EN
The article co-authored by Dr. Deng Tao and the GCP Center of the Chinese Academy of Medical Sciences has been published in CANCER CELL, a sub-journal of Cell.
2021-02-18
Article Details
On January 12, 2021, the article co-authored by Dr. Deng Tao and the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences/GCP (Good Clinical Practice) Center was published in CANCER CELL, a sub-journal of Cell with an impact factor of 26. The authors include Academician Hao Jie, Director of GCP and President of Cancer Hospital, Chinese Academy of Medical Sciences. The article provides a comprehensive analysis of the current clinical research status of cellular and gene therapies worldwide, especially their clinical applications in solid tumors.
The article published by Cancer Institute & Hospital, Chinese Academy of Medical Sciences
Cell therapy and gene therapy, with their diverse mechanisms of action and active ingredients, are widely studied in clinical trials worldwide as new strategies for treating malignant tumors. Some products have been approved, while the majority are still in early-stage research. Therefore, this field presents a mix of controversies, opportunities, and challenges.
Cell therapy generally refers to adoptive cell therapy (ACT), which primarily uses immune cells to kill tumors. Cell therapies can be classified into non-gene-edited and gene-edited cellular products based on their mechanisms, or by cell type into T-cells, NK cells (natural killer cells), DCs (dendritic cells), CIK cells (cytokine-induced killer cells), TILs (tumor-infiltrating lymphocytes), and MSCs (mesenchymal stromal cells). Both non-gene-edited and gene-edited cell therapies are undergoing extensive clinical research, and some have already obtained clinical indications, including T-cells (CAR-T, TCR-T, gdT cells, and gene-edited T-cells), TILs, DCs, and macrophages.
Gene therapy aims to modify or manipulate gene expression or alter the biological properties of living cells for therapeutic purposes. Based on the treatment method, gene therapy can be divided into in vivo or in vitro therapy, and based on the gene delivery system, it can be further classified into viral vectors and non-viral vectors. Gene-edited cell therapy falls into the category of in vitro gene therapy, where cells (normal or tumor cells) are removed from the patient, and the target gene (DNA or RNA) is introduced into the cells cultured outside the body. Cells with high expression of the target gene are then selected for expansion and finally transplanted back into the patient to treat the tumor. In vivo gene therapy involves directly introducing the target gene into the patient's cells through a vector. Oncolytic viruses (OVs), with their good tumor-lysing effect, tumor selectivity, and high immunogenicity, represent a promising in vivo gene therapy approach.
Research Findings and Conclusions
Conclusion 1: Cell and gene therapies have shown great potential in the treatment of solid tumors.
From January 1, 2010 to December 31, 2019, 491 clinical trials were conducted on 178 cell and gene therapies worldwide. The number of related clinical trials grew by an average of 16.1% per year, almost doubling in 2017 from the previous year. Phase I and II clinical trials in cell and gene therapies accounted for more than 90% of new trials opened each year (Figure A).
Conclusion 2: These trials covered 26 solid tumor types, with melanoma, non-small cell lung cancer (NSCLC), and ovarian cancer being the three most common (Figure B).
Conclusion 3: Over the past decade, a total of 318 clinical trials of cell therapy have been conducted worldwide, covering all treatment stages from neoadjuvant therapy for early-stage solid tumors to the endline of advanced solid tumors (Figure C), with advanced solid tumors accounting for the vast majority of them (88.1%, Figure D).
Vaccines are more frequently studied in all therapeutic stages of solid tumors. In addition, there are 374 registered clinical trials for gene therapy (including gene-edited cell therapy).
Conclusion 4: Although China ranks second in the number of cell and gene therapy clinical trials, there is still a large gap between China and the top-ranked United States, such as the overall number of 39 in China and 120 in the United States (Figure E).
