Our laboratory is interested in the development of chimeric antigen receptors (CAR) to target hematologic and solid tumor malignancies. Recent clinical trials have demonstrated the potential of targeting the CD19 antigen for B cell malignancies with CAR T cells. These trials have demonstrated that an acute B cell malignancy, B cell acute lymphoblastic leukemia (B-ALL), is much more sensitive to autologous CD19 CAR T cells than indolent B cell malignancies. These early Phase I trials, while exciting, leave many questions to be answered, which oftentimes is best done in pre-clinical animal models. There are three major research areas in the laboratory.
1. We have created a syngeneic animal mouse model of B-ALL using the Eμ-ALL cell line, which was derived from the Eμ-myc transgenic mouse prone to B cell malignancies. The Eμ-ALL mouse model allows us to evaluate important mechanistic questions involving targeting B cell malignancies with CD19 CAR T cells in a relevant animal model. Complementary questions will be evaluated using primary patient samples.
2. We recognize that targeting CD19, and thereby B cell malignancies, is just the beginning of this new field and we are developing new CARs against other hematologic and solid tumor malignancies. This work will involve the creation of new single chain variable fragments that encode tumor antigen-specificity. This will be followed by in vitro and in vivo validation of these new CARs.
3. It is clear from the initial clinical experience using CAR T cells that there are significant toxicities that are associated with this therapy, which have been classified as a cytokine release syndrome (CRS). Therefore we are interested in developing a rational mouse model of the CRS and identify possible interventions that may ameliorate the CRS, but not ameliorate T cell directed killing of tumor cells.