Research Focus: Multivalent immunomodulators for CAR T cell manufacturing and T cell-engager immunotherapy

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 bispecific 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 improve CAR T cell fitness or to enhance BiTE-mediated cytolysis of cancer cells represent an urgent and unmet clinical need.

For both BiTEs and CAR T cells, lack of prolonged survival post-treatment may be partly attributed to CD19-antigen escape and suboptimal T-cell phenotype. Efforts to target alternative B-cell markers like CD20 and CD22 with either treatment modality are at nascent stages of development. To address these limitations, we have designed multivalent immunomodulators (MIMs) for use (1) as a novel BiTE compound or (2) as an artificial antigen presenting cell (aAPC) reagent for inclusion within the CAR T cell manufacturing process. Recent work from the Dreaden Lab at Emory University demonstrated 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 (termed BiTEokines) with lytic activity comparable to FDA-approved immunotherapies. In my work, I will apply this high-throughput assembly and screening approach to both further improve the tumor cell clearance achievable by the BiTEokine platform and develop a novel aAPC reagent for production of CAR T cells with superior anti-tumor phenotypes.

Relevant Publications:

• Do P, Perdue LA, Chyong A, Hunter R, Dougan J, Henry CJ, Porter CC, Dreaden EC. Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia. ACS Comb. Sci. 2020;22(10):533-541
• Uricoli B, Birnbaum LA, Do P, Kelvin JM, Jain J, Costanza E, Chyong A, Porter CC, Rafiq S, Dreaden EC. Engineered Cytokines for Cancer and Autoimmune Disease Immunotherapy. Adv. Healthc. Mater. 2021;10(15):2002214