The University of Chicago

Other

Arch Development Corporation

Thomas F Gajewski

Stefani Spranger

Robbert M Spaapen

Yuanyuan Zha

Yan Zheng

Michael Leung

Francesca Fallarino

Jason Williams

Brendan Horton

Jessica Fessler

Jason Luke

Ayelet Sivan

Vyara Matson

Riyue Bao

Leticia Corrales

Robert M Spaapen

Provided herein are compositions and methods for the treatment of cancer by inhibition of β-catenin or a β-catenin pathway. In particular, inhibitors of β-catenin and/or the Wnt/β-catenin signaling pathway are employed prevent or reverse evasion of immune response or immunotherapy by cancers.

Beta-catenin inhibitors in cancer immunotherapy

Embodiments concern methods and composition related to anergic T-cells in patients, such as cancer patients.

Methods and compositions related to T-cell activity

Provided herein are compositions and methods comprising microbiome biomarkers of responsiveness/resistance to immunotherapy (e.g., anti-PD1/PD-L1 therapy), and diagnostic, prognostic and therapeutic uses thereof. In particular, the amount, identity, presence, and/or ratio of microflora in the microbiome of a subject is used to determine the responsiveness/resistance of the subject to immunotherapy, and/or the microbiome of a subject is manipulated to enhance the responsiveness of the subject to various immunotherapies and co-therapies.

Microbiome biomarkers immunotherapy responsiveness: diagnostic, prognostic and therapeutic uses thereof

Provided herein are compositions and methods for detecting and/or targeting dysfunctional tumor antigen-specific CD8T cells in the tumor microenvironment for diagnostic, therapeutic and/or research applications. In particular, dysfunctional tumor antigen-specific CD8T cells are detected and/or targeted via their expression of cell surface receptors described herein, such as 4-1BB, LAG-3, or additional markers that correlate with 4-1BB and LAG-3 expression, such as markers differentially expressed on the surface of the T cells.

Dysfunctional antigen-specific CD8T cells in the tumor microenvironment

The present disclosure provides combinations of immunologic inhibitors for the treatment of cancer. In some embodiments, the methods involve the use of a combination of at least two of the following: an inhibitor of indoleamine-2,3-dioxygenase (IDO), an inhibitor of the PD-L1/PD-1 pathway, an inhibitor of CTLA-4, an inhibitor of CD25, or IL-7.

Synergistic combination of immunologic inhibitors for the treatment of cancer

Provided herein are compositions and methods for the treatment of cancer by inhibition of &#x3b2;-catenin or a &#x3b2;-catenin pathway. In particular, inhibitors of &#x3b2;-catenin and/or the Wnt/p-catenin signaling pathway are employed prevent or reverse evasion of immune response or immunotherapy by cancers.

In some embodiments, the methods involve the use of a combination of at least two of the following: an inhibitor of indoleamine-2,3-dioxygenase (IDO), an inhibitor of the PD-L1/PD-1 pathway, an inhibitor of CTLA-4, an inhibitor of CD25, or IL-7. The inventors particularly observed a major synergistic effect of combining anti-CTLA-4 with either an IDO inhibitor, with anti-PD-L1 mAb, or with CD-25 depletion. Such combinations have been found to demonstrate a synergistic effect in treating cancer and tumors, for example by reducing tumor size, increasing the percentage of antigen-specific T cells, and increasing T cell function.

Embodiments concern methods and composition related to anergic T-cells in patients, such as cancer patients. T cell anergy is a hyporesponsive state induced by TCR engagement in the absence of costimulation (Schwartz, 2003). Anergy induction was initially observed in vitro using chemically-fixed antigen presenting cells (APCs). Subsequently, it was found that anergy could be induced by immobilized anti-CD3 mAb or calcium ionophores (such as ionomycin) in vitro, and by superantigen and soluble antigenic peptide in vivo. Indirect evidence has suggested that T cell dysfunction in the tumor microenvironment and establishment of transplant tolerance is partially due to T cell anergy (Gajewski et al., 2011).

Provided herein are methods of treatment and/or prevention of cancer by manipulation of commensal microflora. In particular, the amount, identity, presence, and/or ratio of microflora (e.g., gut microflora) in a subject is manipulated to facilitate one or more co-treatments.

Treatment of cancer by manipulation of commensal microflora

T cell anergy has been correlated with defective Ras signaling. However, neither a causal relationship nor the mechanism of Ras hypoactivation have been established. Using adenoviral transduction of CAR Tg T cells to enable genetic manipulation in nonproliferating cells, we show that Ras61L restores IL-2 production and MAP kinase signaling in T cells anergized in vitro or in vivo. A gene array screen revealed upregulated diacylglycerol kinase (DGK) in the anergic state, which was confirmed by RT-PCR and Western blot analysis. A DGK inhibitor significantly restored IL-2 production by anergic cells. Our data support a causal role for DGK and defective Ras signaling in T cell anergy.

T cell anergy is reversed by active Ras and regulated by diacylglycerol kinase

The invention provides methods of inducing the production of cytolytic T lymphocytes directed against malignancy or infectious agent by a mammal and treating such disease such that deleterious side effects are minimized and treatment of metastatic melanomas are surprisingly and dramatically improved.

Growing community of inventors

Chicago, IL, United States of America

Thomas F Gajewski