Dr. Ravi Majeti: 2020 CDP Achievement Award Winner

Dr. Majeti

2020 LLS-CDP SCHOLAR ACHIEVEMENT AWARD

co-awardee

 

Dr. Ravi Majeti is Professor of Medicine, Chief of the Division of Hematology, and Member of the Institute for Stem Cell Biology and Regenerative Medicine at the Stanford University School of Medicine. He is a board-certified hematologist. While at Stanford, he completed post-doctoral training in the laboratory of Irving Weissman, MD, where he investigated acute myeloid leukemia (AML) stem cells and therapeutic targeting with anti-CD47 antibodies. Dr. Majeti directs an active NIH-funded laboratory that focuses on the molecular characterization and therapeutic targeting of leukemia stem cells in human hematologic disorders, particularly AML, and has published over 100 peer-reviewed articles.

"I feel so honored to have been chosen for the Leukemia and Lymphoma Society Scholar Award, which has made a major impact on my career focused on developing new approaches to the treatment of AML and other hematologic malignancies. As a junior investigator, the LLS Scholar Award allowed me to focus on my research and growing my independent lab. This crucial support helped during a critical funding time to bridge me from my start-up to sponsored research grants. Most importantly, it allowed me to pursue innovative and risky projects that otherwise would have been difficult to undertake. The contributions of my lab to the field and advances in blood cancer research would not have been possible without this support. I feel very fortunate to have been selected for the Scholar Award and for the multiple ways in which LLS has supported me, my lab, and patients with blood cancers."

 

Dr. Majeti was awarded the CDP Scholar Award in 2015 for his project titled Pre-Clinical Development of Monoclonal and Bispecific Antibodies Targeting MDS/AML Stem Cells.

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are cancers of the blood that cause significant clinical problems and in many cases, death. In our previous work, we identified antibody targets on the outer surface of the AML and MDS stem cells including CD47, TIM3, and CD99. We initially focused on targeting of CD47 with blocking anti-CD47 antibodies that enable removal of AML stem cells by the immune system, and synergized with second cancer-specific antibodies to clear disease. We have now generated antibodies specific for TIM3 and CD99, and here propose the pre-clinical development of single and dual-specific antibodies against these targets. Our specific aims are to: (1) investigate targeting of AML stem cells with anti-TIM3 and anti-CD99 antibodies; (2) develop dual-specific antibodies targeting CD47, TIM3, and/or CD99 and assess their activity; and (3) conduct pre-clinical development of the single and dual-specific antibodies. Ultimately, we hope to identify lead antibodies for downstream clinical development.

During the award period (2015-2020) the Majeti lab has focused on the characterization of human AML stem cells (AML LCSc). Some highlights:

  • As an extension on their previous work of CD47 therapeutic antibody targeting, they have now focused on developing bispecific CD47/CD20 targeting formats as earlier studies demonstrated synergy with this combination.
  • Developed a novel xenograft model to generate humanized ossicles in NGS mice.
  • generated AML-derived iPSCs from individual single cells and clones present in primary AML specimens (allowing the physical separation and investigation of AML subclones for the first time)
  • used single cell genotyping to examine AML measurable residual disease (MRD): cells that have been proposed to be enriched in AML LSCs, thereby eventually giving rise to relapse
  • isolated pre-leukemic HSCs and demonstrated that pre-leukemic mutations occur primarily in genes that regulate the epigenome that were subsequently identified in clonal hematopoiesis
  • used superenhancer profiling to identify a RARA biomarker-positive AML subset responsive to the RARA agonist tamibarotene (SY-1425) now in clinical trials
  • showed that the IDH2 mutant-specific inhibitor enasidenib can independently drive erythroid differentiation and are actively pursuing clinical applications beyond IDH2-mutant AML

All corresponding author publications during the award period:

  • Sci Transl Med. 2020;12(538).
  • Blood Adv. 2020;4(5):943-952.
  • J Clin Invest. 2020;130(4):1843-1849.
  • Elife. 2017;6.
  • Nat Protoc. 2017;12(10):2169-2188.
  • Cancer Discov. 2017;7(10):1136-1153.
  • Nat Commun. 2017;8:15580.
  • Cell Stem Cell. 2017;20(3):329-344 e327.
  • Nat Genet. 2016;48(10):1193-1203.
  • PLoS One. 2016;11(7):e0159189.
  • Nat Med. 2016;22(7):812-821.
  • Clin Cancer Res. 2016;22(20):5109-5119.
  • Cell Stem Cell. 2015;17(6):675-688.
  • Nat Commun. 2015;6:8489.
  • PLoS One. 2015;10(9):e0137345.
  • MAbs. 2015;7(5):946-956.