Myeloid cell-selective, oligonucleotide-based STAT3 inhibition combined with total marrow and lymphoid irradiation for immunotherapy of acute myeloid leukemia

PROJECT SUMMARY

There has been little or no long-term improvement in outcomes for patients with treatment-refractory acute

myeloid leukemia (AML). The recently developed image-guided radiation strategy, total marrow and lymphoid

irradiation (TMLI) delivers high radiation doses to major leukemia reservoirs while sparing normal tissues.

Although TMLI prior to allogeneic hematopoietic cell transplantation (HCT) improved patients’ 2-year overall

survival (OS) rate from 50% leukemic blasts in the bone marrow) by providing time for the generation of

adaptive T-cell driven immune responses. The preliminary results demonstrated that the TMLI regimen can

improve uptake of CSI-2 by AML, thereby reducing leukemia-initiating potential, augmenting AML

immunogenicity, and thereby inducing potent CD8+ T cell-mediated antileukemic immune responses. We

propose to: 1. elucidate the molecular mechanisms of TMLI/CSI-2 effect on AML cell differentiation; 2. optimize

TMLI to maximize the effect on leukemic bone marrow vascular structure, CSI-2 delivery, leukemogenic

potential, and immunogenicity; 3. assess the efficacy and cellular mode-of-action of the TMLI/CSI-2 combination

treatment compared to either treatment alone in human or mouse AML models in humanized or syngeneic mice,

respectively. The overarching goal of this interdisciplinary proposal is to produce a clinically relevant, effective,

and safe combinatorial radiation-immunotherapy for patients with relapsed/recurrent AML, representing the

highest unmet need in cancer therapy.