Overview of CD123-Targeted CAR Cell Therapies

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Background of CD123

CD123 is an alpha subunit receptor that belongs to the interleukin 3 (IL-3) family of cytokines. It is predominantly expressed in hematopoietic tissues and leukemic cells, as well as fibroblasts, dendritic cells, and macrophages. CD123 plays a crucial role in regulating the proliferation and differentiation of stem cells and leukocytes during hematopoiesis. Its structure comprises an external N-terminal domain, a membrane domain, and an internal C-terminal domain. CD123 expression levels are often associated with malignancy, prognosis, and the risk of metastasis. In acute myeloid leukemia (AML), high levels of CD123 expression are linked with poor prognosis, relapse, and metastasis, making it a promising target for AML treatment. CD123 is also of interest in other malignancies, such as myeloproliferative neoplasms (MPN), multiple myeloma (MM), and chronic lymphocytic leukemia (CLL).

Fig.1 Structure of CD123

CD123 Signaling Pathways

Both CD123 and IL-3 are molecules associated with the immune system. CD123 acts as a membrane receptor that plays a significant role in dendritic cells, macrophages, and mast cells. IL-3 is a cytokine that, by binding to CD123, forms a trimeric complex with other subunits IL-3Rβ and γc, thereby activating downstream signaling pathways. The IL-3/CD123 signaling pathway is involving in numerous biological responses, including cell proliferation, survival, and differentiation. In dendritic cells, activation of the IL-3/CD123 signaling pathway promotes their maturation and antigen-presenting functions, facilitating the immune response of T cells. In mast cells and macrophages, activation of the IL-3/CD123 signaling pathway promotes cell proliferation and survival and is involved in physiological and pathological processes such as allergic and inflammatory responses. In addition to malignancies such as leukemia and lymphoma, the IL-3/CD123 signaling pathway plays an important role in autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), where CD123 expression is significantly increased in patients. Blocking CD123 can suppress the autoimmune response , reducing the clinical symptoms of diseases such as SLE and RA. CD123 is a promising therapeutic target in malignant tissues, playing a critical role in various cancers.

Clinic Status of CD123-Targeted CAR Cell Therapies

CD123 is currently being widely studied and used in chimeric antigen receptor (CAR)-T cell therapy for hematologic tumors, such as AML and chronic myeloid leukemia/myelodysplastic syndrome (CMML/MDS). Early findings suggest that CD123 CAR-T cells significantly inhibit cancer cell proliferation and have long-term viability. CD123 is a monoclonal antibody that is highly expressed in leukemia, myelodysplastic syndromes, and other hematologic malignancies, making it a potential therapeutic target. CAR T-cell therapy is a novel immunotherapeutic approach that uses modified T cells to recognize and kill cancer cells. Preclinical studies of CD123 CAR-T cell therapy have shown that this therapy induces the removal of CD123-positive leukemia cells and has a significant therapeutic effect on certain diseases. For example, an early study demonstrated that CD123 CAR-T cells effectively removed AML cells and enhanced survival in a mouse model. Another study found that CD123 expression levels were high in blood and bone marrow samples from human pre-B lymphoblastic leukemia (pre-B ALL) patients, and that CD123 CAR-T cell therapy was effective in removing leukemia cells and reducing the risk of metastasis and relapse. Based on preclinical studies, CD123 CAR T-cell therapy has entered preliminary clinical trials. Additionally, several ongoing studies are attempting to explore the combination of other types of CAR T-cell therapeutic targets with CD123 to improve treatment efficacy.

