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CD33, also known as sialic acid-binding immunoglobulin-like lectin 3 (Siglec-3), is a cell surface molecule that plays a regulatory and inhibitory role in the immune system. It belongs to the leukocyte antigen recognition family and is involved in the regulation of inflammation and immune response. The CD33 gene is located on human chromosome 19 and is approximately 57.2 kilobase pairs in length. Polymorphisms in the CD33 gene have been associated with a variety of diseases. For example, certain CD33 gene variants have been associated with an increased risk of Alzheimer's disease, while other CD33 variants have been found to be associated with the development of acute myeloid leukemia. CD33 is highly expressed in early bone marrow and progenitor cells and is specifically expressed in various leukemias, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myeloid sarcoma. The biological function of CD33 is primarily related to its role as a recognition molecule for monocytes and macrophages. It can be involved in cell adhesion, migration, and apoptosis by binding to glycosyl groups such as N-acetyl ceramide acid (Neu5Ac). In addition, CD33 can affect the immune response by regulating the activation status of T cells and natural killer cells (NK cells).
Fig.1 Structure of CD33
CD33 is a transmembrane receptor expressed by leukemia cells and stem cells in the bone marrow, which plays a crucial role in tumor development. CD33 inhibits lymphocyte activation by binding to ligands on lymphocytes, thereby reducing the immune response and promoting tumor evasion of immune attack.
Moreover, CD33 can influence tumor development by regulating the transforming growth factor-beta (TGF-beta) signaling pathway. CD33 acts as a TGF-beta signaling regulatory molecule that binds to the TGF-beta receptor through its extracellular domain and inhibits the activation of the TGF-beta signaling pathway. This action may be achieved through competitive bindings, blockage of extracellular sites of the receptor, and endocytosis.
In tumors, the expression level of CD33 is often aberrantly regulated. For example, in acute myeloid leukemia, CD33 expression is significantly increased and is widely used as a therapeutic target, providing an opportunity to investigate the mechanism of CD33 action in depth. Several studies have shown that CD33 promotes tumor cell proliferation and invasion through inhibition of the TGF-β signaling pathway and affects immune regulation of the tumor microenvironment. Specifically, CD33 can inhibit TGF-β-mediated cell cycle arrest and promote tumor cell proliferation and metastasis. Furthermore, CD33 can reduce TGF-β-induced conversion of macrophages to M2-type polarization, thereby suppressing the immunosuppressive effects in the tumor microenvironment. In addition, CD33 expression is associated with tumor stem cells, and its inhibition of the TGF-β signaling pathway may help maintain the steady state of tumor stem cells. Since CD33 is expressed at low levels in normal tissues, it becomes an important molecule for targeted therapy.
CD33 Chimeric Antigen Receptor (CAR) T cells have shown potential therapeutic effects in AML and CML. CD33 CAR-T cell therapy works by introducing CD33 CAR into T cells, enabling them to recognize and kill CD33 cancer cells. Specifically, the CARs in CD33 CAR-T cells recognize CD33 and activate the effector function of T cells, causing them to release cytotoxins that destroy cancer cells and ultimately achieve therapeutic goals. CAR-T therapy with CD33 has undergone pre-clinical and clinical trial stages. Currently, CD33 CAR-T cells have been tested in phase 1 and phase 2 clinical trials for the treatment of AML and ALL, and some preliminary therapeutic results have been achieved. Among these, the most extensive studies have explored the use of CD33 CAR-T cells for the treatment of CD33-positive AML. Studies have shown that overall progression-free survival (PFS) and overall survival (OS) of patients were significantly improved after treatment with CD33 CAR-T cells. Also, some patients can achieve durable complete remission.
