Targeting CD26hi T-cells for Cancer Therapy

Description:

Inventors at MUSC have identified a unique human CD4+ T cell population that expresses high levels of surface CD26, termed CD26high T cells, which mediate durable antitumor immunity in vivo, and have immediate clinical relevance for designing new vaccines and cellular therapies.

 

CD26high T cells simultaneously secrete elevated IL-17A, IFN- and IL-22 compared to Th1, Th2 or Th17 cells. When infused into mice bearing human tumors, CD26high T cells more efficiently reconstituted immunodeficient hosts and persisted long-term compared to other subsets. Remarkably, CD26high T cells engineered with a first generation CD3 mesothelin-specific chimeric antigen receptor (CAR) were capable of ablating large human mesothelioma tumors when infused into mice. Treatment with CAR-engineered Th1, Th2 or Th17 cells was less effective than treatment with CD26high T cells. This finding is surprising given that first generation CARs (consisting of either the cytoplasmic domain of the Fc receptor γ chain or CD3ζ signaling modules alone) historically do not elicit robust antitumor effects in preclinical or clinical trials, when compared to second generation CARs with the addition of a co-stimulatory domain. In contrast to pervious studies showing that CD26 impairs CD8+ T cell persistence within the tumor and thus dampens antitumor immunity, inventors found that human CD26high T cells enhanced the persistence and polyfunctionality of co-infused tumor-specific CD8+ T cells. Interestingly, CD26high, but not Th17 cells, were capable of clearing tumor in NSG mice without cytolytic assistance from CD8+ T cells. Additional investigation revealed that inherent therapeutic effectiveness of CD26high T cells was likely due to their robust cytotoxic potential and distinct inflammatory signature.

 

Overview: In response to costimulation and cytokine cues, naive CD4+ T cells differentiate into one of several T helper (Th) subsets. These subsets are commonly identified by their ability to secrete IFN-y, IL-4 or IL-I7A and are termed Th1, Th2 and Th17 cells, respectively. Each subset has been reported to enhance immune responses against cancer in murine models. In contrast, regulatory CD4+ T cells that express high CD25 and master transcription factor FoxP3, dampen immune responses to tumors. Traditionally, IFN--secreting Th1 cells were regarded as the most effective antitumor T cell subset in various murine models of cancer. However, recent reports demonstrated that murine Th17 cells are more effective at killing tumor than their Th1 or IL-2-expanded CD4+ T cell cohorts. While the role of distinct murine CD4+ T cell subsets are clearly defined, the human CD4+ T cell subset with durable antitumor memory responses remains unknown.

 

CD26, also known as Dipeptidyl peptidase-4 (DPP4) and adenosine deaminase complexing protein 2, is an antigenic enzyme expressed on the surface of most cell types and is associated with immune regulation, signal transduction and apoptosis. It is an intrinsic membrane glycoprotein. CD26 plays an important role in tumor biology, and is useful as a marker for various cancers, with its levels either on the cell surface or in the serum increased in some neoplasms and decreased in others. Although expressed in some organs, CD26 expression level is tightly regulated on T cells, and its density is markedly enhanced after T cell activation. CD26 itself is involved in the processes of T cell signal transduction as a receptor capable of generating T cell co-stimulatory signals. In the resting state of human T lymphocytes, CD26 is preferentially expressed on a subset of CD4+ helper/memory T cells* (termed CD26high). This CD26high T cell population has been shown to respond maximally to recall antigens. Inventors’ results identify a new human CD4+ T cell subset with remarkable antitumor properties; which could be harnessed to design next generation cancer immunotherapies for the clinic.

 

Applications: Cancer immunotherapies

Advantages:  CD26high T cells are better at eradicating tumors than other T cell populations; CD26high enhances the regression of pancreatic cancer; CD26high T cells persist longer in vivo than Th1 or Th17

Key Words: T cells, immunotherapy, cancer

 

Inventors: Chrystal M. Paulos

Patent Status: PCT Application Filed 04/25/2017

MUSC-FRD Technology ID: P1679

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Chelsea Ex-Lubeskie
Licensing Manager, Devices
MUSC Foundation for Research Development
843-876-1900
exlubesk@musc.edu
Inventors:
Michelle Nelson
Stefanie Bailey
Chrystal Paulos
Keywords:
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