CD38 mediated metabolic axis in anti-tumor T cell immunotherapy
Technology: MUSC researchers have identified T cells with reduced surface expression of NADase CD38 exhibited intrinsically higher NAD+ levels, enhanced oxidative phosphorylation, higher glutaminolysis and altered mitochondrial dynamics that vastly improved tumor control. Inventors identified combining the culture conditions of Th17ILβ+TGFβ (IL6, IL1β, IL23, TGFβlo) and Th1 cells resulted in hybrid Th1/Th17 cells resulted in reduced susceptibility to immunosuppression and increased anti-tumor activity. Intracellular NAD+ levels control anti-tumor potential of hybrid Th1/Th17 cells through the NAD+-Sirt1-Foxo1 axis. Ex vivo programmed hybrid Th1/Th17 cells have increased stemness features along with increased IL-17 and IFN-γ levels. Th1/Th17 hybrid cells activated in the presence of anti-CD38 antibody exhibit reduced CD38 expression, increased cytokine secretion and higher Sirt1 deacetylase activity. Low Sirt1 activity leads to decreased stemness phenotype and Importantly, NAD+ mediated Sirt1 activity regulates acetylation levels of Foxo1, which in turn affects its transcriptional activity and modulates the functional outcome of a T cell immune response. Importantly, mice treated with a combination of anti-CD38 antibody and T cells exhibit durable tumor control and longer survival. Overview: Adoptive T cell therapy (ACT) is a powerful strategy for combating tumor growth, yet the elimination of established tumor is hampered by loss of effector function and/or persistence of T cells. Established strategies to improve effector function and persistence in ACT include duration of expansion, using different cytokines (IL2, IL15, IL21) and employing different helper T or cytotoxic subset of cells programmed ex vivo (Th1 or Tc1, Th9, Th17 or Tc17). Here, MUSC researchers show that T cells programmed ex vivo to display a combination of effector(Th1) and stemness phenotypes(Th17) could enhance the efficacy of ACT. Hybrid Th1/Th17 cells persisted longer while maintaining their effector functions and these hybrid cells are metabolically distinct from Th1 and Th17 cells and depend upon glutaminolysis. Applications: Adoptive T-cell therapies, immunotherapiesAdvantages: The invention will potentially result in cost effective and less complex treatment, ultimately, allowing the widespread application of ACT.Publication: Chatterjee S et al. CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metabolism (2018).Key Words: T-cell, cancer, immunotherapy, CD38, ACT, tumor Inventors: Shikhar Mehrotra and Shilpak ChatterjeePatent Status: PCT published 5.17.18MUSC-FRD Technology ID: P1716
美国
