ABSTRACT
PURPOSE: The aim of this study is to determine immune-related biomarkers to predict effective antitumor immunity in myelodysplastic syndrome (MDS) during immunotherapy (IMT, αCTLA-4, and/or αPD-1 antibodies) and/or hypomethylating agent (HMA). EXPERIMENTAL DESIGN: Peripheral blood samples from 55 patients with MDS were assessed for immune subsets, T-cell receptor (TCR) repertoire, mutations in 295 acute myeloid leukemia (AML)/MDS-related genes, and immune-related gene expression profiling before and after the first treatment. RESULTS: Clinical responders treated with IMT ± HMA but not HMA alone showed a significant expansion of central memory (CM) CD8+ T cells, diverse TCRß repertoire pretreatment with increased clonality and emergence of novel clones after the initial treatment, and a higher mutation burden pretreatment with subsequent reduction posttreatment. Autophagy, TGFß, and Th1 differentiation pathways were the most downregulated in nonresponders after treatment, while upregulated in responders. Finally, CTLA-4 but not PD-1 blockade attributed to favorable changes in immune landscape. CONCLUSIONS: Analysis of tumor-immune landscape in MDS during immunotherapy provides clinical response biomarkers.
Subject(s)
Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Humans , Immune Checkpoint Inhibitors/therapeutic use , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , ImmunotherapyABSTRACT
The aim of this study is to investigate whether the peripheral blood (PB) can serve as a surrogate immune-microenvironment to bone marrow for genetic and immune monitoring in myelodysplastic syndrome (MDS). We compared the composition of T cell subsets and somatic mutation burden in 36 pairs of PB and matching bone marrow aspirate (BMA) using multi-parameter flow cytometry and NGS-based targeted sequencing analysis, respectively. Our immune-subset and NGS-based mutation analysis of BMA showed significant concordance with those of PB in MDS. Therefore, PB can provide easily accessible tumor immune-microenvironment for monitoring in the immune and genetic landscapes for MDS patients.
ABSTRACT
Despite substantial advances in the treatment of acute myeloid leukemia (AML), only 30% of patients survive more than 5 years. Therefore, new therapeutics are much needed. Here, we present a novel therapeutic strategy targeting PR1, an HLA-A2 restricted myeloid leukemia antigen. Previously, we have developed and characterized a novel T-cell receptor-like monoclonal antibody (8F4) that targets PR1/HLA-A2 and eliminates AML xenografts by antibody-dependent cellular cytotoxicity (ADCC). To improve the potency of 8F4, we adopted a strategy to link T-cell cytotoxicity with a bi-specific T-cell-engaging antibody that binds PR1/HLA-A2 on leukemia and CD3 on neighboring T-cells. The 8F4 bi-specific antibody maintained high affinity and specific binding to PR1/HLA-A2 comparable to parent 8F4 antibody, shown by flow cytometry and Bio-Layer Interferometry. In addition, 8F4 bi-specific antibody activated donor T-cells in the presence of HLA-A2+ primary AML blasts and cell lines in a dose dependent manner. Importantly, activated T-cells lysed HLA-A2+ primary AML blasts and cell lines after addition of 8F4 bi-specific antibody. In conclusion, our studies demonstrate the therapeutic potential of a novel bi-specific antibody targeting the PR1/HLA-A2 leukemia-associated antigen, justifying further clinical development of this strategy.
