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Rapidly Switchable Universal CAR-T Cells for Treatment of CD123-Positive Leukemia
- Source :
- Molecular Therapy: Oncolytics, Vol 17, Iss, Pp 408-420 (2020), Molecular Therapy Oncolytics 17(2020), 408-420, Molecular Therapy Oncolytics
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
Abstract
- Chimeric antigen receptor T cells (CAR-T) targeting CD19 or B cell maturation antigen (BCMA) are highly effective against B cell malignancies. However, application of CAR-T to less differentially expressed targets remains a challenge due to lack of tumor-specific antigens and CAR-T controllability. CD123, a highly promising leukemia target, is expressed not only by leukemic and leukemia-initiating cells, but also by myeloid, hematopoietic progenitor, and certain endothelial cells. Thus, CAR-T lacking fine-tuned control mechanisms pose a high toxicity risk. To extend the CAR-T target landscape and widen the therapeutic window, we adapted our rapidly switchable universal CAR-T platform (UniCAR) to target CD123. UniCAR-T efficiently eradicated CD123+ leukemia in vitro and in vivo. Activation, cytolytic response, and cytokine release were strictly dependent on the presence of the CD123-specific targeting module (TM123) with comparable efficacy to CD123-specific CAR-T in vitro. We further demonstrated a pre-clinical proof of concept for the safety-switch mechanism using a hematotoxicity mouse model wherein TM123-redirected UniCAR-T showed reversible toxicity toward hematopoietic cells compared to CD123 CAR-T. In conclusion, UniCAR-T maintain full anti-leukemic efficacy, while ensuring rapid controllability to improve safety and versatility of CD123-directed immunotherapy. The safety and efficacy of UniCAR-T in combination with TM123 will now be assessed in a phase I clinical trial (ClinicalTrials.gov: NCT04230265).<br />Graphical Abstract<br />CAR-T cell treatment of acute leukemia beyond CD19 remains challenging. Loff et al. demonstrate that rapidly switchable universal CAR-T cells in combination with soluble CD123-specific adaptors achieve robust anti-leukemic responses, while hematotoxicity is rapidly reversible, enabling safe targeting of such less differentially expressed target antigens and broadening of the therapeutic window.
- Subjects :
- 0301 basic medicine
Cancer Research
Myeloid
medicine.medical_treatment
lcsh:RC254-282
Article
CD19
UniCAR
03 medical and health sciences
0302 clinical medicine
Antigen
AML
medicine
Pharmacology (medical)
B cell
biology
adoptive cell therapy
Immunotherapy
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Chimeric antigen receptor
CAR-T
Haematopoiesis
Leukemia
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
CD123
biology.protein
Cancer research
Molecular Medicine
immunotherapy
ALL
Subjects
Details
- Language :
- English
- ISSN :
- 23727705
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy: Oncolytics
- Accession number :
- edsair.doi.dedup.....ff1fc9916ab82f0e31555c5fbef7b009