作者: Kortylewski, Marcin ; Alcantara, Marice ; Su, Yu-Lin ; Lee, Peter ; Moreira, Dayson ; Sampath, Sagus ; White, Seok Voon ; Massarelli, Erminia ; Wang, Chongkai ; Maghami, Ellie ; Won, Haejung

The tumor microenvironment affects the outcome of radiotherapy against head and neck squamous cell carcinoma (HNSCC). We recently found that tolerogenic myeloid cells accumulate in the circulation of HNSCC patients undergoing radiotherapy. Here, we analyzed tumor-containing lymph node biopsies collected from these patients. After 2 weeks of radiotherapy, we found an increase in tumor-associated macrophages (TAMs) with activated STAT3, while CD8+ T cells were reduced as detected using multiplex IHC. Gene expression profiling indicated upregulation of M2 macrophage-related genes (CD163, CD206), immunosuppressive mediators (ARG1, LIF, TGFB1), and Th2 cytokines (IL4, IL5) in irradiated tumors. We next validated STAT3 as a potential target in human HNSCC-associated TAMs, using UM-SCC1 xenotransplants in humanized mice. Local injections of myeloid cell-targeted STAT3 antisense oligonucleotide (CpG-STAT3ASO) activated human DCs/macrophages and promoted CD8+ T cell recruitment, thereby arresting UM-SCC1 tumor growth. Furthermore, CpG-STAT3ASO synergized with tumor irradiation against syngeneic HPV+ mEERL and HPV- MOC2 HNSCC tumors in mice, triggering tumor regression and/or extending animal survival. The antitumor immune responses were CD8+ and CD4+ T cell dependent and associated with the activation of antigen-presenting cells (DCs/M1 macrophages) and increased CD8+ to regulatory T cell ratio. Our observations suggest that targeted inhibition of STAT3 in tumor-associated myeloid cells augments the efficacy of radiotherapy against HNSCC.

2018-12-01·Clinical Cancer Research1区 · 医学

STAT3 Inhibition Combined with CpG Immunostimulation Activates Antitumor Immunity to Eradicate Genetically Distinct Castration-Resistant Prostate Cancers

1区 · 医学

Article

作者: Zhao, Xingli ; DePinho, Ronald A. ; Adamus, Tomasz ; Kortylewski, Marcin ; Zhang, Zhuoran ; Swiderski, Piotr ; Moreira, Dayson ; White, Seok Voon ; Pal, Sumanta K. ; Su, Yu-Lin ; Lu, Xin

AbstractPurpose:Prostate cancers show remarkable resistance to emerging immunotherapies, partly due to tolerogenic STAT3 signaling in tumor-associated myeloid cells. Here, we describe a novel strategy combining STAT3 inhibition with Toll-like Receptor 9 (TLR9) stimulation to unleash immune response against prostate cancers regardless of the genetic background.Experimental Design:We developed and validated a conjugate of the STAT3 antisense oligonucleotide (ASO) tethered to immunostimulatory TLR9 agonist (CpG oligonucleotide) to improve targeting of human and mouse prostate cancer and myeloid immune cells, such as myeloid-derived suppressor cells (MDSC).Results:CpG-STAT3ASO conjugates showed improved biodistribution and potency of STAT3 knockdown in target cells in vitro and in vivo. Systemic administration of CpG-STAT3ASO (5 mg/kg) eradicated bone-localized, Ras/Myc-driven, and Ptenpc−/−Smad4pc−/−Trp53c−/− prostate tumors in the majority of treated mice. These antitumor effects were primarily immune-mediated and correlated with an increased ratio of CD8+ to regulatory T cells and reduced pSTAT3+/PD-L1+ MDSCs. Both innate and adaptive immunity contributed to systemic antitumor responses as verified by the depletion of Gr1+ myeloid cells and CD8+ and CD4+ T cells, respectively. Importantly, only the bifunctional CpG-STAT3ASO, but not control CpG oligonucleotides, STAT3ASO alone, or the coinjection of both oligonucleotides, succeeded in recruiting neutrophils and CD8+ T cells into tumors. Thus, the concurrence of TLR9 activation with STAT3 inhibition in the same cellular compartment is indispensable for overcoming tumor immune tolerance and effective antitumor immunity against prostate cancer.Conclusions:The bifunctional, immunostimulatory, and tolerance-breaking design of CpG-STAT3ASO offers a blueprint for the development of effective and safer oligonucleotide strategies for treatment of immunologically “cold” human cancers.

Frontiers in Immunology

Targeting STAT3 in tumor-associated antigen-presenting cells as a strategy for kidney and bladder cancer immunotherapy

Article

作者: Tang, Wilson S ; Alcantara, Marice B ; Moreira, Dayson ; Kortylewski, Marcin ; Pal, Sumanta K ; Dizman, Nazli ; Kaniowski, Damian ; Hsu, JoAnn ; Hall, Jeremy ; Horsager, Alan ; Zengin, Zeynep ; Kang, Elaine ; Wang, Dongfang ; Chehrazi-Raffle, Alexander ; Egelston, Colt ; Meza, Luis

IntroductionImmune checkpoint blockade (ICB) improved clinical outcomes in renal and bladder cancer patients, but the response rates remain limited especially in metastatic disease. While STAT3 transcription factor is well-known master regulator of tumor immune evasion, little is known about the role of STAT3 in the resistance of renal or bladder cancers to immunotherapy.MethodsTo 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.ResultsWe observed that non-responders showed elevated levels of proinflammatory mediators, such as IL-1RA, IL-6, IL-8 and to lesser extent IL-10, which are associated with STAT3 activation and tumor immunosuppression. In addition, we found STAT3 activation primarily in circulating myeloid immune cells such as tolerogenic MDSCs. 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). Our results in syngeneic models of renal and bladder cancers in mice demonstrated potent antitumor activity of CpG-STAT3ASO alone in contrast to PD1 blockade alone in both models. The CpG-STAT3ASO/anti-PD1 combination improved therapeutic efficacy especially against bladder tumors. 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.Discussion/ConclusionOur 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.