Table 1. Ongoing CD123-Targeted CAR Cell Therapy Clinical Trials

NCT Number

Title

Status

Conditions

Sponsor/Collaborators

Phases

NCT05574608	Allogenic CD123-CAR-NK Cells in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia	Recruiting	Acute Myeloid Leukemia Refractory\|Acute Myeloid Leukemia Recurrent	Affiliated Hospital to Academy of Military Medical Sciences\|Beijing JD Biotech Co. LTD.	Early Phase 1
NCT04272125	Safety and Efficacy of CD123-Targeted CAR-T Therapy for Relapsed/Refractory Acute Myeloid Leukemia	Recruiting	Leukemia\|Leukemia, Myeloid\|Leukemia, Myeloid, Acute	Chongqing Precision Biotech Co., Ltd	Phase 1\|Phase 2
NCT04318678	CD123-Directed Autologous T-Cell Therapy for Acute Myelogenous Leukemia (CATCHAML)	Recruiting	AML\|B-ALL\|T-ALL\|BPDCN\|MDS	St. Jude Children's Research Hospital	Phase 1
NCT04109482	Trial to Evaluate the Safety and Efficacy of MB-102 in Patients With BPDCN.	Recruiting	Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)	Mustang Bio	Phase 1\|Phase 2
NCT02159495	Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed/Refractory Acute Myeloid Leukemia and Persistent/Recurrent Blastic Plasmacytoid Dendritic Cell Neoplasm	Active, not recruiting	Adult Acute Myeloid Leukemia in Remission\|Acute Biphenotypic Leukemia\|Early Relapse of Acute Myeloid Leukemia\|Late Relapse of Acute Myeloid Leukemia\|Recurrent Adult Acute Myeloid Leukemia\|Secondary Acute Myeloid Leukemia\|Blastic Plasmacytoid Dendritic Cell Neoplasm\|Acute Myeloid Leukemia\|Adult Acute Lymphoblastic Leukemia\|Interleukin-3 Receptor Subunit Alpha Positive\|Minimal Residual Disease\|Refractory Acute Myeloid Leukemia\|Untreated Adult Acute Myeloid Leukemia	City of Hope Medical Center\|National Cancer Institute (NCI)\|Mustang Bio, Inc.	Phase 1
NCT05528887	Study of CAR-T Cell Therapy in the Treatment of Relapsed/Refractory Hematological Malignancies	Recruiting	Relapsed/Refractory Hematological Malignancies\|Lymphoma\|Myeloma\|Leukemia	The Affiliated People's Hospital of Ningbo University\|UTC Therapeutics Inc.	Phase 1
NCT04599543	IL3 CAR-T Cell Therapy for Patients With CD123 Positive Relapsed and/or Refractory Acute Myeloid Leukemia	Not yet recruiting	Acute Myeloid Leukemia	Zhejiang University\|Yake Biotechnology 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
NCT04430530	4SCAR-T Therapy Post CD19-targeted Immunotherapy	Recruiting	CD19 Negative B-cell Malignancies	Shenzhen Geno-Immune Medical Institute\|ShiJiaZhuang Zhongxi Children Hospital\|Shenzhen Children's Hospital\|The Seventh Affiliated Hospital of Sun Yat-sen University	Phase 1\|Phase 2
NCT04016129	CAR-T Immunotherapy Targeting CD19- ALL	Recruiting	B-cell Leukemia	Shenzhen Geno-Immune Medical Institute	Phase 1\|Phase 2
NCT04230265	Dose-escalating Trial With UniCAR02-T Cells and CD123 Target Module (TM123) in Patients With Hematologic and Lymphatic Malignancies	Recruiting	Acute Myeloid Leukemia (AML)	AvenCell Europe GmbH\|PHARMALOG Institut für klinische Forschung GmbH	Phase 1
NCT03190278	Study Evaluating Safety and Efficacy of UCART123 in Patients With Relapsed/ Refractory Acute Myeloid Leukemia	Recruiting	Relapsed/Refractory Acute Myeloid Leukemia	Cellectis S.A.	Phase 1
NCT05457010	Phase I Study of Cell Therapies for the Treatment of Patients With Relapsed or Refractory AML or High-risk MDS	Recruiting	Acute Myeloid Leukemia\|Myelodysplastic Syndromes	Arcellx, Inc.	Phase 1
NCT03098355	Interleukin-2 Following 4SCAR19/22 T Cells Targeting Refractory and/or Recurrent B Cell Malignancies	Suspended	B-Cell Leukemia\|B-Cell Lymphoma	Zhujiang Hospital\|Shenzhen Geno-Immune Medical Institute	Phase 1\|Phase 2
NCT04678336	CD123 Redirected T Cells for AML in Pediatric Subjects	Active, not recruiting	Acute Myeloid Leukemia, in Relapse\|Acute Myeloid Leukemia, Pediatric\|Acute Myeloid Leukemia, Refractory	University of Pennsylvania	Phase 1
NCT03766126	Lentivirally Redirected CD123 Autologous T Cells in AML	Active, not recruiting	Acute Myeloid Leukemia, in Relapse\|Acute Myeloid Leukemia, Adult\|Acute Myeloid Leukemia, Refractory	University of Pennsylvania	Phase 1

References

Tang, Xiaowen, et al. "First-in-man clinical trial of CAR NK-92 cells: safety test of CD123-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia." American journal of cancer research 8.6 (2018): 1083.
You, Liangshun, et al. "Decitabine-mediated epigenetic reprograming enhances anti-leukemia efficacy of CD123-targeted chimeric antigen receptor T-cells." Frontiers in Immunology 11 (2020): 1787.
Nong, L., et al. "Blastic plasmacytoid dendritic cell neoplasm: A clinico-pathological retrospective analysis of thirteen cases." Beijing da xue xue bao. Yi xue ban= Journal of Peking University. Health Sciences 55.2 (2023): 308-314.
Wei, C., et al. "Clinical and molecular characteristics and prognosis of classical hairy cell leukemia and hairy cell leukemia variant." Zhonghua nei ke za zhi 62.4 (2023): 416-421.
Klatka, Maria, et al. "The Role of Toll-like Receptor 2 (TLR2) in the Development and Progression of Hashimoto’s Disease (HD): A Case Study on Female Patients in Poland." International Journal of Molecular Sciences 24.6 (2023): 5344.
Hammond, Danielle, and Naveen Pemmaraju. "Tagraxofusp for blastic plasmacytoid dendritic cell neoplasm." Hematology/Oncology Clinics 34.3 (2020): 565-574.
Sonder, Soren Ulrik, et al. "Towards standardizing basophil identification by flow cytometry." Frontiers in Allergy 4 (2023).
DiNardo, Katherine W., Thomas W. LeBlanc, and Hui Chen. "Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting." Journal of Hematology & Oncology 16.1 (2023): 1-3.
Chin, Lynn, Chantelle Ye Gwen Wong, and Harinder Gill. "Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation." International Journal of Molecular Sciences 24.4 (2023): 3161.