Cellular therapies are by nature heterogeneous, but regulatory and industry groups have focused on defining products with "critical product attributes" while minimizing heterogeneity or discounting the challenges of obtaining homogenous populations of cells. Understanding the potential risks and benefits of cellular heterogeneity, in both post-transplant and immune effector cell populations, is important information for cell therapy practitioners and researchers alike. In this session, we will hear from speakers with expertise in studying both natural and purposefully designed heterogeneous cellular products and will consider the benefits and technical challenges of obtaining purely homogenous populations of cells.

Dr. Good will present research on factors correlating with response and toxicity outcomes in chimeric antigen receptor (CAR) T cell treatment of large B cell lymphoma (LBCL). In particular, she will discuss the heterogeneity of CAR T cells, focusing on the impact of CAR T regulatory cells (Treg) on efficacy and neurotoxicity. Additionally, Dr. Good will share unpublished findings on T cell intrinsic factors affecting CAR T cell expansion, persistence, and tumor homing, results obtained from lineage tracing studies using endogenous T cell receptor sequences.

As screening tools have improved, we are now able to simultaneously query the entire genome to rapidly pinpoint key genetic nodes that govern human T cell behaviors. Dr. Carnevale will share studies using these screening tools to pressure test T cell therapies and identify loss- and gain-of-function gene targets that can be used to steer T cells into desired therapeutic behaviors. Specifically, she will cover lessons learned and steps being taken to successfully harness pooled screening approaches in T cells. She will also describe how these efforts might be translated to a clinical future where engineered pools of T cell products are created based on a variety of unique gene edits in CD4 and CD8 T cells.

Treg maintain immune homeostasis and are a promising cell therapy to induce transplantation tolerance. Dr. Levings will discuss the challenges to the wider applicability of Treg therapy, including a difficulty in obtaining large numbers of homogeneous cells and the technical ability to maximize the potency of the finalized product. In particular, work towards the scale up and clinical testing of an allogeneic “off the shelf” Treg product, as well as the use of chimeric antigen receptor engineering to maximize Treg potency and tolerance induction, will be discussed.