Celeste Richardson

Pre-clinical validation of B cell maturation antigen (BCMA) as a target for T cell immunotherapy of multiple myeloma

Multiple myeloma has a continued need for more effective and durable therapies. B cell maturation antigen (BCMA), a plasma cell surface antigen and member of the tumor necrosis factor (TNF) receptor superfamily, is an attractive target for immunotherapy of multiple myeloma due to its high prevalence on malignant plasma cells. The current work details the pre-clinical evaluation of BCMA expression and development of a chimeric antigen receptor (CAR) targeting this antigen using a fully human single chain variable fragment (scFv). We demonstrate that BCMA is prevalently, but variably expressed by all MM with expression on 25–100% of malignant plasma cells. Extensive Immunohistochemical analysis of normal tissue expression using commercially available polyclonal antibodies demonstrated expression within B-lineage cells across a number of tissues as expected. Based upon the highly restricted expression of BCMA within normal tissues, we generated a set of novel, fully human scFv binding domains to BCMA by screening a naïve B-cell derived phage display library. Using a series of in vitro and pre-clinical in vivo studies, we identified a scFv with high specificity for BCMA and robust anti-myeloma activity when used as the binding domain of a second-generation CAR bearing a CD137 costimulatory domain. This BCMA-specific CAR is currently being evaluated in a Phase 1b clinical study in relapsed and refractory MM patients (NCT02546167).

399. Evaluation of CD123 Targeting CART Cells in Non-Human Primates

The CAR-T platform has provided an exceptionally potent means to treat cancers that have proven resistant to standard treatments. This potency, however, can work against normal tissue as well. Some clinical trials have identified adverse consequences as a result of CAR-T cell targeting of critical normal tissue. To enable as many targets as possible using the CAR-T cell approach, it is important to understand the potential liabilities of those targets in normal tissues prior to initiating clinical trials. CD123, the IL-3 receptor alpha subunit, is a viable target for treatment of acute myeloid leukemia, as it is expressed highly on primary AML blasts. We have previously shown that, in mice transplanted with human hematopoietic stem cells, CD123 targeting CAR T-cells eradicated these precursors and, in turn, normal hematopoiesis (Gill et al 2014xPreclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Gill, Saar, Tasian, Sarah K., Ruella, Marco, Shestova, Olga, Li, Yong, Porter, David L., Carroll, Martin, Danet-Desnoyers, Gwenn, Scholler, John, Grupp, Stephan A., June, Carl H., and Kalos, Michael. Blood. 2014; 123: 2343–2354Crossref | PubMed | Scopus (120)See all ReferencesGill et al 2014). Here, we describe an animal model developed to address the potential effects of targeting CD123 on non-hematopoietic tissue, namely endothelial cells that are found to express significant levels of CD123. An scFv that bound cynomolgus monkey CD123 was identified and a chimeric lentivirus that efficiently transduced monkey PBMCs was developed. Cells were demonstrated to be active in vitro and dosed into monkeys, after which cellular expansion was observed. In vivo safety assessments and histopathology results will be discussed.