Chronic Myeloid Leukemia Patients Clinical Trial
Official title:
Effect of Tyrosine Kinase Inhibitors on Myeloid Derived Suppressor Cells in Chronic Myeloid Leukemia Patients
The suppression of the immune system creates a permissive environment for development and progression of cancer. One population of immunosuppressive cells that have become the focus of intense study is myeloid derived suppressor cells , immature myeloid cells able to induce immune-escape, angiogenesis, and tumor progression. Two different subpopulations have been identified and studied: granulocytic and monocytic myeloid derived suppressor cells with a different immunophenotype and immunosuppressive properties
Myeloid-derived suppressor cells utilize different mechanisms to block both innate and
adaptive arms of anti-tumour immunity, mostly through inhibition of T cell activation and
expansion . Human monocytic myeloid derived suppressor cells are mostly identified as CD14+
cells with negative or low expression of HLADR. And also express high levels of CD11b and
CD33 antigen . Human granulocytic myeloid derived suppressor cells are usually defined as
CD66b+ CD11b+ CD15+ HLADR- cells and display an intermediate expression of CD33 and a
variable expression of CD11b, depending on their maturation stage .
Chronic myeloid leukemia (CML) is a hematological cancer, characterized by a reciprocal
chromosomal translocation between chromosomes 9 and 22 [t(9;22)], producing the Bcr-Abl
oncogene. Tyrosine kinase inhibitors represent the standard of care for CML patients and
exert a dual mode of action: direct oncokinase inhibition and restoration of
effector-mediated immune surveillance, which is rendered dysfunctional in CML patients at
diagnosis, prior to TKI therapy. TKIs such as imatinib, and more potent second-generation
nilotinib and dasatinib induce a high rate of deep molecular response (DMR, BCR-ABL1 ≤ 0.01%)
in CML patients. As a result, the more recent goal of therapy in CML treatment is to induce a
durable deep molecular response as a prelude to successful treatment-free remission .
Accumulation of both Gr-MDSCs and Mo-MDSCs cells has been found in the peripheral blood of
chronic myeloid leukemia (CML) patients. They are part of the tumor clone showing BCR/ABL
expression.
BCR-ABL tyrosine kinase inhibitors (TKI) are able to induce remission in CML patients but not
to eliminate leukemia stem cells , which can regenerate leukemia on drug discontinuation .
Unfortunately, molecular relapse is observed after cessation of tyrosine kinase inhibitors in
61-66% of CML patients, previously in complete molecular response (presumably due to the
reactivation of dormant CML LSCs that are resistant to TKI-induced leukemic cell ablation.
Thus, current research efforts aim to develop additional therapies to target these
TKI-refractory CML LSCs .
With the aim of increasing cure rates and make it possible for patients to discontinue
treatment, TKI therapies are currently evaluated in combination with immune modulators .
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