BAFF-R CAR T cell therapy for ALL

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PROJECT SUMMARY B-cell acute lymphoblastic lymphoma (B-ALL) is a neoplasm of B-cell lymphoid precursors that typically affects children, but occurs in adults as well. While intensive multi-agent chemotherapy is highly effective in the pediatric population, outcomes remain poor in adults and high-risk patients. The recent introduction of blinatumomab and CD19-directed CAR T therapy has transformed the care of patients with relapsed and refractory (r/r) B-ALL. However, an increasing number of reports describe a high rate of post-treatment relapse due to acquired resistance to these immunotherapies, notably via down-regulation or loss of CD19 surface expression. CAR T cells that were recently developed against another target, CD22, showed similar shortcomings with relapses associated with diminished antigen expression. The search for alternative targets is therefore essential to overcoming antigen escape. To address this issue, we have developed CAR T cells against a new B-ALL target, the B-cell activating factor receptor (BAFF-R). BAFF-R is a marker of B cells that is also functionally expressed in B-ALL, including in patients with CD19-negative relapse. Although one of BAFF-R’s ligands (BAFF) has been successfully targeted for the treatment of autoimmune diseases, we are the first to have developed BAFF-R CAR T cells that are effective against B-cell malignancies in vivo, including in CD19-negative mouse models. Because BAFF-R is a critical regulator of B-cell function and survival, we can expect that the tumor’s ability to escape therapy by down-regulation of BAFF-R will be limited. While we anticipate clinical efficacy of BAFF-R CAR T cell therapy, dual targeting of CD19 and BAFF-R can prevent the emergence of resistance and improve clinical outcomes. Therefore, we are also developing bispecific CD19- BAFF-R CAR T cells that we aim to rapidly translate from the bench to the bedside. In Specific Aim 1, we will evaluate BAFF-R CAR T cell therapy in a first-in-human clinical trial in patients with r/r B-ALL who are ineligible for or have failed prior CD19-directed therapy. The trial, currently open at City of Hope, will use our TN/MEM- derived manufacturing platform, which yields a naïve/memory T-cell enriched T cell product and has shown remarkable efficacy and tolerability in B-ALL. We will conduct extensive correlative studies using cutting-edge technologies, such as assessing the kinetics of the CAR T cells and that of diverse cytokines, therapeutic effect, and potential mechanisms of relapse and antigen escape. In Specific Aim 2, we will establish the therapeutic efficacy of bispecific CD19-BAFF-R CAR T cells against mixed (CD19-negative + BAFF-R- negative) B-ALL tumor models that mimic the heterogenous tumor phenotype leading to resistance. We will also perform extensive testing of cGMP-grade bispecific CD19-BAFF-R CAR T cells that is required prior to submission of an IND application to the FDA. Our proposal addresses the urgent need for new therapeutic options in patients with r/r B-ALL and could also benefit patients with other B-cell malignancies.