety and continuous effectiveness of iPSC source products, and the development space of iPSC source products.
iPSC technology currently has a certain bottleneck in itself. In terms of industrialization, iPSCs need to complete the transformation path from laboratory-grade products to pharmaceutical industrialized cell drugs. This issue requires the coordination and cooperation of regulatory authorities, industry, scientific research and other parties. Fate has completed this process and has conducted several clinical trials. On the other hand, iPSCs can theoretically differentiate into various tissue and organ cell types, but the reality is that the potential for iPSC differentiation after reprogramming is insufficient, including epigenetic memory and abnormalities during somatic reprogramming, and heterogeneity between iPSC cell lines, which limit the research and development of iPSC cell drugs. In response to this problem, the scientific community has been exploring, based on years of research on somatic reprogramming of cell fate regulation mechanism, we have developed a unique somatic reprogramming method, significantly improving the stem of iPSCs and the potential for future industrialization.
Regarding the safety and continuous effectiveness of iPSC-derived products, on the one hand, in terms of tumorigenesis and stability, there are some concerns about iPSC-derived products. However, with the establishment of a strict quality control method for iPSC cell drugs in the GMP production process, the improvement of the grasp of preclinical evaluation methods, and the feedback of the current Fate clinical trial results, although there are challenges in terms of safety, the safety of products can be guaranteed through the system we have established.
On the other hand, the challenge of the durability of iPSC-derived product efficacy is also the development trend of continuous optimization in the future. For example, adding relevant synthetic components to the iPSC source product transformation, the scientific research community and our previous scientific research work have accumulated a lot of experience, I believe that in the near future can show you more results.
Arterial Network: Back to you, as a scientist in the field of iPSCs, how do you plan to apply what you have learned next to help the development of this emerging industry?
Dr. Xiaodong Liu: We believe that iPSC-derived universal cell therapy is the ultimate solution, and based on my and other core members' previous years of accumulation in the field of iPSC research and industry, we hope that our team can make our contribution in this field and provide affordable cell therapy to countless patients. That's why we founded Akai Biotech to develop generic cell therapy drugs derived from iPSCs. Since its establishment 10 months ago, Aikai Bio has successfully built an iPSC reprogramming platform, an iPSC gene editing platform and an algorithm-guided iPSC differentiation platform, etc., which are targeted and efficient to solve some of the technical pain points currently facing.
At present, Aikai Bio has completed the construction of clinical-grade cell bank, reached a global strategic cooperation with Pumis, jointly developed a variety of iPSC-CAB-NK cell therapy products for solid tumors, realized the research and development of scientific research products to industrial products, and has now started the construction of a 2500-square-meter GMP production workshop project in Suzhou. It is believed that in the near future, Akai Bio will bring safe, fast and effective cell therapy solutions to countless patients.
>>>> about Dr. Liu Xiaodong:
Dr. Liu Xiaodong has been engaged in research at Monash University in Australia, francis Crick Institute in the United Kingdom and cambridge university, and has nearly ten years of research experience in iPSC, epigenetics, cell fate regulation, gene editing and human embryo development.
In the course of his research, the application of single-cell sequencing and epigenetic omics sequencing techniques has fully revealed the dynamic epigenetic regulation in the process of iPSC reprogramming for the first time in the world, revealed the dynamic cell fate regulation in the process of human somatic cells to induced stem cell (iPSC) reprogramming, and captured the cellular states of primitive pluripotent stem cells, trophoblast stem cells and other cellular states using induced reprogramming (Nature Methods, 2017; Nature, 2020) The world's first somatic reprogramming method was used to successfully construct human blastocyst structures in vitro (Nature, 2021, cover article), and the research results were selected as one of the top ten breakthroughs of the year in Science magazine in 2021.
>>>> about Aikai:
Based on the accumulation of Dr. Liu Xiaodong and other core members in the field of iPSC and industry for many years, Aikai Bio came into being, focusing on the research and development of general-purpose cell therapy drugs derived from iPSC. Since its establishment in March 2021, Aikai has successfully built an iPSC reprogramming platform, an iPSC gene editing platform and an algorithm-guided iPSC differentiation platform, etc., to solve some of the technical pain points currently facing it in a targeted and efficient manner.
Aikai has now completed the construction of clinical-grade cell banks, and has reached a global strategic cooperation with Pumis Bio to jointly develop a variety of iPSC-CAB-NK cell therapy products for solid tumors, realizing the research and development of scientific research products to industrial products. The company has obtained the support of many well-known investment institutions, completed more than 100 million yuan of financing, and started the construction of a 2500 square meter GMP cell production workshop in Suzhou.