In CP-CML, Deep Molecular Responses to TKIs Result from Immune Suppressor Activity

In CP-CML, Deep Molecular Responses to TKIs Result from Immune Suppressor Activity
In CP-CML, Deep Molecular Responses to TKIs Result from Immune Suppressor Activity

ORLANDO, FL—Patients with chronic-phase chronic myeloid leukemia (CP-CML) with deep molecular responses to tyrosine kinase inhibitors (TKI) have increased effector natural killer and cytotoxic T cell immune responses to leukemia-associated antigens, results of a study at presented at the 57th American Society of Hematology (ASH) Annual Meeting have shown.1

These heightened responses are associated with a concomitant reduction in immune suppressor activity, Amy Hughes, PhD, Department of Haematology - SA Pathology, School of Medicine, University of Adelaide in Australia, said, adding that “methods to augment these responses may result in greater rate of success in TKI cessation studies.”

Dr Hughes and colleagues hypothesized that immune responses contribute to deep BCR-ABL molecular responses in patients with CP-CML taking TKIs.

To test this hypothesis, they studied 51 patients comprising 60 samples: 17 patients (and 17 samples) at CP-CML diagnosis, 15 patients (and 19 samples) with major molecular response (MMR) BCR-ABL <0.1% with a median time on TKI of 3.25 years (range, 0.3-11 years), and 19 patients (and 24 samples) with deep molecular response (MR4.5) BCR-ABL <0.0032% with a median time on TKI of 2.4 years (range, 0.6-11.5 years).

Of patients with MMR, 8 were treated with imatinib and 7 with nilotinib and, of those in MR4.5, 15 had received imatinib, 4 received nilotinib, and 2 received dasatinib.

Flow cytometry was used to characterize the effector immune responses of natural killer cells, and functional analysis was studied using CD107a degranulation assay.

Results showed that compared with patients at diagnosis and MMR, patients in deep molecular response  “displayed increased antigen-specific cytotoxic T lymphocyte responses to leukemia-associated antigens,” both in number and frequency of responses.

“The most abundant leukemia-associated antigen response was to PRAME (51% of patients in MR4.5 compared to 31% in MMR and 0% at diagnosis) and WT1 (31% of patients in MR4.5 compared to 28% in MMR and 0% at diagnosis),” Dr Hughes reported. “PR3-specific immune responses were the least abundant, with no difference in response between MR4.5 and MMR (both 3%) compared to 0% at diagnosis.” Clinical trials are currently investigating the role of WT1, PRAME, and PR3, she said. The polycomb complex protein BMI-1 had a 25% response among patients in MR4.5, 19% in MMR, and 0% a diagnosis.

Also compared at diagnosis, the absolute regulatory T cells number/µl was significantly lower in patients with MMR and MR4.5.

Dr Hughes explained that the PD-1/PDE-L1 pathway “is a promising therapeutic target” in cancer. Nivolumab is being studied in patients with CML in a phase 1 trial. Overall, PD-1 expression was lower in natural killer cells in patients with CML but was significant in MMR and MR4.5  compared to diagnosis. No difference in PD-1 expression were seen in B cells or monocytes.

“Precise mechanisms involved and/or the order in which ‘immune re-activation' occurs remains unknown,” Dr. Hughes concluded. “Once identified, methods to augment these responses may result in greater rates of success in TKI cessation studies.”

Reference

1. Hughes A, Tang C, Clarson J, et al. Chronic myeloid leukemia patients with deep molecular responses to tyrosine kinase inhibitors have increased effector natural killer and cytotoxic T cell immune responses to leukaemia-associated antigens and concomitant reduced immune suppressors [abstract]. Blood. Available at: https://ash.confex.com/ash/2015/webprogram/Paper84302.html. Accessed December 5, 2015.

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