Jeffrey Molldrem
Professor
The University of Texas MD Anderson Cancer Center
Department of Hematopoietic Biology & Malignancy
Our laboratory has a longstanding interest in elucidating the molecular mechanisms underlying the curative graft-versus-leukemia (GVL) effect mediated by donor T cells against recipient leukemia following allogeneic stem cell transplantation. By combining high-throughput single-cell multi-omics of donor T cells and patient malignant cells, our laboratory was the first to identify leukemia-associated antigens and cognate T cell receptors that drive GVL. Additionally, we uncovered mechanisms of immune tolerance such as activation-induced cell death that can mitigate GVL, and we continue to study these mechanisms.
Significant work in the lab is dedicated to developing novel immunotherapies based on our discoveries. As examples, in addition to the development and translation of leukemia vaccination strategies, we developed first-in-class T cell receptor mimic (TCRm) monoclonal antibodies (mAbs) and bispecific mAbs that recognize and target peptide/HLA on leukemia cells. These antibodies have been advanced to the clinic for patients with acute myeloid leukemia.
Our work to understand antigen presentation on leukemia led us to identify a surface receptor on leukemia and solid tumors as a novel mediator of cross-presentation of exogenous antigens on tumor cell MHC-I molecules. This discovery inspired the lab to explore the potential therapeutic efficacy of exogenous antigen-coupled anti-receptor mAbs to “paint” tumor cells with exogenous antigens such as viral peptides normally targeted by circulating anti-viral host T cells and to redirect these T cells to kill tumor cells. In addition, our research characterizing GVL effector mechanisms and tolerance also led us to identify a cell surface lipid receptor that is upregulated following T cell activation. We developed a conditional knock out of this receptor in mice to study its role in T cells. This receptor plays a crucial role in regulating T cell proliferation and effector function in pre-clinical models of anti-tumor immunity and autoimmunity, and we are working to characterize receptor signaling pathways and downstream metabolic reprogramming that regulate T cell function. Opportunities for tutorials may focus on basic or translational projects. Basic laboratory projects in the lab include the identification of novel antigens and antigen receptors on cancer cells, mechanisms of antigen cross-presentation, and mechanisms of T cell selection and modulation by cancer as well as how cancer cells co-evolve under the selective process of adaptive immunity. Translational laboratory projects focus on discoveries made in our laboratory and involve therapeutic agents at all stages of clinical development, including (1) development of novel immune therapeutics such as a T cell receptor-like monoclonal antibody, (2) development of gene modified T cells that are adoptively transferred into patients in the context of stem cell transplantation, and (3) cancer vaccines. Laboratory techniques include genetic cloning and expression; protein expression and purification; receptor biology; multi-parameter flow cytometry and cell sorting; confocal microscopy; monoclonal antibody development; therapeutic gene modification, expansion, and characterization of immune cells; immune monitoring; and gene expression profiling. In addition, students are exposed to critical translational aspects of pre-clinical and clinical therapeutic development, including pre-IND studies, animal modeling, and protocol development. The laboratory environment includes students, post-doctoral scientists, clinical fellows, staff senior scientists, technicians, and junior faculty, which affords broad expertise within the group.
Education & Training
M.D. - University of Minnesota - 1990