1
The CAR-T cell therapy race is in full swing.
Bringing new hope to tumor treatment
The commercialization of CAR-T therapy is accelerating, with remarkable product revenues.
In 2017, the US FDA successively approved Novartis' Kymriah and Gilead's Yescarta for marketing. CAR-T products officially stepped onto the historical stage and were quickly approved in multiple countries or regions due to their remarkable therapeutic effects in lymphoma and leukemia. In the Chinese market, in 2021, the NMPA successively approved two CD19-targeted CAR-T products, Yike Da and Benotumab. In 2023, the BCMA-targeted product Foksu was successfully launched, providing new treatment options for patients with hematological malignancies in China. As of October 2023, six CAR-T products have been approved for marketing overseas, targeting CD19 (four) and BCMA (two); domestically, three CAR-T products have been launched, two targeting CD19 and one targeting BCMA.
The revenue of listed CAR-T products has maintained a growth trend. According to the company's annual report and official website information disclosure, Yescarta ranked first in CAR-T product revenue with $1.16 billion in 2022, while Abecma also reached $388 million. The listed CAR-T product BeiGene in China achieved revenue of 146 million RMB in 2022, a 374% increase compared to the 30.8 million RMB in 2021, indicating accelerated volume growth.
Figure: Overview of Listed CAR-T Products
*: Yikaida has introduced Yescarta from Kite Pharma to Fosun Kate
Data source: Company's official website & annual report, public information, Frost & Sullivan analysis
CAR-T therapy has significant advantages and brings hope of cure to patients.
Chimeric antigen receptors (CARs) mainly consist of extracellular single-chain antibodies, transmembrane domains, and intracellular signaling domains. Chimeric antigen receptor T cells (CAR-T) target and capture antigens on the surface of cancer cells through membrane-expressed chimeric antigen receptors. After successful binding, CAR-T cells destroy cancer cells by releasing cytokines, perforin, and other factors. This therapy can also form memory CAR-T cells, providing patients with an anti-tumor long-term mechanism, effectively prolonging survival rates and even potentially achieving a cure.
Figure: Advantages of CAR-T cell therapy
Source: Public information, Frost & Sullivan analysis
The CAR-T market is expanding rapidly, with broad prospects.
Since the approval of two CAR-T products for marketing in 2017, they have brought hope to patients with malignant blood tumors and the market size has continued to grow steadily. According to Frost & Sullivan analysis, the global CAR-T market grew rapidly from about $0.1 billion in 2017 to $1.73 billion in 2021. It is expected to grow at a compound annual growth rate (CAGR) of 47% from 2021 to 2025 to reach $8.03 billion and at a CAGR of 21% to reach $211.4 billion by 2030.
Although CAR-T was only approved for marketing in China in 2021, the market size has been growing rapidly. It is expected to grow from $0.2 billion in 2021 at a CAGR of 178% to $1.09 billion by 2025, and reach $4.31 billion by 2030. The future market potential is enormous.
Figure: Global and China CAR-T Therapy Market Size
Data source: Analysis by Frost & Sullivan
The R&D of CAR-T therapies is accelerating, with the continuous expansion of indications.
China has strong CAR-T R&D capabilities and is expected to lead the global cell therapy field. According to the CDE official website, three domestically developed CAR-T products are under BLA approval: Zelbilimumab (Zyvoximab) from Keytruda Oncology and Xidaximab (Ximlimab) from Legend Biologics, both targeting BCMA and indicated for relapsed/refractory multiple myeloma (R/R MM); Hycelimumab (tentative name) from Hebei UniGene Biologics targets CD19 and is indicated for relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL).
In addition, Fosun Kite's marketed CAR-T product YikeDa has been approved for a new indication in June 2023: adult B-cell lymphoma that is refractory to first-line immunotherapy or recurs within 12 months after first-line immunotherapy. The approval of this second-line treatment indication not only brings new progress to the treatment of lymphoma patients but also marks a successful expansion of CAR-T product indications from end-stage to first-line, continuously expanding the patient population suitable for clinical use.
