SAPA GP president-elect Dr. Han Dai first introduced the topic of the symposium, cell and gene theraphy. Symposium co-chair Dr. Haifeng Cui then gave opening remarks to welcome everyone to attend the symposium.
SAPA GP vice president Dr. Jing Yang introduced the objectives, structure, major activities, and membership program of SAPA-GP.

1. Developing Gene Therapies for Rare Diseases, a History of Synergy Between Academia and Industry
Speaker: Frderico Mingozzi, Ph.D.
Dr. Mingozzi’s presentation reviewed the development efforts of gene therapies for rare diseases in academia and industry, using the development of Spark therapeutics as an example. He then introduced Spark therapeutics’ pipeline and clinical trials. He especially pointed out the development opportunities in China, due to the fast research development and strong government support. Finally, he emphasized the importance of collaboration between academia and industry towards the development of gene therapy.

2. Progress in the Delivery of Ex Vivo Cell and Gene Therapy Products
Speaker: Joseph Tarnowski, Ph.D.
Dr. Tarnowski first introduced Lentivirus and AAV as virus carrier, compared their advantages and disadvantages. He then used Strimvelis, the first ex-vivo stem cell gene therapy to treat patients with a very rare disease called ADA-SCID (Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency) developed by GSK, as an example to illustrate the advantage of cell and gene therapy. At last, he analyzed the widely discussed price issue of gene therapy. He broke down the cost of gene therapy development, and provided a GSK solution based on the latest research.

3. Novel CAR-T Targets & Technologies: Capital Efficient Strategies to Clinical Proof of Concept.
Speaker: Wyle Solomon, MBA, CEO, iCell Gene Therapeutics
iCell Gene Therapeutics is a private company founded by Dr. Yupo Ma in 2014. Dr. Ma is a physician-scientists in the field of leukemia and lymphoma. Due to his profound professional and personal connections with China, iCell used a unique China forward strategy to fulfill clinical proof-of-concept. Investigator-sponsored clinical trials are being conducted at Chengdu Military General Hospital, generating data that can be used for cFDA application, and ultimately product launch in the China market. Meanwhile, US IND/EU CTA RMAT designation is being processed simultaneously. Notable, the clinical proof-of-concept in the US/EU started 2 years earlier, while the first treatment in patient has already been conducted in China, which is highly efficient. When being asked why iCell chose China to conduct clinical proof-of-concept first, Mr. Solomon said, “I think it really comes down to the government. The government is switching to high-tech manufacturing. These types of technology that we work on are the technologies that the Chinese government has focused to want to be a leader in. That government support allowed these things to happy quickly. We find sources of support.” During the presentation, Mr. Solomon shared the unique clinical proof-of-concept experience in China, which was very inspiring. Previously, China keeps following the Biotech/Pharmaceutical new product development trend in the US/EU. But thanks to the financial and regulatory support from Chinese government, as well as the continuous effort from the pharmaceutical industry and business field, this situation is gradually changing. By leveraging the “China speed”, hopefully China can be one of the world leaders in the near future.

4. A Phase I Study to Evaluate the Safety of Multi-Antigen Stimulated Cell Therapy-I in Patients with Advanced Solid Tumors
Speaker: Shell Li, MD, MS, Global Chief Medical Officer, Vice President, Global Clinical Development, HRYZ Biotech Co.
During the presentation, Dr. Li shared the preclinical and clinical data about a novel cancer immunotherapy product developed by HRYZ Biotech, Multi-Antigen Stimulated Cell Therapy-I (MASCT-I). MASCT-I is comprised of two different types of cells, autologous multi-peptide loaded DC and autologous polyclonal effector T cells. Through leukapheresis, the monocytes (pre-DC) will be extracted from the patient’s peripheral blood, which then stimulated to become immature DC. After exposure to multiple antigens, these immature DC will become mature DC. Part of these cells will be injected back to the patients subcutaneously, while the other part of them will be co-cultured with T cells, helping them to activate and proliferate into polyclonal effector T cells. Eventually, the effector T cells will be intravenously transfused back to the patients. For each MASCT-I treatment cycle, three courses of DC and T cell treatment are included.
From 2012 to 2016, over 3000 MASCT-I infusions were conducted. Due to the passive collection methodology, only 27 cases of adverse event were reported. The most common adverse events include fever, erythema, itching, edema, headache, limb pain, local lymph nodes enlargement etc. Though it’s not a typical clinical trial, these results still indicated the preliminary safety record of this new cell therapy. Meanwhile, through retrospective medical chart review study, it showed that MASCT-I helped to extend overall survival time in hepatocellular carcinoma patients.
Right now, three formal MASCT-I clinical trials (Phase I and Phase II), targeting different solid tumors, are being conducted in China. Dr. Li is looking forward to the clinical results, which would help to confirm the safety and efficacy of MASCT-I.

