Immunotherapy Combination Treatment Containing both TLR4 and TLR2/6 Agonists, a Checkpoint Inhibitor, and a STING agonist.

Melanoma is an aggressive form of skin cancer that commonly becomes metastatic, spreading to nearby tissue or other parts of the body, including distant skin or subcutaneous sites such as the lungs, liver, brain, or bone. Metastatic melanoma is very drug resistant and difficult to treat, and therefore, the prognosis for these patients is poor. There is a need for effective therapies for aggressive melanoma and other drug-resistant solid cancers. 

In recent years, a lot of scientific interest has focused on using the innate immune response to treat cancer. Toll-like receptors (TLRs) are a class of proteins that play a crucial role in the innate immune system. TLRs have also been shown to play a role in angiogenesis (developing new blood vessels) and are expressed in cancer cells, including melanoma cells. TLR agonists have been evaluated extensively in cancer immunotherapy for use as adjuvants due to their ability to activate immune cells and promote inflammation. The activation of TLRs expressed on the surface of dendritic cells (DCs) induces the production of proinflammatory cytokines, resulting in an active antitumor immune response. 

Researchers at the National Cancer Institute (NCI) developed a combination of agents capable of treating cancers such as resistant melanin producing M3 melanoma. This combination consists of administering:

1. A Toll-like receptor (TLR) 4 agonist (i.e., HMGN1);
2. A TLR2/6 agonist (i.e., FSL-1);
3. An immune checkpoint inhibitor (e.g., PD-L1 inhibitor, a PD-1 inhibitor, a TNFR-2 inhibitor);
4. A STING agonist (such as cGAMP or c-di-GMP).

The researchers showed that HMGN1 and FSL-1 synergize to activate human and mouse dendritic cells (DCs). HMGN1 and FSL-1 upregulate the cytokine production by DCs resulting in the polarization of Th1 immune responses. This immune activating effect, in combination with an immune checkpoint inhibitor (anti-PD-L1) to diminish tumor-associated immunosuppression, had promising effects on treating mice bearing melanin-producing melanomas but was not completely curative. However, when additionally combined with cGAMP, a STING agonist to further boost the immune activating effects, the researchers saw a curative rate of 100% in the resistant melanin producing M3 melanoma in mice. Therefore, this combination provides a new therapeutic approach for curing resistant melanin-producing melanoma tumors, and possibly other types of resistant solid tumors, without the need to identify and use relevant protective tumor antigens. 

Development of this combination therapeutic approach continues and is available for licensing and co-development.

Competitive Advantages:

• Synergistic treatment approach to reduce drug resistance and provide substantial therapeutic anti-cancer benefits
• Novel therapeutic approach for resistant tumors such as melanin-producing melanoma tumors 
• Combination of synergistic dendritic cells activators to reduce potential off target adverse effect
• In vivo demonstration of the impact of novel combination cancer therapy
• Partially established regulatory path since components were previous used in human clinical trials

Commercial Applications:

• Treatment of solid tumors – including, but not limited to, melanoma, colorectal cancer, and kidney cancer
• Treatment of drug-resistant metastatic melanoma