Advances in CAR-T therapy for multiple myeloma
Multiple myeloma (MM) is a malignant proliferative plasma cell tumor characterized by the abnormal accumulation of monoclonal plasma cells in the bone marrow and the production of monoclonal immunoglobulin or its fragment (M protein), which damages related organs and tissues. Hypercalcemia, renal insufficiency, anemia and bone destruction are common clinical manifestations. The global incidence of MM has increased significantly in recent years, increasing by 126% between 1990 and 2016 [1], and is now the second most common malignancy in the blood system. Although proteasome inhibitors, immunomodulators, monoclonal antibodies and other drugs have made remarkable progress in the treatment of multiple myeloma, relapse and the emergence of drug resistance remain a major challenge, and MM is still not completely cured. Therefore, the research progress of CAR-T therapy for multiple myeloma is of great significance.
一、CAR-T therapy
Car-t cell immunotherapy is a new type of treatment, which uses the patient's own immune system to fight cancer cells. Simply put, T cells in the collected peripheral blood of the patient are isolated, and the isolated T cells express CAR through gene transduction technology, and then these cells are injected back into the patient for anti-tumor therapy. CAR consists of a single-stranded variable fragment (scFv) from a monoclonal antibody, a hinge region from a CD8, a transmembrane domain, and an intracellular signaling domain (Figure 1). The first generation of CAR contained only one intracellular signaling domain, and the second generation added co-stimulatory domains such as CD28 or 4-1BB to enhance the anti-tumor effects of CAR T. The third generation further increased the co-stimulatory domain to two on the basis of the second generation to promote the proliferation and activation of CAR-T. The fourth generation added cytokines on the basis of the third generation to improve the lethality of CAR T to the tumor. Researchers have developed a novel CAR construct that encodes a truncated cytoplasmic domain from the interleukin (IL) -2 receptor beta chain (IL-2rβ) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif. As well as the TCR signal transduction (CD3ζ) and co-stimulatory (CD28) domains, which are considered fifth-generation CAR[2], although this concept is currently in the exploratory stage, compared to CAR T cells expressing the CD28 or 4-1BB co-stimulatory domains alone, The structure showed excellent in vivo persistence and antitumor effect in hematoma and solid tumor models, which brings hope for the treatment of solid tumors. After CAR T infusion into patients, tumor cells expressing specific antigens can be specifically recognized and killed through three ways of cytolysis, release of cytokines and Fas/FasL, and are not restricted by the Maior histocompatibility complex (MHC).
FIG. 2 MM therapeutic targets
FIG. 3 Schematic diagram of two-target CAR design
Compared with traditional proteasome inhibitors, monoclonal antibodies and immunomodulators, CAR-T cell therapy has more significant targeting and stronger killing ability, which makes the remission degree and survival of patients continue to improve. However, recurrence due to issues such as immune escape of tumor cells remains a huge challenge for researchers. At present, in response to this problem, multi-target, especially dual-target CAR-T clinical studies have achieved initial results. It is believed that with more research and clinical trials, the safety and effectiveness of CAR-T cell therapy will be further improved, bringing more hope to multiple myeloma patients.
At present, Shenzhen Cell Valley won the bid of the "GMP Grade Cell Product production and Preparation" project of Huazhong University of Science and Technology Union Shenzhen Hospital, providing industrial preparation and clinical application of anti-BCMA CAR-T cell products based on retroviral vector. The good news is that the patient achieved a very good partial remission one month after receiving CAR T cell therapy. The patient has been discharged from the hospital for several months and has now achieved complete response (CR), and the M protein level has now dropped to 0 g/L!! Welcome interested readers to contact Shenzhen Cell Valley for in-depth exchanges!
Reference：
[1] VAN DE DONK N W C J, PAWLYN C, KL Y.Multiple mye-lomalJ. Lancet, 2021, 397(10272):410-427.
[2] Kagoya, Y.; Tanaka, S.; Guo, T.; Anczurowski, M.; Wang, C.H.; Saso, K.; Butler, M.O.; Minden, M.D.; Hirano, N. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat. Med. 2018, 24, 352–359.
[3] NOOPUR RAJE M D J B. Anti-BCMA CAR T-Cell Therapybb2121 in Relapsed or Refractory Multiple Myeloma[J]. TheNew England Journal of Medicine, 2019(380) :1726-1737.
