CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients

M Matsushita,Y Kawakami,S Kanchi,Y Hattori,N Tsukamoto,K Ozawa,M Nakamura,E Matsuki,T Shimizu,S Okamoto,D Ichikawa,T Suzuki,H Kasahara,H Nakajima,M Sakurai,N Nakano,T Mori,D Karigane

doi:10.1038/bcj.2017.84

Abstract

Although the introduction of tyrosine kinase inhibitors (TKIs) has improved overall survival of patients with chronic myeloid leukemia (CML), about half of the patients eventually relapse after cessation of TKIs. In contrast, the remainder of the patients maintain molecular remission without TKIs, indicating that the patients’ immune system could control proliferation of TKI-resistant leukemic stem cells (LSCs). However, the precise mechanism of immunity against CML-LSCs is not fully understood. We have identified a novel immune target, CXorf48, expressed in LSCs of CML patients. Cytotoxic T cells (CTLs) induced by the epitope peptide derived from CXorf48 recognized CD34+CD38− cells obtained from the bone marrow of CML patients. We detected CXorf48-specific CTLs in the peripheral blood mononuclear cells from CML patients who have discontinued imatinib after maintaining complete molecular remission for more than 2 years. Significantly, the relapse rate of CXorf48-specific CTL-negative patients was 63.6%, compared to 0% in CXorf48-specific CTL-positive patients. These results indicate that CXorf48 could be a promising therapeutic target of LSCs for immunotherapy to obtain durable treatment-free remission in CML patients.

Highlights

We identified the first epitope peptide and investigated whether CXorf[48] could be a therapeutic target as leukemic stem cells (LSCs) antigen in chronic myeloid leukemia (CML) patients, in the context of treatment-free remission (TFR)
Blood Cancer Journal expression was detected in 12 out of 17 (70%) of Bone marrow mononuclear cells (BMMNC) samples from CML patients at diagnosis (Figure 1b)
Immunotherapy against LSC-specific antigens is one of the promising strategies to achieve a cure for CML

Summary

Introduction

Recent studies reported that long-term administration of tyrosine kinase inhibitors (TKIs) increased economic burden and adverse events, including vascular events and impaired quality of life in patients with chronic myeloid leukemia (CML).[1,2,3] To resolve these problems, the feasibility of discontinuation of TKIs after sustained complete molecular response (CMR) has been evaluated in several clinical trials; these trials have shown that about half of patients can maintain CMR after the discontinuation of TKIs, which means treatment-free remission (TFR).[4,5,6] TFR is considered as the therapeutic goal of CML after achieving CMR.[7,8]. In patients achieving TFR, the immune system is thought to play a role in controlling proliferation of TKI-resistant leukemic stem cells (LSCs) or keeping LSCs quiscent.[9,10,11] immunotherapy directly targeting LSCs may be a promising strategy for achieving TFR. The detail of T-cell immunity against CML-

Methods

Results

Conclusion