Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy: A Recent Study | Chapter 6 | Current Innovations in Medicine and Medical Science Vol. 3

 Despite the success of fantastic antigen receptor( Auto) T cells in clinical studies, a significant proportion of responding cases ultimately regressed, with the ultimate relating with low Auto T cell expansion and continuity.

Using case- deduced 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 Auto T cell remedy. AZA given 1 day previous to Auto T cell infusion delayed leukemia growth and promoted Auto T cell expansion and effector function. Priming leukemia cells with AZA increased Auto T cell/ target cell conjugation and target cell payoff, promoted Auto T cell divisions and expanded IFNγ effector T cells in cocultures with CD19 leukemia Nalm- 6 and Raji cells. Transcriptome analysis revealed activation of different vulnerable pathways in leukemia cells insulated from mice treated with AZA. We propose that epigenetic priming with AZA induces transcriptional changes that acclimatize excrescence cells to posterior Auto T cell treatment. Among the seeker 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 largely specific for actuated T cells. TNFSF4 is heterogeneously expressed in a panel of pediatric PDXs, and high TNFSF4 expression identified with increased Auto T cell figures linked inco-cultures with individual PDXs. High OX40L expression in Nalm- 6 cells increased their vulnerability to Auto T cell payoff while OX40L leaguer reduced leukemia cell payoff.

Conclusion We propose that treatment with AZA activates OX40L/ OX40co-stimulatory signaling in Auto T cells. Our data suggest that the clinical use of AZA before CAR T cells could be considered.

Author(s) Details:

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.

Please see the link here: https://stm.bookpi.org/CIMMS-V3/article/view/8380