5. Solve the Supply Problem of Gene Therapy – AAV Manufacturing Technology Overview
Speaker: Jeffrey Hung, PhD, MBA, CCO of Vigene Biosciences
Dr. Hung continued the discussion of Dr. Tarnowski’s talk regarding the supply problem of gene therapy and deepened the topic with more examples and data. He initiated the talk with the reasons of the increasing demand of adeno-associated virus (AAV) - low toxicity, affordability and applicability. Currently, 483 gene therapy vectors are in development/market and 48% of vectors are viral based. For one gene therapy, using BioMarin – BMN270 for treating hemophilia as an example, to treat 90,000 patients, more than 4 million liter of cells or 389 of non-stop 200-liter bioreactors are needed. “Gene therapy hits a peculiar roadblock: a virus shortage.” Dr. Hung also cited the article from New York Times and then addressed technical reasons of the shortage. He provided the overview of 3 technology AAV production platforms - helper virus system, baculovirus system and helper free-plasmid based AAV production, and their advantages, weakness and corresponding solutions. The major technical disadvantages are long-time preparation, contamination and increased purification requirement for helper virus and baculovirus system, and low scalability, low productivity for helper-free transfection. The overall commercial disadvantages for all the platforms are high cost and long production time. Dr. Huang then highlighted a few purification AAV challenges, and at last provided some insights on how to overcome the supply problem for gene therapy. He thought that it’s highly desired to build up more facilities and improve production and purification technologies. He also believed that there is room to lower the treatment dose in clinical trial.

6. TCR-Based Gene Therapy for Cancer
Speaker: Rafael Amado, MD, CMO of Adaptimmune
Dr. Amado firstly introduced adoptive T-cell and four components to an effective adoptive therapy: T cell must recognize a cancer cell via a guiding receptor; the guiding receptor must have affinity and specificity; the T cell needs to be resistant to suppression; the T cell need to break cancer immune tolerance. However, since naturally – occurring cancer TCRs have very low natural affinity to antigen, a complex process of TCR discovery and optimization is required. Dr. Amado mentioned that “ T-cell receptor (TCR) therapy is very powerful technology if governed properly”. He presented Adaptimmunes’ Standard Preclinical Package, including potency and efficacy, cell screen and molecular safety, and reported the in vitro data. Finally, he introduced NY-ENY-ESO-1c259 TCR Synovial Sarcoma Study. For subjects who have the HLA tissue-type marker, the T cells would be engineered to recognize a substance called "NY-ESO-1". After putting this new gene in T cells the investigators will grow the cells in the laboratory and give these cells back to subjects. Dr. Amado went over the development of NY-ENY-ESO-1c259 TCR and the study plan, and reported the result of clinical trial. NY-ESO-1 SPEAT T-cells were detectable in the periphery 28 months following infusion and persisting cells were minimally exhausted. The persisting transduced T-cell pool was enriched for stem cell memory cells, which is consistent with cells capable of long-term immunological memory. Dr. Amado also discussed treatment resistance in the clinical study and said that it is important to learn more from the persistence experience and improve T-cell functions to overcome the tumor microenvironment and induce a broader immune response.

