Beckman Research Institute of the City of Hope Archives

2017

Young Investigator

Dr. Leo Wang

Duarte, CA

Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized the way we think about and treat hematologic malignancies. However, application of this transformative technology to solid tumors has been disappointing, largely because the solid tumors create a local microenvironment for themselves that enables their immune evasion. Although the precise mechanisms responsible are poorly understood, it is clear that myriad cellular, soluble, and anatomic inputs contribute to make solid tumors resistant to immune attack.

As a result, initial efforts to use CART cells in solid tumors have been underwhelming. Attempts have been made to improve CART cell potency through a variety of mechanisms. These efforts, however, do not address the problem of CART cell persistence. Indeed, despite our recent very encouraging clinical results using IL 13Ra2-targeted CART cells in glioblastoma multiforme, we have found that CAR T cells vanish within 7 days of administration, thus necessitating frequent delivery. Furthermore, we have shown that CART cells in cell culture rapidly lose the ability to kill brain tumor cells.

The goals of this project are:

To understand why CART cells disappear quickly from pediatric brain tumors, limiting their utility;
To use cutting-edge mass spectrometry to identify proteins that can make CART cells persist for longer without losing their potency;
To engineer those proteins into CART cells to improve their persistence and efficacy.

Many strategies for improving persistence have achieved limited utility, but there are significant obstacles to their widespread adoption .. Our group, in particular, manufactures CART cells from central memory T cells (Tern), as we have found that these cells are more persistent once transduced. However, this improves persistence at the expense of anti-tumor potency. Fundamentally, cellular persistence is a cell-intrinsic process; outside-in signaling ultimately must trigger an internal program of protein expression and activation that results in longevity. However, it is well documented that gene expression programs of naive and memory T cells are highly overlapping. Thus, their significant biological differences must be explicable at a protein level. Identifying the protein-level events responsible for T cell persistence will be critical to solving the problem of how to keep CART cells from disappearing. Application of comprehensive mass spectrometry-based proteomic approaches to this problem will yield attractive strategies for improving CART cell therapies.