Biaggio Uricoli
BME PhD Defense Presentation

Date: 2023-12-05
Time: 1:00 PM - 2:30 PM
Location / Meeting Link: EBB 5029 / https://us06web.zoom.us/j/87590494866

Committee Members:
Erik Dreaden, PhD (Co-Advisor); Krishnendu Roy, PhD (Co-Advisor); Wilbur Lam, MD/PhD; Christopher Porter, MD; Sarwish Rafiq, PhD; Khalid Salaita, 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, represents an established therapeutic approach with a growing range of modalities and addressable disease indications. 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 can fail to achieve durable treatment responses following therapy. Methods to thus improve CAR T cell persistence or to enhance BiTE-mediated cytolysis of cancer cells represent an urgent and unmet clinical need. To address this need, 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 adapted this rapid assembly and screening approach to identify multivalent micro- and nano- particles that 1) selectively expanded efficacious and long-lived subsets of CAR T cells during manufacturing and 2) acted as potent BiTE immunotherapies in cell culture cytotoxicity assays incorporating B cell cancers. In this work, we studied the therapeutic impact of these new compounds 1) on the targeting, persistence, and efficacy of CAR T cell immunotherapy in mouse models of B cell malignancies and 2) as liposomal and iron oxide BiTEs for induction of malignant B cell death ex vivo. Following completion, this work presented a multivalent particle discovery platform for the identification of novel immunotherapeutics and generated new immunomodulators with the potential to improve treatment outcomes for patients with B cell malignancies.