Table 1. Ongoing CD33-Targeted CAR Cell Therapy Clinical Trials
NCT Number | Title | Status | Conditions | Sponsor/Collaborators | Phases |
NCT05445765 | Anti-CD33 CAR-T Cells for the Treatment of Relapsed/Refractory CD33+ Acute Myeloid Leukemia | Not yet recruiting | Relapsed and/or Refractory Acute Myeloid Leukemia|High Risk Hematologic Malignancies | iCell Gene Therapeutics|iCar Bio Therapeutics | Phase 1 |
NCT05473221 | Evaluate the Safety and Efficacy of CD33 CAR-T in Patients With R/R AML | Not yet recruiting | AML | Zhejiang University | Phase 1 |
NCT05467254 | Evaluate the Safety and Efficacy of CLL1+CD33 CAR-T in Patients With R/R AML | Not yet recruiting | AML | Zhejiang University | Phase 1 |
NCT05672147 | CD33-CAR T Cell Therapy for the Treatment of Recurrent or Refractory Acute Myeloid Leukemia | Not yet recruiting | Acute Myeloid Leukemia|Recurrent Adult Acute Myeloid Leukemia|Refractory Acute Myeloid Leukemia|Secondary Acute Myeloid Leukemia | City of Hope Medical Center|National Cancer Institute (NCI) | Phase 1 |
NCT05008575 | Anti-CD33 CAR NK Cells in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia | Recruiting | Leukemia, Myeloid, Acute | Xinqiao Hospital of Chongqing|Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Phase 1 |
NCT04835519 | Phase I/II Study of Enhanced CD33 CAR-T Cells in Subjects With Relapsed or Refractory Acute Myeloid Leukemia | Recruiting | Acute Myeloid Leukemia|Relapse Leukemia|Refractory Acute Myeloid Leukemia | Beijing Boren Hospital | Phase 1|Phase 2 |
NCT03795779 | CLL1-CD33 cCAR in Patients With Relapsed and/or Refractory, High Risk Hematologic Malignancies | Recruiting | Hematologic Malignancy|Acute Myeloid Leukemia|Myelodysplastic Syndromes|Myeloproliferative Neoplasm|Chronic Myeloid Leukemia | iCell Gene Therapeutics|The General Hospital of Western Theater Command|iCAR Bio Therapeutics Ltd.|Peking University Shenzhen Hospital | Early Phase 1 |
NCT03971799 | Study of Anti-CD33 Chimeric Antigen Receptor-Expressing T Cells (CD33CART) in Children and Young Adults With Relapsed/Refractory Acute Myeloid Leukemia | Recruiting | Acute Myelogenous Leukemia | Center for International Blood and Marrow Transplant Research|National Marrow Donor Program|St. Baldrick's Foundation | Phase 1|Phase 2 |
NCT05248685 | Optimized Dual CD33/CLL1 CAR-T Cells in Subjects With Refractory or Relapsed Acute Myeloid Leukemia | Recruiting | Acute Myeloid Leukemia | Beijing Boren Hospital | Phase 1 |
NCT05016063 | Dual CD33-CLL1-CAR-T Cells in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia | Not yet recruiting | Leukemia, Myeloid, Acute | Xinqiao Hospital of Chongqing|Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Early Phase 1 |
NCT05215015 | Study of Anti-CD33/CLL1 CAR-NK in Acute Myeloid Leukemia | Recruiting | Acute Myeloid Leukemia | Wuxi People's Hospital|Imbioray (Hangzhou) Biomedicine Co., Ltd. | Early Phase 1 |
NCT04010877 | Multiple CAR-T Cell Therapy Targeting AML | Recruiting | Acute Myeloid Leukemia | Shenzhen Geno-Immune Medical Institute | Phase 1|Phase 2 |
NCT05105152 | PLAT-08: A Study Of SC-DARIC33 CAR-T Cells In Pediatric And Young Adults With Relapsed Or Refractory CD33+ AML | Recruiting | Acute Myeloid Leukemia|Acute Myeloid Leukemia Refractory|Acute Myeloid Leukemia, in Relapse | Seattle Children's Hospital|2seventy bio | Phase 1 |
NCT05654779 | CLL-1/CD33 Targeted LCAR-AMDR Cells in Patients With Relapsed or Refractory Acute Myeloid Leukemia | Recruiting | Acute Myeloid Leukemia | Institute of Hematology & Blood Diseases Hospital|Nanjing Legend Biotech Co. | Phase 1 |
NCT05665075 | Natural Killer (NK) Cell Therapy Targeting CD33 in Acute Myeloid Leukemia | Recruiting | AML, Adult | Zhejiang University|Hangzhou Qihan Biotech Co.,Ltd. | Phase 1 |
NCT03927261 | PRGN-3006 Adoptive Cellular Therapy for Relapsed or Refractory AML or Higher Risk MDS | Recruiting | Acute Myeloid Leukemia|Myelodysplastic Syndromes | Precigen, Inc | Phase 1 |
NCT05601466 | Natural Killer(NK) Cell Therapy for Acute Myeloid Leukemia | Recruiting | AML, Adult | Institute of Hematology & Blood Diseases Hospital|Hangzhou Qihan Biotech Co.,Ltd. | Phase 1 |
References
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