UCLA researchers from the Department of Surgery have developed a novel approach to partially reprogram exhausted tumor-infiltrating T cells into stem-like memory T cells capable of durable tumor elimination.
BACKGROUND: Adoptive cell therapies, such as tumor-infiltrating lymphocyte (TIL) therapy involve isolating T cells from a patient’s tumor, expanding them ex vivo, and reinfusing them to eliminate tumor cells. This approach recently received FDA approval in February 2024 as a treatment for patients with advanced cancers. However, the success of TIL therapy depends on the presence and transfer of stem-like memory T cells, which possess the ability to self-renew, proliferate, and sustain anti-tumor responses. A major current limitation is that the majority of tumor-specific T cells are non-functional due to chronic stimulation and suppressive signals within the tumor microenvironment. These signals lead to “T cell exhaustion,” an epigenetically mediated differentiation state characterized by widespread chromatin remodeling that constrains stemness, proliferation, and anti-tumor functions. Previous attempts to restore T cell function have focused on fully reprogramming T cells into induced pluripotent stem cells (iPSCs), followed by differentiation back into T cells. However, both the T cell to iPSC reprogramming and subsequent differentiation into mature T cells are inefficient and technically challenging. Furthermore, full reprogramming risks loss of the tumor antigen specificity. Thus, there is a pressing need for a method to efficiently reprogram T cells into stem-like memory cells while maintaining T cell identity.
INNOVATION: UCLA researchers from the Department of Surgery have developed a strategy that enables partial reprogramming of exhausted T cells to recover stemness and anti-tumor functionality. Through delivery of select transcription factors, tumor-derived CD8 T cells can be partially reprogrammed, resetting the chromatin state and gene regulatory networks that enforce T cell exhaustion. Using this method enables precise stabilization of cells at intermediate differentiation stages. Importantly, this strategy preserves the endogenous T cell receptor sequence, ensuring that tumor antigen specificity is maintained. These cells can then be expanded ex vivo and reinfused into patients, leading to improved outcomes for adoptive cell therapies.
POTENTIAL APPLICATIONS:
- Enhancing TIL therapy for solid tumors
- Improving adoptive cell therapies (e.g. CAR-T)
- Generating stem-like memory T cells
ADVANTAGES:
- Use of CD8 T cells harvested from tumor as adoptive cell therapy has already been FDA approved
- Restores stem-like memory properties to exhausted tumor-specific T cells
- Preserves endogenous tumor-specific T cell receptor sequences
- Avoids inefficient and costly full reprogramming to iPSCs
- Expansion of functional anti-tumor T cells is scalable
DEVELOPMENT-TO-DATE: UCLA researchers have demonstrated that partial reprogramming of exhausted T cells can reset epigenetic programs associated with exhaustion and restore stem-like memory and anti-tumor functionality while preserving T cell identity and antigen specificity.
Related Papers (from the inventors only):
McCaw TR, Restifo NP, Plath K, Crompton JG. Regenerative Immunotherapy for Cancer: Transcription Factor Reprogramming of Tumor-Specific T Cells. Cancers (Basel). 2025 Jul 2;17(13):2225. doi: 10.3390/cancers17132225. PMID: 40647523; PMCID: PMC12248891.
Keywords: T cell exhaustion, adoptive cell therapy, TIL therapy, immunotherapy, stem-like memory T cells, partial reprogramming, tumor-infiltrating lymphocytes, oncology, cancer therapy