[4] LIN Y, MARTIN T, BERDEJA J G,et al. Ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients withrelapsed/refractory multiple myeloma: 2-year post LPI resultsfrom the phase 1b/2 CARTITUDE-1 study[J]. HemaSphere,2022, 6(Suppl) :851-852.
[5] Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target forthe treatment of multiple myeloma. Clin Cancer Res. 2008; 14 (9) : 2775-2784.
[6] Smith E L, Harrington K, Staehr M, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells[J]. Science translational medicine, 2019, 11(485): eaau7746.
[7] SHAH N N, MAATMAN T, HARI P, et al. Multi TargetedCAR T Cell Therapies for B-Cell Malignancies[J]. Frontiers inOncology, 2019,9 :146.
[8] TAHMASEBI S, ELAHI R, KHOSH E,et al. Programmableand multi-targeted CARs: a new breakthrough in cancer CAR-Tcell therapy[J]. Clinical and Translational Oncology, 2021, 23(6):1003-1019.
[9] Xie, B.; Li, Z.; Zhou, J., Wang, W., Current status and perspectives of dual-targeting chimeric antigen receptor T-cell therapy for the treatment of hematological malignancies. Cancers 2022, 14.
Disclaimer: Shenzhen Cell Valley is committed to the research of cell and gene therapy, in order to promote emerging technologies, so that more people understand the new development of biomedicine. The content of this article is only used for information exchange, and the platform remains neutral on the content, statements and opinions of the article, and does not represent the position and views of Shenzhen Cell Valley. The relevant information in this article shall not be used for diagnosis or treatment, and cannot replace professional medical advice, and this public platform will not assume any responsibility. The final interpretation of the content of the above statement belongs to the public platform, and this statement will apply to all the articles shared on the platform at all times, thank you for your cooperation!
一、CAR-T therapy
Car-t cell immunotherapy is a new type of treatment, which uses the patient's own immune system to fight cancer cells. Simply put, T cells in the collected peripheral blood of the patient are isolated, and the isolated T cells express CAR through gene transduction technology, and then these cells are injected back into the patient for anti-tumor therapy. CAR consists of a single-stranded variable fragment (scFv) from a monoclonal antibody, a hinge region from a CD8, a transmembrane domain, and an intracellular signaling domain (Figure 1). The first generation of CAR contained only one intracellular signaling domain, and the second generation added co-stimulatory domains such as CD28 or 4-1BB to enhance the anti-tumor effects of CAR T. The third generation further increased the co-stimulatory domain to two on the basis of the second generation to promote the proliferation and activation of CAR-T. The fourth generation added cytokines on the basis of the third generation to improve the lethality of CAR T to the tumor. Researchers have developed a novel CAR construct that encodes a truncated cytoplasmic domain from the interleukin (IL) -2 receptor beta chain (IL-2rβ) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif. As well as the TCR signal transduction (CD3ζ) and co-stimulatory (CD28) domains, which are considered fifth-generation CAR[2], although this concept is currently in the exploratory stage, compared to CAR T cells expressing the CD28 or 4-1BB co-stimulatory domains alone, The structure showed excellent in vivo persistence and antitumor effect in hematoma and solid tumor models, which brings hope for the treatment of solid tumors. After CAR T infusion into patients, tumor cells expressing specific antigens can be specifically recognized and killed through three ways of cytolysis, release of cytokines and Fas/FasL, and are not restricted by the Maior histocompatibility complex (MHC).
Figure 1 Schematic diagram of CAR structure
二、MM CAR-T therapy target
At present, B cell maturationantigen (BCMA), Signaling lymphocyte activation molecule familymember F7, Signaling lymphocyte activation molecule familymember F7, SLAMF7), G protein-coupled receptor class C group 5member D (GPRC5D), etc., have been used as targets for MM CAR-T therapy. There are currently three approved CAR-T products targeting BCMA on the market. Among them, BCMA CAR-T product bb2121 has been approved for market in March 2021, another product cilta-cel has been approved for market in February 2022, the latest approved for market is the Focosu injection jointly developed by China's reindeer/Xinda Biology, and the research of other antigens is also in progress.
