City of Hope® Research Spotlight features the latest research defining the future of medical treatment. This first roundup highlights a T cell engager that shows promise as a novel treatment for acute myeloid leukemia, findings linking immune aging to thymic involution and a potential way of eliminating myeloma with weak antigen expression.
To learn more about research at City of Hope, visit the Research & Innovation page.
IL1RAP-Specific T Cell Engager Depletes Acute Myeloid Leukemia Stem Cells
The novel anti-IL1RAP/CD3 T cell engager (TCE) BIF002 effectively targets and eliminates leukemic stem cells (LSCs) and bulk blasts in acute myeloid leukemia (AML) without harming normal hematopoietic stem cells (HSCs), showing significant potential as a new treatment for AML, according to a Journal of Hematology and Oncology study. Interleukin-1 receptor accessory protein (IL1RAP) is highly expressed on AML bulk blasts and LSCs, but not on normal HSCs — offering a unique therapeutic target. Researchers, led by Guido Marcucci, M.D., professor and chair, along with Bin Zhang, Ph.D., and Lucy Ghoda, Ph.D., of the Department of Hematologic Malignancies Translational Science at Beckman Research Institute of City of Hope, and working closely with the IDDV-supported, Antibody Generate Engine led by John Williams, Ph.D., and Miso Park, Ph.D., Department of Cancer Biology and Molecular Medicine, isolated antibodies to IL1RAP from CD138+ B cells collected from immunized mice through optoelectric positioning and single-cell sequencing. They produced and characterized individual mouse monoclonal antibodies (mAbs), from which they developed BIF002, an anti-human IL1RAP/CD3 TCE using Fab arm exchange. The antileukemic activity of BIF002 was characterized both in vitro and in vivo, utilizing multiple cell lines and patient-derived AML samples. This TCE showed potent efficacy in vitro and in vivo, effectively activating T cells to target and destroy IL1RAP-expressing leukemic cells at very low concentrations, with the effect dependent on effector-to-target ratios. The novel anti-IL1RAP/CD3 TCE, BIF002, was shown to eradicate LSCs and significantly prolong survival of AML xenografts, representing a promising, novel treatment for AML.
For more information, read the Journal of Hematology and Oncology study.
Age-related epithelial defects limit thymic function and regeneration
Age-related thymic involution involves the emergence of atypical thymic epithelial cell states, which were found to aggregate into nonfunctional clusters, disrupt normal cell signaling and impair the organ's ability to regenerate, particularly following acute injury, thus contributing to decreased immune function in older individuals, according to a Nature Immunology study. The thymus is critical for establishing adaptive immunity but undergoes age-related involution, impairing immune function. It is also sensitive to acute damage, and its regenerative ability declines with age for unknown reasons. Researchers, including Marcel van den Brink, M.D., Ph.D., president of City of Hope Los Angeles and City of Hope National Medical Center and Deana and Steve Campell Chief Physician Executive Distinguished Chair, Anastasia I. Kousa, Ph.D., senior bioinformatics and data science consultant at City of Hope, and Andri Lemarquis, M.D., Ph.D., staff scientist at City of Hope, used advanced techniques like single-cell and spatial transcriptomics, lineage tracing and imaging to study changes in the thymus's nonhematopoietic stromal cells with age. They identified the development of two unusual thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed dense clusters in the thymus, lacked thymocytes and displayed characteristics of epithelial-to-mesenchymal transition with decreased FOXN1 expression. Their analysis showed that aaTECs disrupt normal TEC function by absorbing growth factors, worsening with age and, after acute injury, leading to poor repair of the thymus. These findings highlight a distinct aspect of thymic aging that could be targeted to enhance immune function in the elderly.
For more information, read the Nature Immunology study.
IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model
Combining engineered interleukin-18 (IL-18) secretion with multi-antigen targeting using CAR T cells enhances their ability to eliminate multiple myeloma cells with weak antigen expression by improving immune cell function and reprogramming the tumor microenvironment, according to a Blood study. Multiple myeloma, considered incurable with conventional therapies, has seen promising treatment advances with CAR T cells targeting B cell maturation antigen (BCMA), particularly in the relapsed and refractory settings. However, the effectiveness of these therapies can fail due to weak expression of BCMA on myeloma cells. This study, lead by researchers Dr. van den Brink and Scott E. James, M.D., with contributions from postdoctoral fellows Adhithi Rajagopalan, Ph.D., Sophia Chen, Ph.D., Kousa and Alyssa Massa, B.S., research associate II at City of Hope, investigated whether combining engineered IL-18 secretion with targeting multiple antigens could enhance CAR T cell efficacy against myeloma with low antigen expression. In a syngeneic murine model of myeloma, while CAR T cells targeting BCMA and BAFF-R failed against weakly expressed antigens, IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. Additionally, dual targeting of BCMA and BAFF-R improved CAR T cell effectiveness, enhancing their ability to eliminate larger myeloma burdens. The findings suggest that the combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.
For more information, read the Blood study.
Awards and Honors
John D. Carpten, Ph.D., City of Hope’s chief scientific officer, Irell & Manella Cancer Center Director’s Distinguished Chair and Morgan & Helen Chu Director’s Chair of the Beckman Research Institute, was named a top diversity leader in U.S. health care by Modern Healthcare magazine, which honors influential U.S. health care executives for their commitment to improving equity and inclusion at their organization and in the overall industry. Read the press release here.
Prajish Iyer, Ph.D., postdoctoral fellow in City of Hope’s Department of Systems Biology, was awarded the CLL Society’s 2024 Young Investigator Award, which encourages the next generation of scientific leaders to perform research that is specific to CLL/SLL.
About City of Hope
City of Hope's mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest and most advanced cancer research and treatment organizations in the U.S., and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center that is ranked top 5 in the nation for cancer care by U.S. News & World Report at its core, City of Hope’s uniquely integrated model spans cancer care, research and development, academics and training, and a broad philanthropy program that powers its work. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHopeTM. For more information about City of Hope, follow us on Facebook, X, YouTube, Instagram and LinkedIn.