SAN FRANCISCO – Immune-enriched acute myeloid leukemias might be amenable to immunotherapy that is tailored to the bone marrow tumor microenvironment, according to findings from a pan-cancer analysis of bone marrow samples.
The analysis, performed with 3D biology technology and an RNA pan-cancer immune profiling panel to characterize bone marrow specimens from 46 children and 28 adults with acute myeloid leukemia (AML), identified heterogeneous immune profiles that correlated with relapse-free survival (RFS) and overall survival (OS), Jayakumar Vadakekolathu, PhD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
The specimens, including 63 from nonpromyelocytic de novo AML, 7 from AML in children with complete remission, 3 from adults with secondary AML, and 1 from an adult with treatment-related AML, were analyzed with the nCounter system from NanoString Technologies, and were visualized via digital spatial profiling, said Dr. Vadakekolathu of Nottingham Trent University in England.
Sharon Worcester/Frontline Medical News
Dr. Jayakumar Vadakekolathu
The investigators identified two distinct immune gene expression profiles (GEPs) that were largely age-differentiated: Cluster A (myeloid-enriched specimens) included 26 children and 8 adults, and cluster B (myeloid-depleted specimens) included 9 children and 18 adults. These GEPs predicted clinical outcome; relapse free survival was 2.2 months in cluster A versus 18.3 months in cluster B (hazard ratio, 2.58) and overall survival was 6.3 months in cluster A, compared with 22.4 months in cluster B (HR, 2.39), Dr. Vadakekolathu reported.
The findings could have implications for the development of new treatment strategies, he said, noting that AML is a highly heterogeneous disease in terms of genetics, clinical manifestations, and outcome.
“Prognosis is determined by cytogenetic and molecular abnormalities, as well as by response to chemotherapy. De novo AML is cured in roughly 70% of children, 35%-40% of adults, and 5%-15% of elderly patients,” he said. Some patients with AML fail to respond to induction chemotherapy, and others eventually relapse despite the lack of adverse risk factors, he added.
The general therapeutic strategy in patients with AML has not changed substantially in more than 30 years, he said.
“High degrees of molecular complexity in AML present a considerable challenge in clinical implementation, and there is an urgent need to discover better biomarkers to identify high-risk patients before starting chemotherapy, which would enable testing of investigational therapeutic strategies in clinical trials,” he said.
In an effort to identify immune gene signatures across the spectrum of AML genotypes and to correlate transcriptomic and proteomic profiles with patient outcomes, he and his colleagues used a pediatric cohort from Children’s Hospital of Philadelphia (median age at diagnosis of 10 years), and an adult cohort from the Technical University of Dresden, Germany (median age at diagnosis, 55.5 years). Bone marrow samples were collected and analyzed at diagnosis.
Hierarchical clustering identified the two distinct clusters. The immune-enriched cluster A had heightened expression of T cells, natural killer cells, and cytotoxic cells, and also expressed CD8A, IFNG, FOXP3, the cell chemoattractants CXCL9 and CXCL10, and inhibitory molecules including IDO1 and the immune checkpoints LAG3, CTLA4, and PD-L1. The immune-depleted cluster B overexpressed genes associated with mast cell functions and CD8 T-cell exhaustion, and showed low expression of T-cell and B-cell genes.
Further analysis of 10 of the inflamed samples from patients with newly diagnosed AML was performed with digital spatial profiling (DSP) to visualize in situ leukemia–immune system interactions, Dr. Vadakekolathu said.
Surface antigens CD123 and CD3 were used as a visualization marker for leukemia cells and to identify bone marrow-infiltrating T cells, respectively. Protein quantification showed a higher concentration of CD3 counts in T-cell-rich versus T-cell-poor areas, and protein expression profiles showed strong correlations with various immunologically relevant molecules. The co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types evident on DSP represents an immune landscape consistent with the establishment of adaptive immune resistance mechanisms of immune escape, he noted.
The findings suggest immune enriched AMLs might be amenable to combination immunotherapies tailored to the bone marrow tumor microenvironment, such as IDO1 inhibitors and checkpoint blockade, Dr. Vadakekolathu said. “Immune gene expression profiles of AML might support rapid prediction of patient outcomes, discovery of novel immune biomarkers and therapeutic targets, and development of integrated patient stratifications,” he said.
This study was supported by grants from the Roger Counter Foundation and the Qatar National Research Fund. Dr. Vadakekolathu reported having no disclosures. Some authors reported employment or other financial relationships with NanoString Technologies.
sworcester@frontlinemedcom.com
SOURCE: Rutella S et al. ASCO-SITC Abstract 50