Dissertation Defense: NITYASHREE SHIVAPRASAD, M.S.
T CELL BASED IMMUNOTHERAPY TARGETING FIBROBLAST GROWTH FACTOR RECEPTOR 4 AS A THERAPEUTIC AGAINST RHABDOMYOSARCOMA
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood, has a low mutational burden with few actionable somatic targets. Fibroblast growth factor receptor 4 (FGFR4) is a candidate therapeutic target in RMS, because it is either mutated or overexpressed in RMS and it plays a key role in RMS cell growth and proliferation. Here we use multiple, complementary methods to demonstrate that cell surface FGFR4 expression is greater in RMS tumors than in normal tissues. We then generated a chimeric antigen receptor (CAR) T cell specific for FGFR4 by screening for single chain variable fragments (scFv) that specifically recognized the extracellular domain of FGFR4. We identified an scFv with high affinity for FGFR4, m410. We engineered an FGFR4-specific CAR T cell by incorporating this m410 scFv into a second generation lentiviral (LV) based CAR backbone. In, RH30_19, which is a patient-derived RMS cell line engineered to express a truncated version of CD19, the m410 FGFR4 CAR showed cytotoxic activity comparable to that of the canonical CD19 CAR, and produced cytokines consistent with T cell activation, including gamma interferon and interleukin 2. m410 CAR also eliminated RMS cells in metastatic xenograft models. In conclusion, FGFR4 is a viable target for immune-based CAR-T cell therapy in RMS and m410 CAR merits further evaluation as a potential therapeutic for metastatic rhabdomyosarcoma.
Monday, June 17, 2019 at 1:30pm
Building D, Warwick Evans
4000 Reservoir Road, N.W., Washington