CD19 and BCMA, as popular targets, are mainly used for B-cell lymphoma/leukemia and multiple myeloma. According to CDE data, as of October 2023, there were 54 CAR-T clinical trials targeting the CD19 antigen and 11 targeting BCMA. However, there are still a large number of unmet clinical needs in the field of oncology treatment. With the deepening research and development of CAR-T, CAR-T therapies targeting new targets such as CD7, B7-H3, and CLDN18.2 are expected to bring new treatment options for more patients with hematological diseases and solid tumors.
2
The prevalence of precursor lymphoma/leukemia continues to grow,
The disease burden is heavy
Precursor lymphoma/leukemia has a high aggressiveness and a heavy disease burden.
Precursor lymphoid Neoplasms are malignant tumors caused by abnormal proliferation of precursor lymphocytes, and most patients can be found to have clonal chromosomal abnormalities. According to the '5th edition of the WHO Classification of Hematolymphoid Tumors' published in 2022, precursor lymphomas are divided into B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) and T-lymphoblastic leukemia/lymphoma (T-ALL/LBL). ALL and LBL share similar clinical and laboratory characteristics (cyto morphology, immunophenotype, genotype, cytogenetics, clinical presentation, and prognosis), but there are differences in clinical features. Typically, those primarily characterized by extramedullary lesions are classified as LBL, while those primarily characterized by extensive involvement of peripheral blood and bone marrow are classified as ALL.
The disease burden of T-ALL/LBL is heavy, with T-ALL accounting for 15% and 25% of ALL cases in children and adults respectively. These patients often have adverse prognostic factors such as high peripheral blood white blood cell counts, organ infiltration, and central nervous system involvement; T-LBL accounts for more than 80% of LBL cases and is highly aggressive.
The current treatment methods for precursor lymphoma are not ideal, and patients have an urgent need for new therapies.
The first-line treatment drugs for precursor lymphoma/leukemia are mainly chemotherapy drugs. However, there is a risk of drug resistance in early chemotherapy, and the efficacy of current treatment regimens is still not ideal. At the same time, the prognosis of adult LBL is worse than that of children. Poor prognostic factors include CNS involvement and residual lesions after induction chemotherapy.
Most relapses of T-ALL are early relapses (within 2 years after diagnosis), accounting for 80% of the overall relapsed population. The prognosis for patients after recurrence is extremely poor, with an 5-year OS rate of only 10%. The proportion of T-ALL patients who achieve CR again after recurrence is significantly reduced. There is no unified treatment standard for relapsed T-ALL; most options are clinical trials or intensive therapy, and traditional chemotherapy alone usually yields poor results. In 2005, the FDA approved neratinib for the treatment of T-ALL that is refractory or relapsed after at least two regimens. The overall response rate for adult patients with relapsed T-ALL treated with neratinib alone was 41% to 46%, and for children it was 55%. After achieving a second remission with neratinib followed by allo-HSCT, the 1-year and 6-year OS rates were 24% and 11%, respectively, indicating that the treatment effect is still not ideal. Moreover, neratinib has not been approved for marketing in China, and there is an urgent unmet clinical need for patients with relapsed T-ALL in China.
According to the 'Chinese Lymphoma Treatment Guidelines (2021 Edition)', for newly diagnosed high-risk patients and those with relapsed or refractory disease, it is recommended to participate in appropriate clinical trials. Patients who are eligible can consider allo-SCT, as there is a huge clinical demand for new treatment methods.
3
CD7-targeted CAR-T therapy stands out.
Challenges and opportunities coexist
Focusing on new targets, CD7-targeted CAR-T therapy has significant advantages
CD7 is a single-chain transmembrane glycoprotein expressed on the surface of T cells, NK cells, and their precursor cells. During lymphocyte development, CD7 is a co-stimulatory receptor for interaction between T and B lymphocytes.
Clinical studies have found that the CD7 molecule is highly expressed in T-ALL cells and T-LBL cells, and it can also be detected on about 30% of tumor cells in AML patients. In addition, undifferentiated leukemia cells and leukemia stem cells (LSCs) have also been confirmed to express the CD7 molecule. Although normal T cells also express CD7, there is also a group of CD7-negative T cells in peripheral blood. Therefore, after using CD7-CAR-T to kill tumors, this group of cells can maintain the body's normal immune function. At the same time, CD7 deficiency has little effect on the normal development and maturation of T cells and the body's homeostasis. Thus, CD7 is a target with good safety advantages for CAR-T therapy.