7. Brain repair with In Situ Glia-to-Neuron Conversion
Speaker: Gong Chen, Ph.D.
Professor Gong Chen of Pennsylvania State University introduced to us a novel glia-to-neuron in vivo cell conversion technology that can be applied to brain and spinal cord repair. First, he pointed out the hurdle for the treatment of neurodegenerative disease like Alzheimer’s disease or Stroke, etc. Not only to find the abnormal protein target is crucial, but also to repair the affected neurons. However, the non-dividable neuron death has limited the chances. Thus, in the light of NeuroD1, the single transcription factor for activation of neural-related genes, professor Chen has been able to develop the method to reverse glial cells into functional neurons in vivo and in situ. His team has also extended the principles to animal model like mice and monkeys, not only by retrovirus but also AAV and small molecules. They have also demonstrated that local neural circuit was rebuilt in NeuroD1-converted neurons. Last but not the least, he mentioned the ongoing efforts to transfer this in vivo reprogramming method to clinical trial, which would be more beneficial than stem cell therapy.

8. New Therapeutic Platforms: More Platform than You Think
Speaker: Mike Naso, Ph.D.
Dr. Mike Naso from Janssen Pharmaceuticals has discussed about the new therapeutic platforms for cell and gene modified cell therapy. He first brought us the current situation of cell and gene therapy that the five leading gene therapy have average cost up to $0.5 million per treatment. Through comparing the manufacturing processes for these therapies, he pointed out the challenges and benefits to form a platform that is capable of broadly manufacturing for most therapeutics. He further analyzed the evolution of monoclonal antibody platforms, rAAV platforms and gene modified cell therapy platforms. He believed that better cost-effective platforms for cell and gene therapy should be developed in the future.

9. Gene-engineered T-cell Therapy – Bench to Bedside and Back again.
Speaker: Laura Johnson, Ph.D., Senior Director, Head Translational Medicine, Oncology Cell Theraphy, GlaxoSmithKline
Dr. Laura Johnson shared with us about the state of gene-engineered T-cell immunotherapy of cancer, how it started on bench, received successes on bedside, and back to bench for further testing and exploration. Laura pointed out that the gene-modified targeted T cells are potent; Solid tumor respond differently to CAR therapy compared with hematologic ones. ‘Therefore, selection of tumor-specific target antigen and preclinical safety testing is of utmost importance!’, She indicated. Also, the work from bench to bedside, toxicity testing of EGFRvIII CAR-based immunotherapy of glioblastoma, was shared.

10. Clinical Experience with ASOs in neuromuscular Disease
Speaker: Toby Ferguson, M.D., Ph.D., Medical Director, Neuromuscular Disease, Biogen
Dr. Toby Ferguson shared with us about the urgent need of therapies for amyotrophic lateral sclerosis (ALS), and the development of antisense oligonucleutides for its treatment. He indicated that the pathogenic cascade of ALS is still controversial, but the consensus view is gain of toxic protein function. To target and knock down the toxic protein SOD1, antisense oligonucleotides that degrade SOD1 mRNA and decrease SOD1 protein expression were developed. Additionally, more potent SOD1 ASO BIIB067 was synthesized and proved to prolong survival in animal models. Furthermore, key points of the phase I trial were introduced.

11. Using CRISPR/CAS9 to Generate Universal T Cells and Improve Adoptive Immunotherapy against Solid Tumors
Speaker: Yangbing Zhao, M.D., Ph.D.
Dr. Yangbing Zhao discussed about strategies to make best in Class CART/TCR-T cells: 1. Manufacture of high quality T cells using CRISPR/CAS9 gene edited T cells. 2. Selecting safe targets with safe and effective NY-ESO-1 TCR development. 3. Overcome Tumor immunosuppressive microenvironment with additional modification with PD1 CD28 switch receptors. He also presented the approval of first-in-human CRISPR gene editing example: Phase I trial of NYCE cells engineered to express NY-ESO-1 TCR and gene edited to eliminate endogenous TCR and PD-1.

Hao Sun overviewed the programs at the end of this symposium. Dr. Han Dai, SAPA-GP President-elect, gave the closing remarks.

Editor: Chun Shao
Reporters: Li Cao, Hao Wu, Yichen Wang, Jia Nong, Jianting Shi, Yixuan Qiu, and Xiaoli Gao
Photographers: Aimin Tang, Fei Sheng, and Peixin Jiang