At present, B cell maturationantigen (BCMA), Signaling lymphocyte activation molecule familymember F7, Signaling lymphocyte activation molecule familymember F7, SLAMF7), G protein-coupled receptor class C group 5member D (GPRC5D), etc., have been used as targets for MM CAR-T therapy. There are currently three approved CAR-T products targeting BCMA on the market. Among them, BCMA CAR-T product bb2121 has been approved for market in March 2021, another product cilta-cel has been approved for market in February 2022, the latest approved for market is the Focosu injection jointly developed by China's reindeer/Xinda Biology, and the research of other antigens is also in progress.
FIG. 2 MM therapeutic targets
01 BCMA
BCMA, a type III transmembrane protein belonging to the tumor necrosis factor receptor (TNFR) family, is up-regulated at the end of B cell maturation, especially selectively expressed on plasma cells, and is highly expressed on most multiple myeloma cells, but is basically not expressed on naive B cells, memory B cells, and other normal tissue cells. BCMA activates the NF-KB and MAPK/JNK pathways to regulate the survival of long-lived plasma cells by binding to B cell activating factor (BAF), and it also promotes the proliferation of MM cells in the bone marrow microenvironment by binding to proliferation-inducing ligands (APRIL).
bb2121 promoted by Bluebird Bio is a CAR-T product transduced by a lentiviral vector containing a BCMA CAR, and Raje et al. [3] reported a study of bb2121 in the treatment of relapsed/refractory multiple myeloma. A total of 36 patients with relapsed refractory MM were enrolled, including 3 patients who dropped out of the study due to disease prior to infusion. The overall response rate for 33 patients was 85%, with 45% having a complete response (9%) or a strict complete response (36%).
In addition, cilta-cel, produced by Johnson & Johnson, is another CAR-T product that targets BCMA and differs from other anti-BCMA CAR-T therapies in that it directly targets two BCMA epitopes (VH1 and VH2) to improve affinity for BCMA-expressing cells. Lin et al. [4] reported early, deep, and long-lasting responses in patients after cilta-cel infusion. A total of 97 patients participated in the study and received a single infusion of 0.75×106/kg cilta-cel after 5 to 7 days with an ORR of 97.9% (95% CI: 92.7 to 99.7), of which 94.9% achieved VGPR and 82.5% achieved sCR. Of 61 patients with MRD uable, 92% were MRD-negative, 44% (27/61) were MRD-negative for more than 6 months, and the 2-year PFS rate was 91% for patients with MRD negative for more than 6 months. 18% of patients were MRD-negative for longer than 12 months. Anti-BCMA CAR-T therapy has achieved satisfactory clinical efficacy in MM therapy, and RRMM patients can also benefit significantly from anti-BCMA CAR-T therapy, but these products have also been observed to have a higher risk of CRS and ICANS. How to further improve the safety and effectiveness of the product remains a challenge to be considered.
02 SLAMF7
SLAMF7, also known as CD319, CRACC, CSSLAMF71, is a member of the signaling lymphocyte activating molecule (SLAM) family that plays an important role in the regulation of immune cell function. In normal tissues, the expression of SLAMF7 is limited to the hematopoietic system, including NK cells, some T and B cells, monocytes, macrophages, and dendritic cells. During the life cycle of normal B cells, SLAMF7 is highly expressed in pre-B cells and plasma cells, and is highly expressed in malignant plasma cells of multiple myeloma, monoclonal gammaglobulinopathy of unknown significance and fuming myeloma stage. Studies have shown that SLAMF7 is uniformly expressed on malignant plasma cells of newly diagnosed (ND) myeloma, and is still retained in recurrent myeloma after intensive chemoradiotherapy [5], and there is no known SLAMF7 expression in other normal human tissues. This discovery makes SLAMF7 a potential target for CAR T cell therapy in myeloma.
