Method for Reducing Tumor Progression and Fibrosis, and Increasing Adaptive Immunity in Malignancy

Categories: “Cancer Therapeutics“

Reference #: 2019-044

OTC Contact: Sharon E. Pula, Esq. (Directory Information | Send a Message)

Descriptions

The invention relates to a method to reduce or prevent growth of a malignancy, treat a malignancy and/or enhance the patient’s anti-malignancy immune response, and reduce malignancy-associated fibrosis in a subject by administering a liver X receptor (LXR) agonist.  The method may also be used to treat malignancy resistance to certain immune checkpoint inhibitor treatment and may be combined with at least one anti-cancer therapeutic agent, including but not limited to a PD-1 immunotherapeutic agent or an anti-PDL1 immunotherapeutic agent.  The combination treats immune resistant malignancies and tumor associated fibroses while significantly enhancing the effect of immune check-point inhibitors such as PD-L1 and cytotoxic T-lymphocyte antigen (CTLA-4). The method also increases the number and activity of CD4+ and CD8+ effector T cells, monocytes, and macrophages in the tumor microenvironment (TME), further enhancing a patient’s anti-tumor response.  

Applications

• Treating immune tolerant malignancies
• Reducing malignancy-associated fibrosis 
• Reduce tumorigenesis 
• Enhancing a patient’s anti-tumor immune response by targeting myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) that lead to immunosuppression

Advantages

• A monotherapy that can also be used in combination with immunotherapy and chemotherapy for the treatment of cancer patients 
• Enhancing the effect of treatment with immune checkpoint inhibitors such as PD-1, PD-L1 and (CTLA-4) 
• Treatable malignancies include, but are not limited to; breast malignancy, pancreatic malignancy, lung malignancy, liver malignancy, gastrointestinal malignancy, esophageal malignancy, colorectal malignancy etc.

Background

Fibrosis occurs as the result of the secretion of chemokines, cytokines, growth factors, and collagen by cancer-associated fibroblasts, into the tumor microenvironment (TME), collectively promoting angiogenesis, tumor growth, invasion and the activation of MDSCs and Tregs.  This process poses a major risk factor for the development of precancerous lesions. As the TME changes, tumors become more malignant and the eventual graduation to metastatic disease leads to poor patient outcomes.  Fibrosis directly impacts immune suppression through secretion of a dense fibrotic collagen matrix that impedes CD8⁺ effector T cell penetration into the tumor bed and by inflammatory factors within the TME.  The current proposal aims to disrupt the immune, metabolic, and signaling pathways that orchestrate the symbiotic relationship between tumor and stromal tissue.

Stage of Development

Available mouse modelling data including transgenic, fibrotic and oncogenic mice.

Inventors

Moshe Levi

Robert Glazer

Hongyan Yuan

Suman Ranjit

Patent Status

PCT Application Filed