Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy: A Recent Study

Authors

  • Ning Xu Children’s Cancer Institute, University of New South Wales, Sydney, NSW, Australia and School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia.
  • Benjamin Tse Children’s Cancer Institute, University of New South Wales, Sydney, NSW, Australia and School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia.
  • Lu Yang Children’s Cancer Institute, University of New South Wales, Sydney, NSW, Australia and School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia.
  • Tiffany C. Y. Tang Children’s Cancer Institute, University of New South Wales, Sydney, NSW, Australia and School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia.
  • Michelle Haber Children’s Cancer Institute, University of New South Wales, Sydney, NSW, Australia and School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia.
  • Kenneth Micklethwaite Department of Hematology, Blood Transplant and Cell Therapies Program, Westmead Hospital, Sydney, NSW, Australia and Sydney Cellular Therapies Laboratory, NSW Health Pathology, Sydney, NSW, Australia and Westmead Institute for Medical Research, Sydney, NSW, Australia and Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
  • Alla Dolnikov Children’s Cancer Institute, University of New South Wales, Sydney, NSW, Australia and School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia.

DOI:

https://doi.org/10.9734/bpi/cimms/v3/7736F

Keywords:

CAR T cells, leukemia, AZA, patient-derived xenografts, gene expression

Abstract

Despite the success of chimeric antigen receptor (CAR) T cells in clinical studies, a significant proportion of responding patients eventually relapsed, with the latter correlating with low CAR T cell expansion and persistence.

Using patient-derived xenograft (PDX) mouse models of CD19+ B cell acute lymphoblastic leukemia (B-ALL), we show that priming leukemia-bearing mice with 5-azacytidine (AZA) enhances CAR T cell therapy. AZA given 1 day prior to CAR T cell infusion delayed leukemia growth and promoted CAR T cell expansion and effector function. Priming leukemia cells with AZA increased CAR T cell/target cell conjugation and target cell killing, promoted CAR T cell divisions and expanded IFNy+ effector T cells in cocultures with CD19+ leukemia Nalm-6 and Raji cells. Transcriptome analysis revealed activation of diverse immune pathways in leukemia cells isolated from mice treated with AZA. We propose that epigenetic priming with AZA induces transcriptional changes that sensitize tumor cells to subsequent CAR T cell treatment. Among the candidate genes up- regulated by AZA is TNFSF4 which encodes OX40L, one of the strongest T cell co- stimulatory ligands. OX40L binds OX40, the TNF receptor superfamily member highly specific for activated T cells. TNFSF4 is heterogeneously expressed in a panel of pediatric PDXs, and high TNFSF4 expression correlated with increased CAR T cell numbers identified in co-cultures with individual PDXs. High OX40L expression in Nalm-6 cells increased their susceptibility to CAR T cell killing while OX40L blockade reduced leukemia cell killing.

Conclusion: We propose that treatment with AZA activates OX40L/OX40 co-stimulatory signaling in CAR T cells. Our data suggest that the clinical use of AZA before CAR T cells could be considered.

Published

2022-10-07

How to Cite

Ning Xu, Benjamin Tse, Lu Yang, Tiffany C. Y. Tang, Michelle Haber, Kenneth Micklethwaite, & Alla Dolnikov. (2022). Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy: A Recent Study . Current Innovations in Medicine and Medical Science Vol. 3, 61–87. https://doi.org/10.9734/bpi/cimms/v3/7736F

Issue

Current Innovations in Medicine and Medical Science Vol. 3

Section

Chapters