DUET-101 / Scopus - LARVOL DELTA

Targeting STAT3 in tumor-associated antigen-presenting cells as a strategy for kidney and bladder cancer immunotherapy. (PubMed, Front Immunol) - "To better understand immune alterations associated with ICB resistance, we assessed blood biomarkers in renal cancer patients classified as responders or non-responders to first line nivolumab/ipilimumab immunotherapy...To assess whether STAT3 inhibition within these cell subsets can promote antitumor immune responses and/or enhance sensitivity to ICB in vivo, we used an original antisense oligonucleotide (ASO) strategy for myeloid-cell selective STAT3 knockdown (CpG-STAT3ASO)...Therapeutic efficacy correlated with activation of dendritic cells (DCs) and M1 macrophages in the tumor microenvironment, reduced percentages of regulatory T cells (Tregs) and the expansion of CD8 T cells in both tumor models. Our study underscores the potential of using myeloid-cell targeted CpG-STAT3 inhibitors for genitourinary cancer therapy to disrupt tolerogenic signaling, restore immune cell activity and sensitivity to immune checkpoint inhibitors and/or T cell-based immunotherapies."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD8 • CXCL8 • IL10 • IL1R1 • IL6 • STAT3

Reprograming of tumor-associated myeloid cells by TLR9-targeted STAT3 antisense oligonucleotides sensitizes malignant glioma to PD1-specific immunotherapy (SITC 2023) - "4 Our initial results demonstrated that CpG-STAT3dsASO was more effective and significantly better tolerated than single-stranded CpG-STAT3ASO when injected intracranially...These conditions unlocked the potential of PD1 blockade to recruit effector CD8 T cells into glioma without indication of lymphocyte exhaustion. Conclusions Our results underscore the potential of using myeloid cell-targeted CpG-STAT3dsASO to overcome glioma immune evasion and thereby to sensitize tumors to PD1 immune checkpoint blockade and potentially other T-cell based cancer immunotherapies."

Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CD4 • CD8 • STAT3 • TLR9

A Novel STAT3 Antisense Oligonucleotide-Based Immunotherapy for Renal Cell Carcinoma (KCRS 2023) - "Ourpreliminary in in vitro studies demonstrate CpG-STAT3ASO treatment can reverse patient-derived CD15+ granulocyte immunosuppression onhealthy T cells and restore T cell proliferation...The proposed project willultimately benefit patients with advanced RCC and raise objective response rates. Finally, the proposed project will provide me with trainingunder a research scientist and a clinical scientist treating patients with RCC that will combine the fields of oncology, molecular biology,chemistry, and immunology to prepare me for a career at the forefront of kidney cancer research."

IO biomarker • Bladder Cancer • Genito-urinary Cancer • Immune Modulation • Kidney Cancer • Oncology • Prostate Cancer • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer • CD8 • IL17A • IL6 • STAT3

Multimodal Glioma Immunotherapy Combining TLR9-Targeted STAT3 Antisense Oligodeoxynucleotides with PD1-Specific Immune Checkpoint Blockade (ASGCT 2023) - "Our results demonstrated that CpG-STAT3dsASO was more effective and significantly better tolerated than single-stranded CpG-STAT3ASO when injected intracranially, without evidence of severe acute neural toxicities within tested dosing... We believe that further development of CpG-STAT3dsASO will pave way to clinical translation of this strategy to immunotherapy of malignant glioma."

Checkpoint block • Checkpoint inhibition • Brain Cancer • CNS Tumor • Glioma • Immune Modulation • Oncology • Solid Tumor • CD8 • PD-1 • STAT3 • TLR9

Novel immunotherapy for prostate cancer combining CAR T cells and myeloid cell STAT3 inhibition (SITC 2022) - P1 | "Thus, we hypothesized that TME modulation with a TLR9-guided STAT3 anti-sense oligonucleotide CpG-STAT3ASO (CSI3) would provide myeloid cell-selective STAT3 inhibition, which combined with PSCA-CAR T cells will improve responses in mCRPC. Methods Using a PSCA knock-in (hPSCA-KI) immunocompetent mouse model of prostate cancer (Murad et.al., 2021 Mol Ther) , we describe cyclophosphamide (Cy) preconditioning as crucial for unleashing the therapeutic potential of PSCA-CAR T cells, yet still achieving approximately 50% curative responses...Our data suggests that myeloid cell-selective STAT3 inhibition in combination with our PSCA-CAR T cells may synergize to improve overall responses and boost endogenous anti-tumor immunity. In sum, this approach presents an exciting avenue for clinical development in mCRPC."

