Blocking GARP (LRRC32) cleavage and Its Application in Immunotherapy

Description:

Technology: Researchers at MUSC have developed a method and peptide composition (the “T250 peptide”) for treating cancer by inhibiting Glycoprotein-A Repetitions Predominant Protein (GARP) cleavage and thus impeding the activation of Transforming Growth Factor-Beta (TGF-β) – a growth factor that suppresses T-cell mediated anti-cancer immunity when active.

 

Studies have shown that by suppressing active TGF-β tumor size can be reduced. It is well known that platelets congregate to cancerous cells and can cause pulmonary embolisms and deep vein thrombosis. These congregated platelets also form a protective “cloak” of fibrin. This layer of fibrin protects tumors from natural killer (NK) cells, neutrophils, macrophages, and cytotoxic T lymphocytes (CTLs). Prior studies have also shown that platelet-induced tumor growth is mediated by α-granules released by platelets upon activation. TGF-β, one of the most abundant soluble factors secreted by platelets, is interesting because it is released in latent and active forms, the latter of which is the main suppressor of T-cell mediated anti-cancer immunity. Researchers at MUSC have found that when GARP expression is absent in a GARP KO mouse (PF4creGARP) the release of active TGF-β decreases significantly (Figure 1a-b).

 

Figure 1: Platelet-intrinsic GARP plays critical roles in generating active TGF-β.  In GARP knockout mice there is a significant decrease in active TGF-β (Figure 2A) despite an increase in total TGF-β (Figure 2B).

 

Efforts by the MUSC inventors have further shown that mice engineered to totally lack GARP expression on platelets demonstrate reduced tumor size as well (Figure 2). The T250 Peptide produces a similar reduction of active TGF-β in normal mice by inhibiting GARP cleavage (Figure 2), potentially enabling a novel treatment for cancer that can be used either independently or as a complement to other cancer treatments such as chemotherapy and immunotherapy.

 

Figure 2: T250 Peptide inhibits active TGF-β expression on thrombin treated platelets (left). Photographs of primary tumors resected from GARP KO and WT mice 6 weeks after injection with MC38 colon cancer cells show reduced tumor size absent GARP cleavage (right).

 

Overview: In 2018 there were an estimated 1.73 million new cancer cases and just above 600,000 cancer related deaths. The direct medical cost of cancer in the US in 2015 was approximated at $80.2 billion. Expanding to a global scope, there were 14.1 million new cases of cancer in 2012, and 8.2 million cancer related deaths. Therefore, it is necessary to uncover methods to improve cancer diagnosis and treatment particularly in difficult to treat cancers. Immunotherapy hold great promise in this respect. Because of the recent successes of monoclonal antibodies, cytokines, and immunomodulators, the market for immunotherapy blossomed up to $58 billion in 2018 with an aggressive expected compound annual growth rate (CAGR) of 14.5%. This market growth projection is due to the ability of immunotherapy to treat a wide variety of patients for a multitude of cancers using a method that is highly effective. In 2018, over 10 new immunotherapies for various types of cancer including CAR-T cell therapies, checkpoint immunotherapies, and antibody-drug conjugates were approved by the FDA. As immunotherapy technologies are built out further and the prevalence of cancer increases, compositions like the one disclosed in this summary that can function independently or as a complement to other therapies will become increasingly important in the market.

 

Applications: Cancer therapy, immunotherapy

 

Advantages:

•       Enhances the efficacy of current cancer treatments

•       Reduces ability of tumorigenic cells to proliferate

•       Enables natural immune system to perform tumoricidal attacks

 

Key Words: Cancer, cancer biology, immunology, medicine, Glycoprotein-A Repetitions Predominant Protein (GARP) cleavage, TGF-β, thrombin, platelets

 

Inventors: Zihai Li       

 

Patent Status:       PCT Application PCT/US2018/042873 filed July 19, 2018       

 

MUSC-FRD Technology ID: P1791

 

Licensing Status: Currently available for licensing

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Troy Huth
Sr Licensing Manager
MUSC Foundation for Research Development
huth@musc.edu
Inventors:
Zihai Li
Keywords:
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