Novel nucleotide-based approaches targeting the STAT3 pathway for the treatment of lymphoma
Project: Novel Nucleotide-based Approaches Targeting the STAT3 Pathway for the Treatment of Lymphoma
Growing evidence links B cell lymphoma patients’ poor survival and immune suppression to persistent activation of signal transducer and activator of transcription 3 (STAT3). In ABC-DLBCL, genetic mutations augment Toll-like receptor 9 (TLR9)/MyD88 signaling, thereby leading to secretion of cytokines that induce STAT3 activation in lymphoma cells and in the tumor-associated immune cells, such as myeloid-derived suppressor cells (MDSCs). The autocrine and paracrine STAT3 activation in cancer cells and in the tumor-associated immune cells enhances lymphoma’s tumorigenic and tolerogenic potential. To overcome the challenge imposed by lack of pharmacological inhibitors of STAT3, we developed a strategy to deliver therapeutic siRNA specifically into myeloid and B cells, by physically linking siRNA to TLR9 ligands/agonists, CpG oligodeoxynucleotides (ODNs). We have demonstrated in multiple tumor models that local tumor treatment using CpG-STAT3siRNA silences STAT3, stimulating systemic antitumor immunity, in addition to inducing direct B-cell lymphoma tumor cell apoptosis and sensitivity to radiation therapy (RT). We propose to move CpG-STAT3siRNA to phase 1b clinical trials in NHL.
In year 10 of the current SPORE, we included in the project a second generation STAT3 inhibitor: linking CpG to a high-affinity STAT3-DNA binding sequence called STAT3decoy ODN (dODN), which effectively competes STAT3 DNA binding. Compared to CpG-STAT3siRNA, CpG-STAT3dODN exhibits improved nuclease-resistance which allows for systemic administration and treatment of advanced, disseminated lymphomas. We anticipate that with the clinical testing of the first CpG-STAT3siRNA strategy together with RT in the local setting, and with the optimization of new CpG-STAT3dODN for systemic administration, the proposed studies will accelerate development of novel, effective and safe nucleotide-based immunotherapeutic strategies for targeting intracellular STAT3 in NHL and potentially other hematologic malignancies.
- Specific Aim 1: Conduct first-in-human phase Ib trial of intratumoral injection of CpG-STAT3 siRNA in combination with local radiation in B-cell non-Hodgkin lymphoma.
- Specific Aim 2: Optimize the CpG-STAT3dODN strategy for targeting B cell lymphoma cells.