Abstract |
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers. PD-L1 was increased in relapsed ALL patients (n=11) and in ALLs refractory to Blinatumomab (n=5). Exhaustion markers (PD-1, TIM-3) were significantly higher on patients' T cells compared to physiologic controls. T-cell proliferation and effector function was target-cell dependent and correlated to expression of co-signaling molecules. Blockade of inhibitory PD-1-PD-L and CTLA-4-CD80/86 pathways enhanced T-cell function whereas blockade of co-stimulatory CD28-CD80/86 interaction significantly reduced T-cell function. Combination of Blinatumomab and anti-PD-1 antibody was feasible and induced an anti-leukemic in vivo response in a 12-year-old patient with refractory ALL. In conclusion, ALL cells actively regulate T-cell function by expression of co-signaling molecules and modify efficacy of therapeutic T-cell attack against ALL. Inhibitory interactions of leukemia-induced checkpoint molecules can guide future T-cell therapies.
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Authors | Judith Feucht, Simone Kayser, David Gorodezki, Mohamad Hamieh, Michaela Döring, Franziska Blaeschke, Patrick Schlegel, Hans Bösmüller, Leticia Quintanilla-Fend, Martin Ebinger, Peter Lang, Rupert Handgretinger, Tobias Feuchtinger |
Journal | Oncotarget
(Oncotarget)
Vol. 7
Issue 47
Pg. 76902-76919
(Nov 22 2016)
ISSN: 1949-2553 [Electronic] United States |
PMID | 27708227
(Publication Type: Journal Article)
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Chemical References |
- Antibodies, Bispecific
- Antibodies, Monoclonal, Humanized
- Antigens, CD19
- Biomarkers, Tumor
- blinatumomab
- pembrolizumab
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Topics |
- Antibodies, Bispecific
(pharmacology)
- Antibodies, Monoclonal, Humanized
(pharmacology)
- Antigens, CD19
(metabolism)
- Biomarkers, Tumor
(immunology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Child
- Female
- Humans
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
(immunology, therapy)
- T-Lymphocytes
(immunology, metabolism)
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