Lead selection studies of novel antisense oligonucleotide for cancer immunotherapy - twin peaks BIO, INC

The National Cancer Institute awarded Twin Peaks Bio, Inc. $398,704 on September 2, 2026, under the Cancer Treatment Research program (CFDA 93.395) to conduct lead selection studies of novel antisense oligonucleotide therapies for head and neck squamous cell carcinoma immunotherapy.

Twin Peaks Bio will develop bi-specific conjugate molecules that pair STAT3 antisense oligonucleotides with synthetic TLR9 agonists (CPG DNA) for targeted delivery to tumor-associated myeloid cells. The approach aims to simultaneously block STAT3 signaling and activate immune responses against solid tumors. The recipient is advancing from first-generation 2'-O-methyl-modified gapmer chemistry to newer locked nucleic acid-modified variants with improved target knockdown and tunable immunostimulatory properties. The work will support movement of these bi-specific conjugates toward clinical trials in head and neck squamous cell carcinoma, alone or in combination with localized radiotherapy.

Performance occurs at Twin Peaks Bio's facility in Newport Beach, California, with work scheduled through August 31, 2027. This is an SBIR Phase I project grant, which supports small business innovation research in early-stage concept development and feasibility assessment.

Abstract head and neck squamous cell carcinoma (HNSCC) is the sixth leading malignancy worldwide with less than half of patients surviving beyond 5 years. HNSCC tumors frequently shown constitutive activation of signal transducer and activator of transcription 3 (STAT3), which correlates with poor prognosis and resistance to standard treatments, such as radiotherapy (RT). STAT3 is well-defined oncogenic transcription factor as well as a central immune checkpoint regulator. However, there are still no FDA-approved direct small molecule inhibitors and efficacy of investigational oligonucleotide-based inhibitors is limited by the lack of efficient and cell-selective delivery methods. To overcome these challenges, we developed a strategy for targeted in vivo delivery of STAT3 antisense oligonucleotides (ASO) to tumor-associated myeloid cells as conjugates with synthetic toll-like receptor 9 (TLR9) agonists, CPG DNA. CPG-STAT3ASO conjugates (CSA) show improved biodistribution to target cells and augmented STAT3 knock-down. Local and systemic CSA administration triggered potent CD8/CD4 T cell-mediated immune responses against solid tumors, such as HNSCC and prostate cancers, leading to long-term mice survival. The novelty of the BI-specific CSA strategy lies in the synergistic effect of blocking STAT3 combined with CPG/TLR9-stimulation, which together unleash immune activation from within the tumor microenvironment. The first generation of CSA was based on the standard 2'-O-methyl-modified chemistry of the gapmer ASO. Recently developed new generations of locked nucleic acid (LNA)-modified csas showed significantly improved target knock-down and tunable immunostimulatory effects. Twin peaks biotherapeutics INC. Plans to move the BI-specific CSA oligonucleotides into clinical trials for HNSCC immunotherapy alone or in combination with localized RT. We hypothesize that LNA-modified csas injected intravenously will show enhanced potency/duration of STAT3 inhibition and generation of antitumor immune responses, thereby providing lead candidates for further IND-enabling studies. Within this phase I sttr proposal, we will assess feasibility and safety of using new LNA-modified csas for targeting STAT3 and immunostimulation using human and mouse HNSCC models in vitro and in mice. The proposed animal studies are required to evaluate the combined effects of local/systemic CSA therapy on tumor growth and antitumor immune responses, as well as organ safety within an intact physiological environment that cannot be modeled adequately in vitro. These studies will generate essential efficacy, pharmacology, and safety data needed to support future IND-enabling studies and clinical translation of CSA for HNSCC. Our aim is to produce clinically relevant, effective and safe CSA-based strategies capable of overcoming RT resistance and generating long term antitumor immune responses in HNSCC and potentially in other solid tumors.