Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors

• DOI: 10.1016/j.xcrm.2023.101053
• Publication Date: 2023-05-23T22:05:23Z
• Authors: In-Young Jung; Estela Noguera-Or...; Robert Bartoszek; Sierra M. Collins; Erik Williams; Megan Davis; Julie K. Jadlowsky; Gabriela Plesa; Donald L. Siegel; Anne Chew; Bruce L. Levine; Shelley L. Berger; Edmund K. Moon; Steven M. Albelda; Joseph A. Fraietta
• Keywords: Receptors, Chimeric Antigen; Neoplasms; Humans; Cytokines; Immunotherapy; Immunotherapy, Adoptive; Article; 3. Good health

Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malignancies, but their effectiveness in non-hematopoietic cancers remains limited. This study proposes enhancing CAR T cell function and localization in solid tumors by modifying the epigenome governing tissue-residency adaptation and early memory differentiation. We identify that a key factor in human tissue-resident memory CAR T cell (CAR-TRM) formation is activation in the presence of the pleotropic cytokine, transforming growth factor β (TGF-β), which enforces a core program of both "stemness" and sustained tissue residency by mediating chromatin remodeling and concurrent transcriptional changes. This approach leads to a practical and clinically actionable in vitro production method for engineering peripheral blood T cells into a large number of "stem-like" CAR-TRM cells resistant to tumor-associated dysfunction, possessing an enhanced ability to accumulate in situ and rapidly eliminate cancer cells for more effective immunotherapy.