The number of CAR-T and TCR-T trials in China was 14 and 5, respectively, compared with 22 and 16 in the rest of the world (excluding China). The target profiles in these trials also differed between China and the rest of the world. The top 3 CAR-T targets in China and the rest of the world outside of China were glypican-3, IL13Rα2/CEA/MUC1, and claudin 18.2/AFP, as well as mesothelin, NKG2D, and IL13Rα2/CEA/MUC1, respectively; and the top 3 TCR-T targets were NY-ESO-1, HBV, and hpve6, as well as NY-ESO-1, individualized tumor-specific neoantigen and MAGE-A4 in other countries; the high expression of HBV and HPV E6 in China reflects the regional characteristics of the high prevalence of HBV-associated hepatocellular carcinoma and HPV-associated cervical carcinoma in the Chinese population. In addition, clinical realization of cell therapy in China is concentrated in a few large cities, such as Shanghai, Guangzhou and Beijing, followed by Shenzhen, Hangzhou and Nanjing.
Based on the incompleteness in R&D technology, implementation process and related policies, most cell and gene therapy studies in the direction of solid tumors are stuck in phase I or II clinical trials.
The main challenges are as follows:
1. few tumor-specific antigens are clearly identified on the cell surface of solid tumors.
2. large heterogeneity of antigens in solid tumors.
3. limited infiltration of gene-transduced T cells in is solid tumor tumor bodies.
4. Immunosuppressive tumor microenvironment is a common feature in patients with advanced tumors, and T-cell failure is more common.
5. Clinical trials for biomarker screening are limited, accounting for only 19.2% (61/318) of cell therapy trials and 14.7% (55/374) of gene therapy trials, and do not allow for early and rapid enrichment of populations for whom therapy may be effective.
In addition, there are operational process challenges. For example, how to simplify and standardize cell and gene therapy preparation processes to optimize preservation, transport, and infusion; and how to provide more efficient and relevant training for all parties involved in cell and gene therapy trials.In the continuous development of cell and gene therapy, there are already some strategies to solve the problems.
For example, optimizing the design of CAR, improving the tumor infiltration ability of cells as well as improving the microenvironment of tumor immunosuppression. In addition, the combined application of different mechanistic therapeutic approaches with cellular gene therapy is also promising to further improve the efficacy. Meanwhile, the development of new manufacturing processes has also facilitated the development of cytogenetic therapies, such as the production process for 2nd generation TILs products, which requires only 22 days for cell preparation, compared to the original 6 weeks. The commercialization of 2nd generation TILs products for the treatment of melanoma and cervical cancer has accelerated in the United States.
In summary, cell and gene therapies have been widely developed for the treatment of solid tumors, and clinical trials covering almost all solid tumor types are increasing rapidly, especially after 2017. Cell and gene therapy in solid tumors still faces many challenges and requires scientists to continuously propose new solutions to further promote the effective and widespread clinical use of cell and gene therapy.
This paper is directed by Prof. Hejie and Prof. Binghe Xu, led by Prof. Ning Li from the National Cancer Center/Chinese Academy of Medical Sciences Cancer Hospital/GCP, in collaboration with Prof. Sun Fa and Dr. Kun Chen from Guizhou Provincial People's Hospital, Prof. Qijing Li from the Department of Immunology at Duke University, Dr. Lu Zhang from TCRCure Biopharma Ltd, USA, Prof. Xu Wang, Founder of Nanjing Karti Medical Science & Technology Co. Ltd.; Dr. Wang Enxiu, Founder; Dr. Wang Chen, Technical Director; Dr. Yuan Qing'an, Chief Scientific Officer, Excyte LLC, USA; Dr. Chen Bin, Chief Executive Officer, Beijing Hersen Genetics; Dr. Deng Tao, CEO of Chengdu MedGenCell; Dr. Liu Yarong, Founder of Zhuhai Gravel Bio-technology Co; Ltd.; Prof. Dongfang Liu, Professor of Pathology and Immunology Laboratory, Rutgers-New Jersey Medical School, and other experts in the field of cellular gene therapy. Dr. Shuhang Wang, Prof. Faye Sun, and Dr. Huiyao Huang, as the first authors, have completed the report of the study - Global Panorama of Clinical Research on Cellular and Genetic Therapy.
References:Shuhang Wang, Fa Sun, Huiyao Huang, Kun Chen, Ning Li, et al. Cancer Cell 39, January 11, 2021.
