Table 1.

A framework for addressing the major clinical challenges of CAR T-cell therapy using systems immunology approaches^*

Clinical challenge	Systems immunology approach
Biomarker discovery	Profiling of serum, tumor, and immune factors prior to infusion Leveraging pre-existing immunological data from other domains using principles of transfer learning
Pre-treatment effects and identifying combination therapies	Modeling the perturbation of immune cell populations in the tumor and peripheral compartments Development of computational methods that account for gene-gene as well as cell-cell interactions between tumor and immune populations
Understanding T-cell aspects to therapy failure	Joint analysis of endogenous and CAR T-cell populations in circulation and in the tumor microenvironment Characterization of the interactions between T-cells and suppressive cell populations
Expanding CAR T-cell therapy to solid tumors	Joint molecular profiling and imaging of cells in the tumor-immune microenvironment Leveraging data generation by ongoing consortia to understand activating and suppressive immune factors
Antigen escape and novel target identification	Understanding genetic and non-genetic causes of antigen loss Systematic identification of candidate targets in tumor and normal tissues
Addressing major toxicities	Understanding immune cell interactions, particularly interactions between lymphoid and myeloid phenotypes Investigating the interactions between CAR T-cells, cytokines, and organ-specific cell types

^*Completed and ongoing clinical trials have brought to light a number of major clinical challenges for CAR T-cell therapy moving forward: Biomarker discovery, pre-treatment effects and identifying combination therapies, understanding T-cell aspects to therapeutic failure, expanding CAR T-cell therapy to solid tumors, antigen escape and novel target identification, and addressing major toxicities. For each of these major clinical challenges, the tools of systems immunology provide a strategy to better understand the complex interactions between tumor and immune cell populations, providing a path forward for the next generation of cellular therapeutics.