Targeting YAP Activity in Combination with Immunomodulation to Alter Regulatory T Cell-mediated Immune Regulation in order to Treat Cancer

TITLE:              INHIBITION OF YAP FOR BREAKING TUMOR IMMUNE TOLERANCE

CASE NUMBER:       C13353

UNMET NEED

Regulatory T cells (Tregs) play critical roles in maintaining self-tolerance and homeostasis  by suppressing the activation and function of other immune cells. At the same time,  the immune-dampening effects of Tregs can inhibit the development of effective immune responses against tumors. Correspondingly, the degree of tumor infiltration by Tregs correlates negatively with patient survival in several cancers. For this reason, depletion or inhibition of Tregs  is a promising anti-cancer therapeutic approach. Foxp3 is a canonical transcription factor expressed in Tregs, but Foxp3 expression alone is not sufficient to  impart the full suppressive capacity of Tregs. It has been suggested that Foxp3 needs to associate with other co-factors in order to properly regulate Treg function. Furthermore, the molecules and pathways responsible for controlling Foxp3 expression in Tregs are incompletely understood. Therefore a continuing need exists in the art to identify and target the key mediators of  Treg suppression that cause immunotolerance to cancers. Therefore, there is an unmet need for new therapeutic strategies to treat cancer based upon Treg modulation.

TECHNICAL DESCRIPTION

JHU inventors report that Yes-associated protein (Yap), a downstream co-activator of the Hippo pathway, is highly expressed in Treg cells, and it is critical for the suppressive activity of these cells. Analysis of the gene expression patterns seen in the presence or absence of Yap revealed that this molecule regulates several factors important for signaling pathways initiated by the anti-inflammatory cytokine TGF-beta. Genetic ablation of Yap expression in CD4+ T cells and Foxp3+ Tregs suppresses the growth of B16-melanoma tumors and upregulates the production of inflammatory cytokines indicative of superior anti-tumor immunity resulting from the disabled Treg cells. Furthermore, pharmacological inhibition of Yap improved the effectiveness of proven immunomodulators such as vaccines and checkpoint inhibitors like anti-PD-1 in an aggressive mouse tumor model. Thus, they have discovered a novel mechanism by which Yap inhibition enhances anti-tumor responses. This discovery informs a new therapeutic approach to cancer that combines Yap inhibitors with other immunotherapies that enhance immune responses such as checkpoint inhibition and vaccination.

MAJOR RESULTS

1.       Discoveries justifying the development of novel inhibitors of Yap

2.       New uses for Verteporfin, a known Yap inhibitor, as a modulator of immune regulation

3.       Proof-of-concept findings that call for the use of novel antagonists of the factors up-regulated by Yap activity to be used as tolerance breaking immunotherapies.

4.       Novel combinatorial strategies for improved anti-cancer immunotherapy

DISEASE INDICATION

Cancers

ASSOCIATED PUBLICATIONS

- None at this time -

TECHNOLOGY CLASSIFICATION

Primary Category: Therapeutics

Primary Subcategory:

ASSOCIATED REPORTS OF INVENTION (ROIs) AND INTELLECTUAL PROPERTY (IP) FILING NUMBERS

ROI #                                          TITLE

C13353                                   INHIBITION OF YAP FOR BREAKING TUMOR IMMUNE TOLERANCE

STATUS                     PRIORITY DATE                            IP FILING NUMBERS

PCT Pending                     2/12/2015                                   US 62/115,414, PCT/US2016/017697