Lucas Ferrari De AndradePhD
Icahn School of Medicine at Mount Sinai
Project Term: July 1, 2022 - June 30, 2025
Acute myeloid leukemia (AML) is a blood cancer characterized by poor clinical outcomes. We developed an antibody that inhibits AML in models by triggering anti-leukemia immunity. Now we developed a new version of this antibody with higher affinity to the leukocyte receptors that mediate anti-leukemia immunity. We will establish the ability of this optimized antibody to elicit greater inhibition of AML. The studies will generate important information about how to induce anti-leukemia immunity.
Acute myeloid leukemia (AML) is a blood cancer that is characterized by poor clinical outcomes. Our goal is to develop a translational means of inducing a protective response against AML by the human’s immune system, in a manner that is similar to the ones that our bodies display against certain infectious diseases. Treatments that harness the immunity are called “immunotherapies”. They have revolutionized cancer care, and the field’s pioneers (Drs. James Allison and Tasuku Honjo) received the Nobel Prize in Physiology or Medicine in 2018.
We discovered a molecule that potently inhibits AML in immunocompetent mouse models. We named this molecule as “7C6”, and it increases the levels of a leukemia marker that can be recognized by the immune system. As consequence, 7C6 enables immune recognition and clearance of leukemia cells from the body. We also discovered that 7C6 works synergistically with a clinically used drug called romidepsin, by further increasing the amount of this leukemia marker in the malignant cells. The marker is called MICA/B and is well known by the scientific community, but our research is pioneer in using it as an immunotherapeutic target.
Recently, we developed a new version of 7C6 that is optimized to trigger a more potent anti-leukemia immunity. Now we propose to test the optimized 7C6 in a novel mouse strain that was genetically engineered to express human receptors that recognize 7C6 and trigger anti-leukemia immunity. We also propose to test “optimized 7C6 + romidepsin” in assays that enable analyses of the cellular interactions that could mediate the inhibition of AML. These new studies will advance our understanding of AML immunobiology by models that recapitulate the human immune system as faithful as possible. The results with these humanized mouse models will provide evidences that patients with AML would experience similar therapeutic effects if administered with our treatment.
AML is mostly incurable, because relapse is common after chemotherapy and bone marrow donors are not always available for transplantation. Resistance to current treatments is a challenging issue that can only be overcome by scientific research with innovative treatments that create new clinical standards. Our laboratory works under the idea that diversity is strength: we are working to diversify the immunotherapeutic armamentarium that will be available for future clinical trials with patients with AML. 7C6 has unique mechanism of action that can generate new insights about anti-leukemia immunity.