03 GPRC5D
GPRC5D is a transmembrane receptor protein that is mainly expressed on the surface of plasma cells. Compared with normal cells, the expression level of GPRC5D in multiple myeloma (MM) cells is significantly increased, so it is considered as one of the potential therapeutic targets for MM. Immunohistochemistry showed that GPRC5D was widely expressed in malignant myeloma cells, similar to but independent of BCMA, and was limited to hair follicles in normal tissues. Based on this, researchers designed a CAR-T containing seven human scFvs targeting GPRC5D [6], which can eradicate MM cells in xenografted MM mouse models and enable mice to achieve long-term survival. 100 days after injection of GPRC5D-CAR-T, mice maintain a 100% survival rate. And there were no side effects such as hair loss or skin damage. The results of this study provide important preclinical evidence for GPRC5D as an important clinical target for MM immunotherapy.
三、Dual-target CAR-T
Although MM patients initially respond well to CAR-T therapy, clinical studies have also found a high percentage of patients relapse due to antigen escape, which may be related to insufficient expansion and persistence of CAR-T cells in vivo, loss or downregulation of tumor-associated antigens, and the presence of immunosuppressive factors in the tumor microenvironment. Due to the limited treatment available, most patients with relapse have a poor prognosis. The development of multi-target CAR-T for multiple antigen receptors is considered to be the most significant solution to the problem of antigen escape, especially the development of dual-target CAR-T, such as the clinical development of BCMA/CD19 dual-target CAR-T.
Theoretically, bisspecific CAR-T cells can be implemented in the following four ways [7-9] : 1) As shown in Figure 3A, Cocktail/Sequential infusion, that is, single-specific CAR-T cell combination therapy (that is, cocktail therapy). The disadvantage of this combination therapy is that the expansion rate of CAR-T cells of two different targets is different in vivo, which eventually leads to the imbalance of the two CAR-T cells and can not better clear the tumor cells. 2) As shown in Figure 3B, Co-transduction means that the two viral vectors encode a monospecific CAR molecule respectively, and then transduction T cells together to form bisectional CAR T cells. However, due to the different transduction efficiency, the ratio of two CAR molecules on CAR-T cells formed by this method is unbalanced, and only one CAR molecule will be expressed on T cells. 3) As shown in Figure 3C, Bicistronic CAR-T cells use a viral vector to encode two monospecific CAR molecules, so that there are two kinds of CAR molecules on the CAR-T cells. The bisspecific CAR T cells constructed by this method can target two antigens and the ratio of the two CAR molecules is equal. However, the disadvantage of this approach is that the viral carrier load is limited. The efficiency of virus encoding two CAR molecules at the same time is low, resulting in low expression of CAR molecule on CAR-T cells and incomplete expression of the second CAR molecule. 4) As shown in Figure 3D-E, Bivalent CAR-T cells showed that one virus encoded a CAR molecule, which contained two antigen-binding sites. The structure of Bivalent CAR T cells can be divided into two forms: linear Tandem or Loop configuration. The two bivalent Cars are the most popular and widely used bisspecific CAR-T cell configurations studied at present.
BCMA, a type III transmembrane protein belonging to the tumor necrosis factor receptor (TNFR) family, is up-regulated at the end of B cell maturation, especially selectively expressed on plasma cells, and is highly expressed on most multiple myeloma cells, but is basically not expressed on naive B cells, memory B cells, and other normal tissue cells. BCMA activates the NF-KB and MAPK/JNK pathways to regulate the survival of long-lived plasma cells by binding to B cell activating factor (BAF), and it also promotes the proliferation of MM cells in the bone marrow microenvironment by binding to proliferation-inducing ligands (APRIL).
bb2121 promoted by Bluebird Bio is a CAR-T product transduced by a lentiviral vector containing a BCMA CAR, and Raje et al. [3] reported a study of bb2121 in the treatment of relapsed/refractory multiple myeloma. A total of 36 patients with relapsed refractory MM were enrolled, including 3 patients who dropped out of the study due to disease prior to infusion. The overall response rate for 33 patients was 85%, with 45% having a complete response (9%) or a strict complete response (36%).