Early clinical trial data of CD7-targeted CAR-T reveal positive signals
Zhang M et al.[1]The Phase I clinical trial data showed that 3 months after injection of autologous CD7-targeted CAR-T drugs into T-ALL/LBL patients, the CR rate was 87.5%. Among them, one T-ALL patient achieved CR with minimal residual disease negative, and one T-LBL patient had a CR lasting more than 12 months. 87.5% of patients only experienced grade 1 to 2 cytokine release syndrome (CRS), and no cases of T-cell aplasia or neurotoxicity were observed. Lu P et al.[2]The results of a phase I clinical trial conducted on 20 patients with relapsed/refractory T-ALL/LBL treated with CD7-targeted CAR-T showed that 19 patients achieved negative bone marrow minimal residual disease (MRD) after 28 days of treatment; the median follow-up time was 142.5 days, and none of the 14 subsequent patients who received allogeneic hematopoietic stem cell transplantation relapsed; only 1 patient experienced grade 3 CRS.
High technical barriers pose challenges to the research and development of CD7-targeted CAR-T.
The expression of CAR target antigen (CD7) on the surface of CAR-T cells leads to a 'suicidal self-destruction' phenomenon, where the CAR-T cells are cleared, limiting their spread in the patient's body and resulting in unsatisfactory tumor-killing effects. To address this issue, companies represented by Wugen Therapeutics and Beam Therapeutics mainly solve the 'suicidal self-destruction' problem by knocking out the CD7 gene in CAR-T cells through gene editing or base editing technologies; Bostin Biosciences, on the other hand, uses a non-genetic editing strategy that only involves endoplasmic reticulum retention of the CD7 protein without any genomic insertion, offering potential safety advantages.
In the process of manufacturing cell products, if T cells from patients with malignant tumors are used to prepare CAR-T products, there is a further challenge of separating normal T cells from cells containing malignant T cells. Using T cells sourced from healthy donors for CAR-T preparation has become a potential solution, but it also faces issues such as graft-versus-host disease (GVHD). Improving CAR-T using gene editing tools and using γδ T cells as the source of CAR-T cells are important potential approaches to solving the GVHD problem in universal CAR-T therapies.
Normal T cells in the patient's body also express target antigens, causing CAR-T cells to recognize and kill normal T cells. However, since some peripheral normal T cells naturally do not express CD7, the potential side effect of On-target, Off-tumor is within an acceptable range for patients.
The CD7-targeted CAR-T has great potential and may become a new treatment method for various hematological malignancies
Due to EBV infection, extranodal NK/T cell lymphoma, nasal type (ENKL), and peripheral T-cell lymphoma, non-specific (PTCL-NOS) are the most common subtypes of peripheral T-cell lymphoma (PTCL) in China[3]The incidence of PTCL accounts for 25% to 30% of non-Hodgkin lymphomas.[4]The primary first-line treatment regimens are chemotherapy protocols such as CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone), but the efficacy is poor, with a 5-year survival rate of about 30%. Hematopoietic stem cell transplantation can improve the long-term prognosis of some patients, but it still faces many clinical dilemmas such as unsatisfactory chemotherapy outcomes and patients' inability to receive hematopoietic stem cell transplantation.
Globally, acute myeloid leukemia (AML) can cause more than 80,000 deaths each year, and it is estimated that this number will double in 20 years.[5]The 'Diagnosis and Treatment Guidelines for Adult Acute Myeloid Leukemia (Non-acute Promyelocytic Leukemia) in China (2021 Edition)' recommend that all AML patients should participate in clinical research if possible, and chemotherapy regimens are used when there is a lack of clinical research conditions. The prognosis of AML patients is poor, with a low long-term survival rate. The long-term survival rate for patients under 60 years old is 35% to 45%, while for those over 60 years old it is only 10% to 15%.[6].
