@article{Identifying:5220,
      recid = {5220},
      author = {Hu, Yifei},
      title = {Identifying, Investigating, and Modulating Anti-CD19 CAR T  Cells for Large B-Cell Lymphoma},
      publisher = {The University of Chicago},
      school = {Ph.D.},
      address = {2022-12},
      pages = {164},
      abstract = {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.},
      url = {http://knowledge.uchicago.edu/record/5220},
      doi = {https://doi.org/10.6082/uchicago.5220},
}