cientific A pproach
The human immune system is designed to kill diseased, malignant cells as well as foreign invaders such as bacteria and viruses. However, tumors can hijack the function of immune cells to create an immunosuppressive tumor microenvironment (TME), providing a haven for tumor growth, proliferation, and metastasis. This new understanding has reshaped our thinking on how to treat cancer - instead of trying to kill cancer cells directly, we reprogram the immune system to restore the full function of the immune system in cancer cell detection and elimination.
The major strategies currently explored in immuno-oncology rely on engineering immune cells (e.g., CAR-T), immune stimulation (e.g., TLR and STING agonists) and alleviating immunosuppression (e.g., by immune checkpoint inhibitors). While these approaches have revolutionized how we treat cancer, many patients relapse post-treatment or remain treatment-refractory. While release of immunosuppression and immune stimulation are necessary for durable, anti-tumor responses, neither approach is sufficient on its own as these two forces remain in a Yin-Yang balance.
The Duet Approach
STAT3: silencing the "undruggable" to release immunosuppression
One of the most sought-after therapeutic targets in cancer is STAT3, an oncogenic transcription factor and a master regulator of immunosuppression. STAT3 is a well-known driver of malignant cell invasion, proliferation, and metastasis in the majority of human cancers (Nature Reviews Immunology, 2007; Nature Reviews Cancer, 2014).
To date, STAT3 has remained undruggable. While numerous STAT3-based therapies have made it into the clinic, there have been no FDA approvals to date. The primary reason STAT3 has remained undruggable is that it’s an intracellular target, making it highly difficult to access (Cancer Immunology, Immunotherapy, 2017).
Duet’s approach to make STAT3 druggable is to combine the STAT3 inhibitor with a CpG DNA recognized by immune receptor, TLR9. Tethering STAT3 to CpG allows for intracellular delivery of the whole molecule and also for triggering potent antitumor immune responses (Nature Biotechnology, 2009; Clinical Cancer Research, 2018).
Selectivity, stimulation, and silencing: the three functions of CpG-STAT3 inhibitors
CpG oligonucleotides serve as a common “danger signal” of bacterial or viral infections detected by TLR9 receptors. Duet links a synthetic CpG oligonucleotide to a STAT3 inhibitor (CpG-STAT3i) to:
- Select the right immune cell types – CpG oligonucleotides are rapidly internalized (~30 minutes) by APCs, such as dendritic cells and macrophages in the TME.
- Stimulate immune signaling – Once the CpG-STAT3 is internalized by APCs, CpG binds to an intracellular TLR9 receptor, stimulating immune signaling.
- Silence STAT3 activity and unleash TLR9-mediated immune responses – The CpG-STAT3i molecule is rapidly released into cytosol, releasing STAT3 immunosuppressive control over TLR9 signaling, thereby maximizing tumor antigen presentation and T cell-mediated antitumor immune responses.