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Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients
- Source :
- International journal of cancerREFERENCES. 148(2)
- Publication Year :
- 2020
-
Abstract
- Chimeric antigen receptor T (CART) cells targeting CD19 have shown promising results in the treatment of chronic lymphocytic leukemia (CLL). However, efficacy seems to be inferior compared to diffuse large B-cell lymphoma or acute lymphoblastic leukemia. Impaired T-cell fitness of CLL patients may be involved in treatment failure. Less-differentiated naive-like T cells play an important role in CART expansion and long-term persistence in vivo. These cells are sparse in CLL patients. Therefore, optimization of CART cell production protocols enriching less differentiated T cell subsets may overcome treatment resistance. The B-cell receptor inhibitor ibrutinib targeting Bruton's tyrosine kinase (BTK) is approved for the treatment of CLL. Besides BTK, ibrutinib additionally inhibits interleukin-2-inducible T-cell kinase (ITK) which is involved in T-cell differentiation. To evaluate the effect of ibrutinib on CART cell production, peripheral blood mononuclear cells from nine healthy donors and eight CLL patients were used to generate CART cells. T-cell expansion and phenotype, expression of homing and exhaustion makers as well as functionality of CART cells were evaluated. CART cell generation in the presence of ibrutinib resulted in increased cell viability and expansion of CLL patient-derived CART cells. Furthermore, ibrutinib enriched CART cells with less-differentiated naive-like phenotype and decreased expression of exhaustion markers including PD-1, TIM-3 and LAG-3. In addition, ibrutinib increased the cytokine release capacity of CLL patient-derived CART cells. In summary, BTK/ITK inhibition with ibrutinib during CART cell culture can improve yield and function of CLL patient-derived CART cell products.
- Subjects :
- Cart
CD4-Positive T-Lymphocytes
Cancer Research
Chronic lymphocytic leukemia
medicine.medical_treatment
T cell
Antigens, CD19
Cell Culture Techniques
Receptors, Antigen, T-Cell
CD8-Positive T-Lymphocytes
Immunotherapy, Adoptive
CD19
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Piperidines
immune system diseases
T-Lymphocyte Subsets
hemic and lymphatic diseases
medicine
Bruton's tyrosine kinase
Humans
Receptors, Chimeric Antigen
biology
business.industry
Adenine
virus diseases
Immunotherapy
medicine.disease
Leukemia, Lymphocytic, Chronic, B-Cell
Chimeric antigen receptor
Culture Media
medicine.anatomical_structure
HEK293 Cells
Oncology
chemistry
030220 oncology & carcinogenesis
Ibrutinib
Case-Control Studies
Cancer research
biology.protein
Cytokines
business
K562 Cells
Subjects
Details
- ISSN :
- 10970215
- Volume :
- 148
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- International journal of cancerREFERENCES
- Accession number :
- edsair.doi.dedup.....e3a68a4c76dec4227304618d8fe00081