Given that the CD7 molecule is highly expressed in T lymphoma cells and can be detected on about 30% of AML patients' leukemia cells, CAR-T therapies targeting CD7 also hold significant potential therapeutic value for PTCL, NKT lymphoma, and AML.
4
Analysis of CD7-targeted CAR-T product R&D companies
Industry Players Overview
The technical barriers for CD7-targeted CAR-T therapy are high, and currently there are few companies deploying in this field. According to ClinicalTrials data, as of September 8, 2023, there were a total of 16 CD7-targeted CAR-T research pipelines globally, broken down by indication: 4 were registered clinical trials and 12 were investigator-initiated trials (IITs). There are only 2 CDE registered clinical trials in China, with the Bostec PA3-17 product being approved for IND in August 2021. It is the world's first approved self-CD7-CAR-T product for registration clinical trials and has now entered Phase II clinical trials, targeting relapsed/refractory T-ALL/LBL; the Senlong Biotech SELN101 product was approved for IND in June 2023, targeting relapsed/refractory T-ALL/LBL. In addition, other Chinese companies such as Yaka Biotech, Beiheng Biotech, and Genxi Biotech have also deployed CD7-targeted CAR-T product pipelines, all of which are IITs.
Figure: Overview of CAR-T pipelines targeting CD7
Data source: ClinicalTrials, China Clinical Trial Registration Center, Frost & Sullivan analysis
Leading the research and development of CD7-targeted CAR-T therapies, Bostec CAR-T products offer significant advantages
Among the CD7-targeted CAR-T products under development, Bostec Biologics and Wugen Therapeutics have disclosed relevant registration clinical trial data.
PA3-17 injection is a self-developed autologous CD7-CAR-T product by Bostec Biologics. The product targets R/R T-ALL/LBL and innovatively uses non-genetic editing strategies and the nanobody VHH6 to obtain normal peripheral blood T lymphocytes from the patient's own body for CAR modification. These modified cells are then reinfused into the patient's body, avoiding risks associated with GVHD. PA3-17 injection has significant advantages and was approved for IND in China in August 2021, making it the world's first autologous CD7-CAR-T product to be approved for IND. The product has received orphan drug designations from the US FDA and the European Union in 2021 and 2022, respectively, and has currently entered Phase II clinical trials.
As of October 15, 2023, the registration phase I clinical trial of PA3-17 injection has completed the evaluation of 11 patients with relapsed/refractory T-ALL/LBL, with an optimal objective response rate (ORR) of 82% (9/11), and an optimal complete response rate (CR) of 82% (9/11). The median duration of response (mDOR) and median progression-free survival (mPFS) have not been reached.
Wugen Therapeutics[7]The WU-CART-007 is a CRISPR/Cas9 gene-editing targeting CD7 product, currently undergoing phase I/II clinical trials for the treatment of relapsed/refractory T-ALL/LBL. As of January 30, 2023, 12 patients have been enrolled. Efficacy data for patients receiving ≥DL2 doses show an ORR of 43% (3/7), with only 1 case of CR; 25% of patients experienced grade 3 or higher adverse reactions; 67% of patients developed CRS, including 1 case grade 3; and 1 patient developed grade 1 immune effector cell-associated neurotoxic syndrome (ICANS). As of the reporting date, Wugen's observed DOR was only 86 days.
With first-class cell therapy technology and production bases, Biosciences helps CAR-T treatment reach new heights
Bosugenix has strong independent R&D capabilities and is equipped with comprehensive cell therapy and molecular biology laboratories. It can carry out research, development, and production of new cell therapy technologies at the international first-class level, covering the development of antigen-binding domains, optimization of CAR structures, functional testing of CAR-T cells, verification of in vivo efficacy trials, as well as a complete full-chain production system for CAR-T cell preparation.
The company possesses multiple advanced technology platforms, including the Safe UCAR-γδT platform, CAR structure and function validation platform, fully automated CAR-T preparation platform, CAR-T in vivo efficacy validation platform, suspension lentivirus vector platform, and NanoBa dual-specific antibody R&D platform. Our strong independent R&D capabilities safeguard innovative products.
