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IF=30.
153) published a review that reviews and summarizes the ten-year history
of the development and clinical application of CAR-T cell therapy.
In terms of innovation and clinical application, China and the United States are in a state of parallel operation, but China needs to improve
in the innovation and commercialization of original targets.
In the future, the next generation of CAR-T cell therapy based on stem cells, synthetic biology and gene editing technologies will rise rapidly in China and has a bright
future.
The article is as follows: CAR-T-cell
therapies in China: rapid evolution and a bright
China's CAR-T Cell Therapy: Rapid Rise, Bright Future
-01-Overview of CAR-T clinical trials in China
-01-Overview of CAR-T clinical trials in China▉ Clinical Trial Overview in China As of November 15, 2021, there are 714 clinical studies of CAR-T cell therapy registered in China, of which ClinicalTrials.
gov
With 510 clinical trials and 204 clinical trial registration studies in China, the total number of CAR-T clinical trial registrations in China and the United States declined by 2021, which has been increasing in previous years (Figure 1A).
In terms of regional distribution, clinical research on CAR-T cell therapy in China is mainly distributed in Beijing (n= 84), Guangdong (n= 65), Zhejiang (n= 65), Jiangsu (n= 59) and Shanghai (n= 54; Figure 1B) and other areas with concentrated medical resources, high scientific research level and more developed economy (Figure B).
In terms of clinical trials, 320 CAR-T clinical studies are underway, most of which (about 70%) are still in PhaseI, PHASE I/II (Figure 1C, D).
Figure 1.
Clinical trials of CAR-T cell therapy in China, and comparison between China and the United States In terms of indications, in the 342 clinical trials underway in 2021, hematological tumors accounted for the vast majority, especially B-cell malignant tumors
.
There were 119 (23%) trials for solid tumors, with the most common trials for solid tumors including liver, pancreatic and brain cancers
.
.
It is worth noting that some companies are already doing indications other than oncology, and the proportion has increased (Figures D and E), and the range of diseases is wide, including autoimmune diseases, infectious diseases and POEMS syndrome
.
Specifically, indications for autoimmune diseases include systemic lupus erythematosus, scleroderma, nephritis, Sjogren's syndrome, neuromyelitis optica spectrum disorders
.
For infectious diseases, including AIDS, chronic active EBV infection and new coronary pneumonia
.
▉ Overview of Clinical Trial Application (IND) for New Drugs in China The number of INDs for CAR-T cell therapy in China is increasing, and 73 CAR-T cell products of 32 companies have submitted IND applications, and 36 have obtained implied licenses to enter clinical trials, of which acute lymphoblastic leukemia and non-Hodgkin lymphoma are one of the most common indications (Table 1.
).
Although there are many clinical studies carried out in China, only two products have been marketed and commercialized in China, which also reflects the imbalance
between research and output.
-02-A key driver of the rapid rise of CAR-T in China
-02-A key driver of the rapid rise of CAR-T in ChinaActive policy and regulatory stimulus (domestic laws and regulations promote the development of cell therapies and accelerate the pace of new cell drug development), sufficient financial support (cumulative financing of US$2.
37 billion from 2018 to 2021, CAGR of 45%), large patient population and fast-growing clinical trial system (large population, increased awareness and participation in clinical trials, growth in clinical trials and investigators).
-03-Ten years of achievements of CAR-T therapy in China
-03-Ten years of achievements of CAR-T therapy in China▉ Targeted innovation: Chinese scholars not only used CD5 and CD7-targeted CAR-T cells for the first time to treat T cell malignant tumors, but also committed to exploring multi-target CAR-T cell therapy to reduce the recurrence rate, such as CD19/CD22 dual-target CAR-T cell therapy ALL and B-NHL, BCMA/CD38 dual-target car-T cell therapy MM, CLL1/CD33 dual-target CAR-T cell therapy AML, etc
.
In the field of solid tumors, Chinese scholars have introduced GPC3 target for hepatocellular carcinoma, Claudin18.
2 target for gastric cancer, B7H3 target for anaplastic meningioma, and EphA2 target for recurrent glioblastoma
.
In the field of non-oncological diseases, CD19/BCMA dual-target therapy for systemic lupus erythematosus (SLE), HIV-1
Clinical trials of CAR-T cells targeting gp120 for the treatment of AIDS are also underway
.
