000005220 001__ 5220
000005220 005__ 20251007025228.0
000005220 0247_ $$2doi$$a10.6082/uchicago.5220
000005220 037__ $$aTHESIS$$bDissertation
000005220 041__ $$aeng
000005220 245__ $$aIdentifying, Investigating, and Modulating Anti-CD19 CAR T Cells for Large B-Cell Lymphoma
000005220 260__ $$bUniversity of Chicago
000005220 269__ $$a2022-12
000005220 300__ $$a164
000005220 336__ $$aDissertation
000005220 502__ $$bPh.D.
000005220 520__ $$aAnti-CD19 chimeric antigen receptor (CAR) T-cell therapy has improved treatment options for patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). During anti-CD19 CAR T-cell therapy, the patient’s T cells are transduced with an anti-CD19 CAR – a synthetic immunoreceptor that directs the T cell to recognize, activate, proliferate, and kill in response to CD19+ lymphoma cells. Despite encouraging ~40% complete response rates, non-responders generally succumb to their disease. Hence, improved CAR T-cell therapy formulations with higher response rates are urgently needed in the clinic. My research questions, experiments, findings, and conclusions in this dissertation are organized around this central clinical problem. In this body of work, after providing a brief introduction to CD19-directed CAR T-cell therapy (Section I), I first reviewed the existing methods used by CAR T-cell scientists to detect and investigate the CAR across the genomic, transcriptomic, proteomic, and organismal levels (Section II). With this background in mind, I designed, constructed, and validated antigen multimers as specific, sensitive, precise, and multifunctional high-avidity reagents to detect the CAR at the proteomic level (Section III). Using antigen multimers to sort CAR T cells from patient biospecimens for longitudinal, single-cell, multi-omics analysis, I next reported that CD28-costimulated CAR T cells undergo two distinct clonal expansion stages in vivo, each of which is dominated by unique phenotypes (Section IV). Finally, using findings from comparing the single-cell data from complete responders and non-responders, I leveraged the type I interferon/interferon response factor 7 pathway for increasing CAR T-cell efficacy in vitro (Section V). Collectively, these findings are expected to introduce a better CAR-detection reagent for CAR T-cell scientists, improve how we understand CAR T-cell expansion and persistence, and synergize CAR T-cell therapy with an existing pharmaceutical in vitro. Ultimately, I hope these efforts will translate into improved CAR T-cell therapy formulations and longer progression-free survival for patients with r/r DLBCL.
000005220 540__ $$a© 2022 Yifei Hu
000005220 542__ $$fCC BY-NC-ND
000005220 650__ $$aImmunology
000005220 650__ $$aBiology
000005220 650__ $$aBioengineering
000005220 653__ $$aantigen multimer
000005220 653__ $$achimeric antigen receptor
000005220 653__ $$ainterferon
000005220 653__ $$alymphoma
000005220 653__ $$asequencing
000005220 653__ $$atwo-stage differentiation
000005220 690__ $$aBiological Sciences Division
000005220 690__ $$aPritzker School of Medicine
000005220 691__ $$aInterdisciplinary Scientist Training Program
000005220 7001_ $$aHu, Yifei$$uUniversity of Chicago
000005220 72012 $$aJun Huang
000005220 72014 $$aErin J. Adams
000005220 72014 $$aJustin P. Kline
000005220 72014 $$aHans Schreiber
000005220 8564_ $$93d6f8de4-7018-4d96-99f4-546a112f1b51$$s17434753$$uhttps://knowledge.uchicago.edu/record/5220/files/Hu_uchicago_0330D_16649.pdf$$ePublic
000005220 909CO $$ooai:uchicago.tind.io:5220$$pDissertations$$pGLOBAL_SET
000005220 983__ $$aDissertation