In addition, cilta-cel, produced by Johnson & Johnson, is another CAR-T product that targets BCMA and differs from other anti-BCMA CAR-T therapies in that it directly targets two BCMA epitopes (VH1 and VH2) to improve affinity for BCMA-expressing cells. Lin et al. [4] reported early, deep, and long-lasting responses in patients after cilta-cel infusion. A total of 97 patients participated in the study and received a single infusion of 0.75×106/kg cilta-cel after 5 to 7 days with an ORR of 97.9% (95% CI: 92.7 to 99.7), of which 94.9% achieved VGPR and 82.5% achieved sCR. Of 61 patients with MRD uable, 92% were MRD-negative, 44% (27/61) were MRD-negative for more than 6 months, and the 2-year PFS rate was 91% for patients with MRD negative for more than 6 months. 18% of patients were MRD-negative for longer than 12 months. Anti-BCMA CAR-T therapy has achieved satisfactory clinical efficacy in MM therapy, and RRMM patients can also benefit significantly from anti-BCMA CAR-T therapy, but these products have also been observed to have a higher risk of CRS and ICANS. How to further improve the safety and effectiveness of the product remains a challenge to be considered.
02 SLAMF7
SLAMF7, also known as CD319, CRACC, CSSLAMF71, is a member of the signaling lymphocyte activating molecule (SLAM) family that plays an important role in the regulation of immune cell function. In normal tissues, the expression of SLAMF7 is limited to the hematopoietic system, including NK cells, some T and B cells, monocytes, macrophages, and dendritic cells. During the life cycle of normal B cells, SLAMF7 is highly expressed in pre-B cells and plasma cells, and is highly expressed in malignant plasma cells of multiple myeloma, monoclonal gammaglobulinopathy of unknown significance and fuming myeloma stage. Studies have shown that SLAMF7 is uniformly expressed on malignant plasma cells of newly diagnosed (ND) myeloma, and is still retained in recurrent myeloma after intensive chemoradiotherapy [5], and there is no known SLAMF7 expression in other normal human tissues. This discovery makes SLAMF7 a potential target for CAR T cell therapy in myeloma.
03 GPRC5D
GPRC5D is a transmembrane receptor protein that is mainly expressed on the surface of plasma cells. Compared with normal cells, the expression level of GPRC5D in multiple myeloma (MM) cells is significantly increased, so it is considered as one of the potential therapeutic targets for MM. Immunohistochemistry showed that GPRC5D was widely expressed in malignant myeloma cells, similar to but independent of BCMA, and was limited to hair follicles in normal tissues. Based on this, researchers designed a CAR-T containing seven human scFvs targeting GPRC5D [6], which can eradicate MM cells in xenografted MM mouse models and enable mice to achieve long-term survival. 100 days after injection of GPRC5D-CAR-T, mice maintain a 100% survival rate. And there were no side effects such as hair loss or skin damage. The results of this study provide important preclinical evidence for GPRC5D as an important clinical target for MM immunotherapy.
三、Dual-target CAR-T
Although MM patients initially respond well to CAR-T therapy, clinical studies have also found a high percentage of patients relapse due to antigen escape, which may be related to insufficient expansion and persistence of CAR-T cells in vivo, loss or downregulation of tumor-associated antigens, and the presence of immunosuppressive factors in the tumor microenvironment. Due to the limited treatment available, most patients with relapse have a poor prognosis. The development of multi-target CAR-T for multiple antigen receptors is considered to be the most significant solution to the problem of antigen escape, especially the development of dual-target CAR-T, such as the clinical development of BCMA/CD19 dual-target CAR-T.
Theoretically, bisspecific CAR-T cells can be implemented in the following four ways [7-9] : 1) As shown in Figure 3A, Cocktail/Sequential infusion, that is, single-specific CAR-T cell combination therapy (that is, cocktail therapy). The disadvantage of this combination therapy is that the expansion rate of CAR-T cells of two different targets is different in vivo, which eventually leads to the imbalance of the two CAR-T cells and can not better clear the tumor cells. 2) As shown in Figure 3B, Co-transduction means that the two viral vectors encode a monospecific CAR molecule respectively, and then transduction T cells together to form bisectional CAR T cells. However, due to the different transduction efficiency, the ratio of two CAR molecules on CAR-T cells formed by this method is unbalanced, and only one CAR molecule will be expressed on T cells. 3) As shown in Figure 3C, Bicistronic CAR-T cells use a viral vector to encode two monospecific CAR molecules, so that there are two kinds of CAR molecules on the CAR-T cells. The bisspecific CAR T cells constructed by this method can target two antigens and the ratio of the two CAR molecules is equal. However, the disadvantage of this approach is that the viral carrier load is limited. The efficiency of virus encoding two CAR molecules at the same time is low, resulting in low expression of CAR molecule on CAR-T cells and incomplete expression of the second CAR molecule. 4) As shown in Figure 3D-E, Bivalent CAR-T cells showed that one virus encoded a CAR molecule, which contained two antigen-binding sites. The structure of Bivalent CAR T cells can be divided into two forms: linear Tandem or Loop configuration. The two bivalent Cars are the most popular and widely used bisspecific CAR-T cell configurations studied at present.