The company has taken malignant tumors as a focal point and has initiated registration clinical trials for two products under development. These are the CAR-T product PA3-17 injection for the treatment of relapsed/refractory T-ALL/LBL, and the CAR-T product TAA06 injection for the treatment of relapsed/refractory neuroblastoma with the B7-H3 target. In addition, the company is accelerating the development of the gammaδT universal cell therapy product and has already laid out research in areas such as autoimmune diseases and aging-related diseases, building a cell therapy network through multiple strategies.
In 2022, the company completed the construction of a commercial production base with an area of 10,000 square meters that meets GMP standards and put it into use. The base is equipped with an internationally first-class CAR-T cell preparation workshop, plasmid and lentivirus GMP production and purification workshop, P2 safety laboratory, as well as advanced quality control laboratories and R&D laboratories. It has a complete production system from plasmids and lentiviruses to CAR-T cell preparation.
Clinical trials of CAR-T therapies targeting CD7 are advancing rapidly, and the conduct of phase II trials will further validate their therapeutic value. In the future, China's independently developed CD7-targeted CAR-T therapies are expected to be among the first to be launched globally, leading the world in cell therapy and bringing new hope to more patients with blood diseases.
Scroll to view references
[1] Zhang M, Chen D, Fu X, et al. Autologous Nanobody-Derived Fratricide-Resistant CD7-CAR T-cell Therapy for Patients with Relapsed and Refractory T-cell Acute Lymphoblastic Leukemia/Lymphoma. Clin Cancer Res. 2022;28(13):2830-2843.
[2] Lu P, Liu Y, Yang J, et al. Naturally selected CD7 CAR-T therapy without genetic manipulations for T-ALL/LBL: first-in-human phase 1 clinical trial. Blood. 2022;140(4):321-334.
[3] Chinese Anti-Cancer Association Lymphoma Professional Committee, Chinese Medical Doctor Association Oncology Physicians Branch, Chinese Medical and Health International Exchange Promotion Association Oncology Internal Medicine Branch. Chinese Lymphoma Treatment Guidelines (2021 Edition) [J]. Chinese Journal of Oncology, 2021, 43(7):29.
[4] Chinese Society of Clinical Oncology Anti-Lymphoma Alliance, Chinese Society of Hematology Leukemia & Lymphoma Group, Chinese Anti-Cancer Association Hematological Oncology Professional Committee. Western medicine-based consensus on the treatment of peripheral T-cell lymphoma with edaravone (2018 edition) [J]. Chinese Journal of Clinical Oncology, 2018.
[5] Foreman KJ, Marquez N, Dolgert A, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016–40 for 195 countries and territories. Lancet 2018; 392: 2052–90.
[6] Experimental Diagnostics Group of the Hematology Branch of the Chinese Medical Association. Expert Consensus on the Detection and Clinical Interpretation of Minimal Residual Disease in Acute Myeloid Leukemia (2021 Edition) [J]. Chinese Journal of Hematology, 2021, 42(11):889-897.
[7] Ghobadi A, Aldoss I, Maude S, et al. P356: Phase 1/2 dose-escalation study of anti-CD7 allogenic CAR-T cell in relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL). Hemasphere. 2023;7(Suppl):e1789302. Published August 8, 2023.
About Frost & Sullivan's Life Sciences Practice
The Life Sciences Practice of Frost & Sullivan has professional analytical capabilities and extensive project experience in the field of life sciences. Leveraging Frost & Sullivan's global think tank resources and the cross-industry business development platform in Greater China, the Life Sciences Practice has unique core advantages in investment and financing services for the life sciences industry. The Life Sciences Practice has a wide range of corporate clients in China and has established a vast client network over the past 20 years, accumulating a wealth of project experience in various sub-sectors of life sciences.
Project types include Knowledge Center projects (in-depth content, promotional activities), Pre-IPO projects (DCF valuation, business plan services), IPO listing projects (industry consulting, clinical audit, fundraising writing), market research, market value management, and strategic consulting. In addition, the firm collaborates with well-known domestic and international information platforms and investment and financing institutions to provide one-stop solutions for enterprises in specialized fields such as pharmaceuticals and medical devices, attracting widespread attention from investors.