CAR T-Cell Therapy • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • IL10 • IL12A • PD-L1 • PSCA • TGFB1 • TLR9

Multimodal glioma immunotherapy combining TLR9-targeted STAT3 antisense oligodeoxynucleotides with PD1-specific immune checkpoint blockade (SITC 2022) - "Our results demonstrated that CpG-STAT3dsASO was more effective but also significantly better tolerated than single-stranded CpG-STAT3ASO when injected intracranially, without evidence of severe acute neural toxicities within tested dosing...While, neither of treatments alone was curative, the combination anti-PD1/CpG-STAT3dsASO therapy resulted in complete rejection of orthotopic GL261 tumors in the majority of treated mice (figure 1). Conclusions We believe that further development of CpG-STAT3dsASO will pave way to clinical translation of this strategy to immunotherapy of malignant glioma."

Checkpoint inhibition • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • CD8 • PD-1 • STAT3 • TLR9

Activation of STAT3 signaling is associated with resistance to immune checkpoint inhibitors in patients (pts) with metastatic renal cell carcinoma (mRCC) (SITC 2022) - "Background Frontline nivolumab plus ipilimumab (N+I) has dramatically improved outcomes in mRCC pts...In addition, our preclinical models indicate that administering anti-PD-1 plus CpG-STAT3ASO leads to significant tumor growth restriction compared to either agent alone...Ethics Approval The protocol was approved by the institutional scientific review committee, data safety monitoring board, and the institutional review board at the City of Hope Comprehensive Cancer Center. The study conformed with the amended Declaration of Helsinki and the International Conference on Harmonization Guidelines."

Checkpoint inhibition • Clinical • IO biomarker • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CXCL8 • IL1R1 • IL2RA • IL6 • PD-L1 • TLR9

Novel Renal Cell Carcinoma Immunotherapy Combining TLR9-Targeted STAT3 Antisense Oligonucleotide with PD-1 blockade (SITC 2022) - "In this preclinical study, we investigated a novel treatment strategy combining anti-PD-1 therapy with our original CpG-STAT3ASO oligonucleotide strategy to knockdown STAT3 specifically within TLR9-positive myeloid cell populations associated with RCC tumors...The improved treatment efficacy is likely related to more potent activation and reprogramming of tumor-associated myeloid cells, particularly macrophages. Our results warrant further investigation into myeloid cell specific STAT3 silencing in combination with Anti-PD-1 in RCC."

Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD4 • CD8 • CXCL8 • IL6 • STAT3 • TLR9

Circulating biomarkers associated with resistance to Nivolumab and Ipilimumab based regimens indicate persistent immunosuppression and activation of STAT3 signaling (KCRS 2022) - "Background Combination anti-PD-1 (Nivolumab) and anti-CTLA-4 (Ipilimumab) have improved objective response rates and overall survival in patients with renal cell carcinoma (RCC) over Sunitinib. indicate that novel immunotherapeutic strategy utilizing oligonucleotide-based STAT3 inhibitor (CpG-STAT3ASO) targeting myeloid cells with anti-PD-1 can achieve significant tumor growth inhibition and warrant further investigation into myeloid cell targeting with anti-PD-1 therapy in RCC. Keywords: Nivolumab, Ipilimumab, RCC, STAT3, myeloid cells, immunosuppression"

Biomarker • IO biomarker • Genito-urinary Cancer • Immune Modulation • Inflammation • Oncology • Renal Cell Carcinoma • Solid Tumor • CD4 • CD8 • CXCL8 • FOXP3 • IL10 • IL1R1 • IL2RA • IL6

Multimodal Immunotherapy for Malignant Glioma Using TLR9-Targeted STAT3 CpG-Oligodeoxynucleotides Based Immunotherapy Reprogramming the Glioma Microenvironment (ASGCT 2022) - "These results were consistent with the maturation and activation of antigen-presenting cells, such as DCs, microglia and macrophages together with increased T cell infiltration into glioma, after the intracranial injections of CpG-STAT3ASOLNA in immunocompetent mice. We believe that our results will pave way to clinical translation of CpG-STAT3ASO for radio-immunotherapy of malignant glioma."

