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Next Generation CD19 CAR-T for the treatment of lymphoid malignancies

Investigators: Preet Chaudhary; Jianming Xie

Chimeric antigen receptor modified T cells (CAR-T) and Bispecific T cell engager (BiTE; such as Blinatumomab) represent two complementary approaches to adoptive cancer immunotherapy that have shown extremely promising results for the treatment of B cell malignancies that express CD19 antigen. One of the limitations of CAR-T cells, however, is their lack of in vivo persistence which has been attributed, in part, to immune response against their antigen binding domain that is generally derived from murine monoclonal antibodies. We have generated a CD19-CAR containing a humanized antigen binding domain and have shown its superiority to CD19-CAR in current clinical trials in preclinical models of B cell malignancies. Multiple Myeloma (MM) and Primary Effusion Lymphoma (PEL) are two malignancies that share similar gene expression profiles and response to therapy. Both these malignancies express undetectable level of CD19 antigen and were believed to be not candidate for CD19-directed CAR-T or BiTE. However, this notion has been disproved by recent studies in which complete or near complete remissions have been obtained in myeloma patients with CD19-CAR-T cells. These responses have been attributed to either low level expression of CD19 on myeloma cells that is sufficient to be targeted by CAR-T cells or to the expression of CD19 on a minor population of disease propagating cells (i.e. myeloma stem cells). The overall goal of this proposal is to test the hypothesis that MM and PEL are suitable candidates for CD19-directed therapies through the following specific aims. In aim 1, we will test the efficacy of our humanized CD19 CAR and Blinatumomab (BiTE) against MM and PEL cells in vitro and determine the optimal T cell population for expression of CAR. We will also conduct mechanistic study of immunological synapse between CAR and CD19. In aim 2, we will test the in vivo efficacy of humanized CD19 CAR against PEL and MM. As Blinatumomab is already FDA approved and CD19-CAR are likely to get FDA approval in the near future, these preclinical studies will provide the basis for clinical testing of these modalities in PEL and MM in the near future. These studies will also inform the design of future clinical trials of the humanized CAR in B cell malignancies, MM and PEL.