CD38 mediated metabolic axis in anti-tumor T cell immunotherapy


Tumor-induced immune suppression constitutes an important barrier for effective anti-tumor immunity and immunotherapy in cancer.  MUSC inventors’ preliminary data suggests that targeting CD38 expression on anti-tumor T cells result in decreased NAD+ levels, which has been shown to result in increased longevity and epigenetically regulating the genes involved in aging. With this rationale, the inventors identified the ex vivo conditions to program the T cells to a hybrid Th1/17 phenotype that exhibits lower CD38 expression and higher NAD+ levels. Thus, the inventors propose a novel role of CD38 regulated NAD+ in shaping T cell function and memory. Further, using lower CD38 expression as biomarker to identify NADhi T cells or reprogramming the T cells with NAD+ will lead to reliable, less toxic and cost-effective adoptive T cell therapy (ACT) not only for melanoma but other tumors as well. We also propose that targeting CD38 expression using anti-CD38 antibody (either as monotherapy or in combination with ACT or anti-PD1) will lead to more stable and better long-term tumor control.


Overview: Adoptive T-cell therapy (ACT) is a powerful strategy for controlling cancer. Yet, elimination of established tumor is hampered either due to loss of T-cell effector function or its survival. Therefore, strategies to increase persistence and sustain effector function of the anti-tumor T cells in the tumor bearing host are of immense importance. Several strategies involving duration of expansion, or using different cytokines and employing different helper T (Th) or cytotoxic T (Tc) subsets programed ex vivo have been tested to improve the efficacy of ACT. While each one of these strategies results in a unique effector signature and show an incremental improvement in tumor control, efforts to incorporate optimal anti-tumor attributes of these strategies into one effector population have not yet been successful.


Different cytokine cues direct naive CD4 T cells to acquire distinct functional and survival traits that differentially affect their anti-tumor response. For instance, Th1 cell secretes IFNy, but due to their poor survivability are less efficacious than Th17 cells with "stem cells like" characteristics in controlling tumor. Although Th17 cells have survival advantage in the tumor-bearing host, the anti-tumor property is solely dependent on their ability to secrete IFNy. Thus it is apparent that defining conditions that would preserve "effector cytokine function" of Th1/Tc1 cells along with the "stem cell-like phenotype" of the Thl17/Tc17 cells would be highly advantageous for ACT.


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.

Key Words: T-cell, cancer, immunotherapy, CD38, ACT, tumor


Inventors: Shikhar Mehrotra and Shilpak Chatterjee

Patent Status: Provisional Patent Filed 11/09/2016

MUSC-FRD Technology ID: P1716


Patent Information:
For Information, Contact:
Mark Hankins
Director of Licensing
MUSC Foundation for Research Development
Shikhar Mehrotra
Shilpak Chatterjee
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