An engineered IL-2 partial agonist promotes CD8+ T cell stemness

• Published in: Nature (London) Vol. 597; no. 7877; pp. 544 - 548
• Main Authors: Mo, Fei, Yu, Zhiya, Li, Peng, Oh, Jangsuk, Spolski, Rosanne, Zhao, Liang, Glassman, Caleb R., Yamamoto, Tori N., Chen, Yun, Golebiowski, Filip M., Hermans, Dalton, Majri-Morrison, Sonia, Picton, Lora K., Liao, Wei, Ren, Min, Zhuang, Xiaoxuan, Mitra, Suman, Lin, Jian-Xin, Gattinoni, Luca, Powell, Jonathan D., Restifo, Nicholas P., Garcia, K. Christopher, Leonard, Warren J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.09.2021; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/109; 13/21; 13/95; 45; 45/15; 45/23; 631/250/127; 631/250/580; 64/60; Acute lymphoblastic leukemia; Adoptive transfer; Agonists; Animal models; Animals; Anticancer properties; Antigens; Cancer immunotherapy; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell differentiation; Cell Differentiation - drug effects; Chimeric antigen receptors; Cytokines; Differentiation; Drug Partial Agonism; Effector cells; Epigenetics; Genes; Glucose; Hepatocyte nuclear factor 1; Humanities and Social Sciences; Immunotherapy; Interleukin 2; Interleukin-2 - agonists; Interleukin-2 - analogs & derivatives; Interleukin-2 - chemistry; Interleukin-2 - genetics; Leukemia; Lymphocytes; Lymphocytes T; Maintenance; Melanoma; Melanoma - metabolism; Metabolism; Mice; Mitochondria; Mitochondria - drug effects; multidisciplinary; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - pharmacology; Mutation; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Receptors; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Robustness; Science; Science (multidisciplinary); Stat5 protein; STAT5 Transcription Factor - metabolism; Stem cells; Stem Cells - cytology; Stem Cells - drug effects; T cell receptors; T Cell Transcription Factor 1 - metabolism; Transcription factors; Translational Research, Biomedical; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03861-0

Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients 1 . Both the number of transferred T cells and their differentiation state are critical determinants of effective responses 2 , 3 . T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells 4 , 5 and lower therapeutic efficacy 6 , whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial 7 . Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8 +  T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8 + T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential. H9T, an engineered IL-2 partial agonist, promotes the expansion of T cells while maintaining a stem-cell-like state, leading to improved efficacy of adoptive cell therapy in mouse models of melanoma and acute lymphoblastic leukaemia.