Anti-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.