Abstract 4108: Transient epigenetic reprogramming enhances T-cell proliferation and tumor clearance

Abstract Manufacturing-induced differentiation and accelerated T-cell exhaustion prevent CAR-T therapies from reaching their full therapeutic potential and broader application in the treatment of cancer. To combat these inherent challenges, Turn Biotechnologies is developing its novel and proprietary mRNA-based technology, Epigenetic Reprogramming of Aging (ERATM), to i) preserve a less differentiated status; ii) diminish (or even eliminate) exhaustion; and iii) improve the cytotoxicity and efficacy of CAR-T cell cells. Prolonged CAR-T cell manufacturing process leads to a more differentiated and effector-like phenotype, which is susceptible to accelerated exhaustion in vivo. Unfortunately, clinical evidence suggests that less differentiated and stem-cell like CAR-T products have increased proliferative capacity, reduced exhaustion, and greater efficacy. Additionally, aging is known to compromise T-cell function, reducing chances of CAR-T therapy candidacy for older patients. These compounded effects of manufacturing and aging severely limit CAR-T cell functionality in terms of proliferation, perdurance, and cytotoxic capacity, as well as precluding wider patient access. Leveraging our previous work with other aged human cells, we hypothesized that the transient expression of ERATM factors could impact manufacturing of CAR-T cells by mitigating their differentiation, promoting T stem cell memory (Tscm) phenotype, reducing/eliminating exhaustion, and resetting the epigenetic clock in CAR-T cells. Here, we present preclinical data showing that ERATM treatment of T cells delivered using our proprietary eTurnaTM platform can restore youthful functionality, reducing exhaustion and effects of aging, improving their ability to fight cancer while safely maintaining cellular identity. ERATM -treated T cells have higher proliferation capacity and cytotoxicity upon tumor cell engagement in vitro compared to control cells. Treatment of ERATM -treated T-cells also increases the production of beneficial cytokines to support their survival and cytotoxic activity. Importantly, ERATM treatment preserves T-cell identity and T-cell repertoire, while avoiding unwanted hyperproliferation or clonal expansion. In murine models of hematological cancers, these effects of ERATM treatment on T-cells results in superior cancer cell killing and clearance. These benefits of ERATM technology to current CAR-T manufacturing processes have the potential to translate into the clinic as improved patient outcomes and survival with reduced side effects, thereby expanding patient access and enabling immunotherapies to serve as a first-in-line lifesaving solution. Citation Format: Alec McQuiston, Junbao Yang, Jason Romero, Naveen Bojjireddy, Travis McQuiston, Vittorio Sebastiano, Mustafa Turkoz. Transient epigenetic reprogramming enhances T-cell proliferation and tumor clearance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4108.