FIG. 3 Schematic diagram of two-target CAR design
Compared with traditional proteasome inhibitors, monoclonal antibodies and immunomodulators, CAR-T cell therapy has more significant targeting and stronger killing ability, which makes the remission degree and survival of patients continue to improve. However, recurrence due to issues such as immune escape of tumor cells remains a huge challenge for researchers. At present, in response to this problem, multi-target, especially dual-target CAR-T clinical studies have achieved initial results. It is believed that with more research and clinical trials, the safety and effectiveness of CAR-T cell therapy will be further improved, bringing more hope to multiple myeloma patients.
At present, Shenzhen Cell Valley won the bid of the "GMP Grade Cell Product production and Preparation" project of Huazhong University of Science and Technology Union Shenzhen Hospital, providing industrial preparation and clinical application of anti-BCMA CAR-T cell products based on retroviral vector. The good news is that the patient achieved a very good partial remission one month after receiving CAR T cell therapy. The patient has been discharged from the hospital for several months and has now achieved complete response (CR), and the M protein level has now dropped to 0 g/L!! Welcome interested readers to contact Shenzhen Cell Valley for in-depth exchanges!
Reference：
[1] VAN DE DONK N W C J, PAWLYN C, KL Y.Multiple mye-lomalJ. Lancet, 2021, 397(10272):410-427.
[2] Kagoya, Y.; Tanaka, S.; Guo, T.; Anczurowski, M.; Wang, C.H.; Saso, K.; Butler, M.O.; Minden, M.D.; Hirano, N. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat. Med. 2018, 24, 352–359.
[3] NOOPUR RAJE M D J B. Anti-BCMA CAR T-Cell Therapybb2121 in Relapsed or Refractory Multiple Myeloma[J]. TheNew England Journal of Medicine, 2019(380) :1726-1737.
[4] LIN Y, MARTIN T, BERDEJA J G,et al. Ciltacabtagene autoleucel, a BCMA-directed CAR-T cell therapy, in patients withrelapsed/refractory multiple myeloma: 2-year post LPI resultsfrom the phase 1b/2 CARTITUDE-1 study[J]. HemaSphere,2022, 6(Suppl) :851-852.
[5] Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target forthe treatment of multiple myeloma. Clin Cancer Res. 2008; 14 (9) : 2775-2784.
[6] Smith E L, Harrington K, Staehr M, et al. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells[J]. Science translational medicine, 2019, 11(485): eaau7746.
[7] SHAH N N, MAATMAN T, HARI P, et al. Multi TargetedCAR T Cell Therapies for B-Cell Malignancies[J]. Frontiers inOncology, 2019,9 :146.
[8] TAHMASEBI S, ELAHI R, KHOSH E,et al. Programmableand multi-targeted CARs: a new breakthrough in cancer CAR-Tcell therapy[J]. Clinical and Translational Oncology, 2021, 23(6):1003-1019.
[9] Xie, B.; Li, Z.; Zhou, J., Wang, W., Current status and perspectives of dual-targeting chimeric antigen receptor T-cell therapy for the treatment of hematological malignancies. Cancers 2022, 14.
Disclaimer: Shenzhen Cell Valley is committed to the research of cell and gene therapy, in order to promote emerging technologies, so that more people understand the new development of biomedicine. The content of this article is only used for information exchange, and the platform remains neutral on the content, statements and opinions of the article, and does not represent the position and views of Shenzhen Cell Valley. The relevant information in this article shall not be used for diagnosis or treatment, and cannot replace professional medical advice, and this public platform will not assume any responsibility. The final interpretation of the content of the above statement belongs to the public platform, and this statement will apply to all the articles shared on the platform at all times, thank you for your cooperation!