2 target treatment for gastric cancer, B7H3 target treatment for anaplastic meningioma, EphA2 target treatment for recurrent glioblastoma, non-tumor disease area, systemic lupus erythematosus (SLE) AIDS
▉ One of the ways to enhance the efficacy of CAR-T cells is to enhance their function
.
Chinese scientists have done this by morphing the CAR structure and blocking immune checkpoint receptors (PD-1, Tim-3 and Lag-3), increasing CAR-T through other biochemical modifications
Cyto-anti-tumor characteristics, drugs combined with CAR-T (decitabine, sorafenib, sunitinib, bridging hemiphasygopoietic hematopoietic stem cell transplantation), optimization of ex vivo culture, cocktail CAR-T cell therapy (CD19 combined with CD22, BCMA combined with CD19) and other means continuously enhance the function of CAR-T cells, and resist the depletion of CAR-T cells to continue to play an anti-tumor effect
.
▉ Precise regulation of Chinese scholars in the introduction of "on/off" concept in CAR-T cells, precise regulation of their biological functions, timely avoid cytokine release syndrome (CRS), neurotoxicity syndrome (ICANS), graft-versus-host disease (GVHD) and other toxic side reactions
.
Serious side effects are still the main obstacle to the widespread clinical application of CAR-T cell therapy, and there are few domestic research reports on the precise regulation of CAR-T cells, so the design of precision regulation is the next generation in China
One of the most important directions of
CAR-T cell design.
▉
The development of general-purpose CAR-T (UCAR-T) cells has the characteristics of healthy donor source, high preparation success rate and wide applicability, and the general-purpose CAR-T cells developed by Chinese scholars have significant efficacy in the treatment of B-ALL and T-ALL, and the toxic side reactions such as CRS, ICANS, GVHD and so on are low
。 However, there are still some limitations, of which GVHD is one of the main challenges hindering clinical application, because existing technologies still cannot completely knock out T cell receptors, and gene editing increases the risk of
gene mutation, clonal amplification, and potential targeted, non-tumor effects.
▉ The establishment of a new preparation platform for traditional CAR-T cells, the preparation mainly relies on lentiviral systems, and randomly integrated CAR insertion sites have certain production process risks
.
The Chinese research team used non-viral system and site-specific CAR insertion technology to prepare CAR-T cell therapy B-NHL, and achieved the best efficacy
at present.
▉ Stem cell directed differentiation induced pluripotent stem cells (iPSCs)
or embryonic stem cells (ESCs) have strong in vitro expansion capabilities and can be gene edited
.
Therefore, stem cell-induced differentiation of immune cells is a reasonable and effective strategy
for future cell therapy.
Chinese scholars explore ways to obtain different sources of CAR cells (such as NK cells, macrophages, etc.
) to achieve stronger tumor cell immunotherapy
.
Figure 3.
Development of CAR-T cell therapy in China
-04 - Future outlook
-04 - Future outlookChina is actively promoting cell therapy research from the laboratory to the clinic
.
CAR-T cell therapy has become a promising cellular immunotherapy that has the potential to benefit the majority of cancer patients, and more and more CAR-T cell products have entered the experimental new drug stage
of therapeutic development.
However, the road to success of CAR-T cell therapy is not smooth, and there are still challenges
in target optimization, precise regulation, function enhancement, synthetic biology, and the design of general CAR-T cell therapy.
In addition, solid tumors hinder the widespread use of CAR-T cell therapy, and the mechanisms and risk of recurrence of adverse effects, including CRS, ICANS, and GVHD, need to be further explored
.
Through the precise regulation of gene editing and synthetic biology technologies, China is making progress
in developing efficient universal CAR-T cell therapy and iPSC-derived cell immunotherapy.
The new strategy of bridging allogeneic HSCT after CAR-T cell therapy in China is expected to obtain better clinical efficacy and safety
.
In general, the innovation of CAR-T cell therapy is expected to improve the clinical application
of cell immunotherapy in China.
In the future, the next generation of CAR-T cell therapy based on stem cells, synthetic biology and gene editing technologies will rise rapidly in China and has a bright
future.
