T-cell therapy can transform cancer treatment, but only if T cells remain both active and specific in targeting cancer cells. And T cells too often become exhausted and inactive or simply disappear.

“One of the issues limiting current approaches to T-cell-based immunotherapies is if you infuse CAR T cells into a patient and those T cells become dysfunctional, either by losing the ability to proliferate or losing the ability to respond effectively to the cancer,” said Caitlin Zebley, MD, PhD, assistant member in Bone Marrow Transplantation & Cellular Therapy at St. Jude Research Children’s Research Hospital. “Epigenetic engineering strategies can help overcome these limitations to create a durable T-cell-based immunotherapy. ”

Zebley will chair a concurrent session on Manipulation of T Cell Signaling and Epigenetics in Cell Therapy at 10:30 a.m. on Feb. 14 in Ballroom C. And while she is working on epigenetic strategies to improve T-cell durability and functionality, T-cell-based therapeutic approaches are expanding on multiple fronts.

One of those fronts is improving the specificity of T-cell receptors. The more specific the receptor, the more effective the T-cell therapy.

Sylvain Simon, PhD, post-doctoral research fellow at the Fred Hutchinson Cancer Center, will explore the latest approaches to developing more effective hybrid T-cell receptors (TCRs). His work is based on the realization that not all T cells are created equal when it comes to immunotherapy.

Some T-cell populations can be modified to express specific genes that can redirect and better focus T-cell specificity to cancer cells. Simon’s talk on sensitive and bispecific chimeric TCRs will describe work developing hybrid TCRs to improve adoptive T-cell therapy.

Tumor immune escape is a problem common to all forms of immunotherapy, including CAR T-cell therapy. Ongoing research into the fundamentals of T-cell biology is producing new generations of CARs with improved efficacy.

Maria Caterina Rotiroti, PhD, research fellow in pediatrics at the Dana-Farber Cancer Institute, is working on innovative strategies to prevent tumor immune escape following adoptive transfer of CAR T cells. She will discuss current work using proximal T-cell signaling pathways to enhance CAR T-cell activity and function.

T-cell exhaustion is a familiar problem. Recognizing that T-cell exhaustion stems from epigenetic changes, Zebley is developing countervailing epigenetic strategies that can confer long-lived immunological activity.

Her most recent work stemmed from a clinical study with programmed cell death ligand-1 (PD-L1) therapy for myelodysplastic syndrome (MDS). A subset of MDS patients with a single mutation common to both the myeloid compartment and T-cell compartment had improved overall survival.

“That prompted us to ask if disruption in T cells could actually be helping those T cells respond to immunotherapy,” Zebley explained. “Then we figured out that it was a novel regulator of the epigenetic checkpoint between progenitor-exhausted and terminally exhausted T cells. You can think about this as a potential translational strategy moving forward.”

Manipulation of T Cell Signaling and Epigenetics in Cell Therapy and other sessions at the 2025 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT® and CIBMTR® will be available for on-demand viewing for registered attendees following the live presentation.

“What is so exciting about this session is that it spans all the way from very fundamental discovery to cutting-edge clinical developments,” Zebley said. “We will be talking about very translationally relevant science that will be the future of clinical trials.”