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Biaggio Uricoli
BME PhD Proposal Presentation
Date:2022-03-24
Time: 1:00 PM – 2:30 PM
Location / Meeting Link: https://us02web.zoom.us/j/84784733373?pwd=RW5mRU8vZjkyMUNBSkJIVlhOT0xkdz09 Meeting ID: 847 8473 3373 Passcode: uj5LUs
Committee Members:
Erik Dreaden, PhD (advisor) Sarwish Rafiq, PhD Christopher Porter, MD Khalid Salaita, PhD Wilbur Lam, MD, PhD
Title: Multivalent immunomodulators for CAR T cell manufacturing and T cell-engager immunotherapy
Abstract: Cancer immunotherapy, a treatment strategy in which immune cells are directed to eliminate cancer cells, has rapidly established itself as a novel and growing treatment modality for a range of malignancies. Two forms of cancer immunotherapy, chimeric antigen receptor (CAR) T cells and bi-specific T cell engagers (BiTEs), induce the clearance of malignant cells via CAR- or drug- induced T cell cytolysis, respectively. These treatments have generated promising initial responses in patients with B cell malignancies, but often fail to achieve durable treatment responses following therapy. Methods to thus improve CAR T cell fitness or to enhance BiTE-mediated cytolysis of cancer cells represents an urgent and unmet clinical need. In recent work, our laboratory developed a strategy for the rapid assembly and screening of compositionally diverse libraries of IgG-conjugated, multivalent immunomodulating nanoparticles, employing it for the identification of cytokine-modified BiTEs with lytic activity comparable to FDA-approved immunotherapies. Here, we propose to adapt this rapid assembly and screening approach to identify multivalent micro- and nano- particles that (i) select for potent and long-lived subsets of CAR T cells during manufacturing and (ii) act as efficacious BiTE immunotherapies in models of B cell leukemia with antigen escape. In this work, we propose to study the therapeutic impact of these new compounds on (i) the targeting, persistence, and efficacy of CAR T cell immunotherapy in mouse models of B cell malignancies and (ii) the efficacy in multi antigen-targeting BiTEs in mouse models of leukemia with immunotherapy resistance due to antigen loss. Following completion, this work will generate new immunomodulators with the potential to improve treatment outcomes in patients receiving CAR T cell immunotherapy or those with immunotherapy-resistant disease.