IO biomarker • Brain Cancer • Glioma • Immunology • Oncology • Solid Tumor • ITGAM • STAT3 • TLR9

Glioma-targeted delivery of exosome-encapsulated antisense oligonucleotides using neural stem cells. (PubMed, Mol Ther Nucleic Acids) - "Peritumoral injections of 5 × 10 NSCs loaded ex vivo with CpG-STAT3ASO inhibited subcutaneous tumor growth more effectively than the equivalent amount of oligonucleotide alone. Based on these results, we anticipate that NSCs and NSC-derived exosomes will provide a clinically relevant strategy to improve delivery and safety of oligonucleotide therapeutics for glioma treatment."

Journal • Brain Cancer • Glioma • Oncology • Solid Tumor • CD63 • IL12A • STAT3

Scopus BioPharma’s Subsidiary — Duet Therapeutics — Announces Release of Preclinical Data Being Presented at 17th Annual Meeting of the Oligonucleotide Therapeutics Society (GlobeNewswire) - "Scopus BioPharma Inc...announced the release of preclinical data being presented at the 17th Annual Meeting of the Oligonucleotide Therapeutics Society...Data from two different studies benchmarked Duet’s proprietary bifunctional oligonucleotides, CpG-STAT3siRNA (DUET-01) and CpG-STAT3ASO (DUET-02), against Checkpoint Inhibitors in lymphoma and prostate tumor models in mice....Dr. Horsager is also presenting results of a study comparing Duet’s antisense-based bifunctional molecule, or DUET-02, to both PD-1 and CTLA-4 Checkpoint Inhibitors in a bone localized tumor model of metastatic prostate cancer...Duet expects....clinical Phase 1 trials beginning in Q1 2023 in the United States."

New P1 trial • Preclinical • Genito-urinary Cancer • Hematological Malignancies • Lymphoma • Oncology • Prostate Cancer

China National Intellectual Property Administration Grants New Patent Covering DUET-02, One of Three Key CpG-STAT3 Inhibitors Comprising the Duet Platform (GlobeNewswire) - “Scopus BioPharma…announced today that the China National Intellectual Property Administration has granted a new patent covering DUET-02, one of three key CpG-STAT3 inhibitors comprising the Duet Platform. The new patent covers the compound and composition, including phosphorothioated oligodeoxynucleotide, and methods of use for CpG-STAT3ASO, Duet’s CpG-STAT3 Antisense inhibitor…The new patent strengthens the patent portfolio for DUET-02. DUET-02 is also covered by a granted patent in the United States. Additionally, patent applications for DUET-02 are in process for the European Union, Canada, and Japan…Duet expects to file two INDs for DUET-02 in Q4 2022 in genitourinary and head & neck cancers, with Phase 1 clinical trials beginning in Q1 2023 in the United States."

IND • New P1 trial • Patent • Genito-urinary Cancer • Head and Neck Cancer • Oncology

Scopus BioPharma Launches Duet Therapeutics (GlobeNewswire) - "DUET-01 is in a Phase 1 clinical trial, as a monotherapy, for B-cell non-Hodgkin lymphoma. In 2022, Duet is targeting to file two INDs for DUET-02 in two separate indications: genitourinary and head & neck cancers. Duet is also evaluating combination therapies with checkpoint inhibitors."

IND • Trial status • Genito-urinary Cancer • Head and Neck Cancer • Hematological Malignancies • Non-Hodgkin’s Lymphoma • Oncology

Scopus BioPharma Expands Immunotherapy Pipeline with Acquisition of Olimmune (GlobeNewswire) - "Scopus BioPharma Inc...announced the acquisition of Los Angeles-based Olimmune Inc....Olimmune’s lead drug candidate, OLIM-01, is being developed for genitourinary and head and neck cancers. It is anticipated that INDs for these indications will be submitted by Q1 2023."

IND • M&A • Genito-urinary Cancer • Head and Neck Cancer • Oncology