CD38 mediated metabolic axis in anti-tumor T cell immunotherapy

Description:

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.

Hybrid Th1/17 Cells Exhibit Superior Anti-Tumor Response

(A) Schematic presentation of the experimental strategy and the differences observed in tumor growth when subcutaneously established B16-A2 tumor in HLA-A+ mice (n = 8 mice/group) were treated by adoptively transferring tyrosinase reactive TIL1383I TCR transgenic T cells differentiated to Th1, Th17, and hybrid Th1/17 cells. Data demonstrate mean tumor size at each time point in one of the three experiments with similar results.

(B) C57BL/6 mice with 10 day subcutaneously established B16-F10 melanoma tumor untreated or treated by transferring 0.5 × 106 TRP-1 Th1/17 cells. The treated group was subdivided to administer 100 μg neutralizing antibody against IFNγ, IL17, or isotype control Ab intraperitoneally every alternate day. Tumor growth curve n=4

(C) C57BL/6 Ly5.1+ recipients were injected (i.v.) with 0.5 × 106 luciferase-transduced B16-F10 (B16-Fluc) and following lympho-depletion (sub-lethally irradiation with 500 cGy) on day 6. Groups of mice were adoptively transferred with either 0.25 × 106 TRP-1 Th1, Th17, or Th1/17 cells on day 7. Survival and tumor growth were followed with bioluminescent imaging. On day 80, recipient mice were re-challenged by injecting 0.5 × 106 B16-Fluc tumors.

 

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, immunotherapies

Advantages: 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 Chatterjee

Patent Status: PCT/US2017/060537 with national stage applications filed in:

              US20190255111A1

              EP3538112

              CA App. Serial no. 3,043,356

 

MUSC-FRD Technology ID: P1716

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Shan Panneer Selvam
MUSC Foundation for Research Development
panneers@musc.edu
Inventors:
Shikhar Mehrotra
Shilpak Chatterjee
Keywords:
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