UCSF

Synthetic immunology harnesses the power of genetic engineering to endow immune cells with novel biological capabilities. Chimeric antigen receptor (CAR) T cells exemplify the successful translation of synthetic immunology into clinical practice, dramatically improving survival rates for certain cancer patients and paving the way for curative treatments where none existed before. While synthetic immunology holds immense promise for harnessing the immune system's antitumor capabilities, its application in solid tumors faces significant challenges. In vivo, CAR T cells interact with the suppressive tumor microenvironment and the systemic and local endogenous immune system and often fail to initiate sufficient persistence, potency, penetrance, or proliferative capacity. Eliciting robust antitumor immune responses to a complex heterogeneous solid tumor will likely require initiation of a broad immune response, suggesting that therapies that target a single arm of the immune system, even with the most potent synthetic tools, may fall short. Systems immunology evaluates the emergent properties arising from the holistic evaluation of the immune system, encompassing all immune cell types and immune communication such as cytokines and chemokines across many tissues. In this thesis we use systems immunology approaches to evaluate how two synthetic immune enhancements, CAR T cells with CARD11-PIK3R3 and constitutively secreted IL27, function in the context of a complete immune system. We elucidate how these novel synthetic enhancements interact with and recruit endogenous immune cells, and explore key factors driving CAR T potency in the solid tumor microenvironment. Beyond T cells, engineering other immune cell types with synthetic capabilities holds immense potential. This thesis also investigates the development of a platform for hematopoietic stem cell (HSC) engineering, enabling the rapid engineering of all immune cells or novel immune cell lineages. Additionally, we applied systems immunology approaches to gain a deeper understanding of the natural antiviral response to SARS-CoV-2 in hospitalized patients through longitudinal peripheral blood samples. Collectively, this dissertation explores natural and engineered immune responses in both human clinical samples and mouse solid tumor models to better delineate the characteristics of effective and ineffective immune responses, paving the way for the development of more efficacious therapies in the future.