Andrew M. Brunner (United States of America)
Massachusetts General Hospital
Leukemia Program
Andrew Brunner, MD, is an assistant in medicine in the Division of Hematology and Oncology at Massachusetts General Hospital Cancer Center and assistant professor at Harvard Medical School, both in Boston. Dr Brunner’s clinical focus is for the treatment of patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), as well as other cancers of the blood and bone marrow. His research focuses on the development of novel therapeutic strategies (typically phase 1 and 2 clinical trials) for patients with MDS and AML. He has been involved in studies that explore unique targets in these cancers, including mutations in the spliceosome, or targets expressed on immune effector cells. At the same time, he researches patient outcomes in MDS, including ways to better understand why certain patients have better responses to treatment than others, and which treatment responses are more meaningful to patients. Overall he seeks to discover novel treatments in MDS which improve survival and patient quality of life. He receives funding support from the Edwards P. Evans Foundation to support his career as an innovative clinical/translational investigator in MDS, and from the NIH Leukemia SPORE at the Dana-Farber/Harvard Cancer Center.

Presenter of 1 Presentation

 Congress Calendar

Antibody-Based Therapy of MDS

Date
05/05/2023
Room
Auditorium
Session Type
Plenary Session
Session Name
0370 - Plenary Session 07: Non Targeted Approaches for HR MDS (ID 37)
Presenter
Lecture Time
14:45 - 15:00

Abstract

Abstract Body

Among novel classes of therapeutics for myelodysplastic syndromes (MDS), there are an increasing number that utilize antibodies to elicit an anti-tumor effect, either by engaging malignancy-specific targets or by activating other cellular mediators of disease response. There are a number of ways that antibodies can be modified for therapeutic gain, including conjugation of a chemotherapeutic for targeted delivery, the use of specific IgG subtype constructs to yield different biological impacts, and the utilization of various components including the Fc region in drug design.

Humanized antibodies that target novel immune checkpoints are currently under investigation for the treatment of MDS, including therapies that target the T-cell immunoglobulin and mucin containing-3 (TIM-3) receptor, and CD47 or integrin associated protein. Immune checkpoint inhibition has been evaluated in other malignancies, notably in solid tumors where the use of PD-1 and CTLA-4 directed antibodies have altered the treatment landscape; to date, therapies targeting PD-1 and CTLA-4 have had less clear impact in hematologic malignancies. CD47 is overexpressed on cancer cells, including on MDS progenitors. CD-47 on tumor cells interacts with signal regulatory protein α (SIRPα) on macrophages to inhibit anti-tumor phagocytosis; anti-CD47 antibodies interfere with this interaction, permitting tumor cell phagocytosis. Magrolimab is an anti-CD47 antibody which is currently in late stage development in MDS; it has been combined with azacitidine based on preclinical data suggesting synergistic activity and is currently being studied in the phase III ENHANCE study comparing azacitidine to azacitidine+magrolimab. Another novel immune target is TIM-3, which is expressed on immune effector cells including T-cells and NK cells, and acts as a negative regulatory immune checkpoint. TIM-3 is also aberrantly expressed on MDS blasts, and may serve a role in autocrine self-renewal of this malignant progenitor population via binding to its ligand, galectin-9. Sabatolimab is an anti-TIM-3 antibody currently being studied in MDS in the phase III STIMULUS trial, comparing azacitidine+placebo to azacitidine+sabatolimab.

Other therapeutics utilize characteristics of antibodies in order to deliver a drug or bind to specific ligands. Luspatercept is a fusion protein which incorporates the Fc portion of the IgG heavy chain, fused to a modified extracellular domain of the activin receptor type IIB (ActRIIB). ActRIIB interacts with ligands from the TGF-β superfamily; when these ligands bind to ActRIIB on the cell surface they activate the SMAD2/3 signaling pathway. The Fc domain fusion permits circulation of this modified ligand “trap” which in turn enhances late stage erythropoiesis in MDS as well as in other anemias. Antibodies can also serve to deliver therapeutics directly to cells based on a target such as CD33 or CD123. There are a number of antibody-drug conjugates currently under investigation in MDS, which may allow for selective targeting of MDS progenitors and relative sparing of healthy stem cells.

Together, antibody-based therapies represent a promising new therapeutic area in MDS. This abstract will review the current landscape of antibody-based therapeutics in MDS, including data for their use to target immune checkpoints, cancer-specific ligands, and also as part of ligand traps for relevant signaling pathways that are overactive in MDS.

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