项与 DUET-02 相关的新闻（医药）

2022-10-18

·GlobeNewswire-Health Care

Scopus Biopharma Completes Recapitalization Designed To Enhance Shareholder Value

Warrants to Purchase Approximately 21 Million Scopus Shares Eliminated Scopus BioPharma’s Pure Play Immuno-Oncology Subsidiary, Duet BioTherapeutics, Independently Valued at $25 Million Scopus Maintains Approximately 90% Ownership Stake in Duet Duet Being Positioned to Go Public in 2023 NEW YORK, Oct. 18, 2022 (GLOBE NEWSWIRE) -- Scopus BioPharma Inc. (Nasdaq: “SCPS”), a biopharmaceutical company developing transformational therapeutics for serious diseases with significant unmet medical need, announced today the completion of a series of related recapitalization transactions designed to enhance shareholder value. These transactions include the elimination of warrants to purchase approximately 21 million shares of Scopus common stock. The recapitalization also independently values Duet BioTherapeutics, Scopus’ pure play immuno-oncology subsidiary, at $25 million. Joshua R. Lamstein, Chairman of Scopus BioPharma, stated, “Highlighting the embedded value of Duet was a key driver for the recapitalization. Scopus retains an approximately 90% ownership stake in Duet. The value of this stake greatly exceeds the total current market capitalization of Scopus. We expect that completing the recapitalization should serve as a catalyst for a significant increase in the trading price of Scopus’ common stock.” Alan Horsager, Ph.D., President – Immuno-Oncology of Scopus BioPharma and President and Chief Executive Officer of Duet BioTherapeutics, stated, “The establishment of a $25 million independent, stand-alone valuation positions Duet to raise capital directly and go public in 2023.” Mr. Lamstein added, “The recapitalization transactions provide us with greater strategic flexibility. The opportunity to secure capital at both the Scopus and Duet corporate levels enables us to pursue the most attractive financing alternatives.” Dr. Horsager added, “The additional financing alternatives afforded to Duet will enhance our access to the capital necessary to accelerate the development of DUET-02, our highly promising antisense technology. Additional capital resources will also enable us to further the on-going research by Marcin Kortylewski, Ph.D., Co-Founder and Senior Scientific Advisor of Duet BioTherapeutics and Professor of Immuno-Oncology at City of Hope, into systemic delivery formulations for DUET-01. We believe that these advancements will enable Duet to go public at a valuation significantly in excess of its current $25 million valuation.”About Scopus BioPharma Scopus BioPharma Inc. is a biopharmaceutical company developing transformational therapeutics for serious diseases with significant unmet medical need. Duet BioTherapeutics, a majority-owned subsidiary of Scopus, was launched in September 2021 by Scopus BioPharma to consolidate its immunotherapy assets. These assets include three distinctive complementary CpG-STAT3 inhibitors: RNA silencing – CpG-STAT3siRNA – (“DUET-01”); Antisense – CpG-STAT3ASO – (“DUET-02”); and DNA-binding inhibitor – CpG-STAT3decoy – (“DUET-03”). The Company is also seeking to develop additional drug candidates and to identify additional compelling technologies for potential acquisition, in-licensing and/or other similar transactions. Forward-Looking Statements This press release may include forward-looking statements that involve risks and uncertainties. Forward-looking statements are statements that are not historical facts. Such forward-looking statements are subject to risks (including those set forth in the Company’s Form 10-K for the fiscal year ended December 31, 2021, as amended, filed with the U.S. Securities and Exchange Commission) and uncertainties which could cause actual results to differ from the forward-looking statements. The Company expressly disclaims any obligations or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in the Company’s expectations with respect thereto or any change in events, conditions or circumstances on which any statement is based. Investors should realize that if our underlying assumptions for the projections contained herein prove inaccurate or that known or unknown risks or uncertainties materialize, actual results could vary materially from our expectations and projections. Further, there can be no assurance that the Company will identify and/or consummate any transaction relating to any additional technologies. Contacts Rodd Leeds/David WaldmanCrescendo Communications, LLCTel: (212) 671-1020Email: SCPS@crescendo-ir.com Hugh Burns/Delia Cannan/Nicholas LeasureReevemarkTel: (212) 433-4600Email: scopus@reevemark.com

免疫疗法并购siRNA

2021-09-03

·BioSpace

Scopus Biopharma Flexes Immuno-Oncology Pipeline Following Its Acquisition of Olimmune

Scopus Biopharma, a New York-based clinical-stage biopharmaceutical firm, recently launched Duet Therapeutics to integrate its immunotherapy assets' management and clinical development with Olimmune, a company it acquired in June for an undisclosed amount. Los Angeles-based Olimmune is a developer of oligonucleotide immunotherapies for treatment-resistant and metastatic cancers. Its lead drug candidate, OLIM-01, is being developed for genitourinary and head and neck cancers and was founded by City of Hope professor and immuno-oncologist Marcin Kortylewski, Ph.D. City of Hope is a world-renowned research and treatment facility for cancer, diabetes, and other life-threatening diseases. Olimmune has exclusive and worldwide licenses to certain patents from City of Hope to develop and commercialize CpG-STAT3ASO and CpG-STAT3decoy. "The integration of the immuno-oncology assets of Scopus and Olimmune creates a comprehensive, industry-leading portfolio of bi-functional cancer-targeting oligonucleotides. Our highly complementary IP-protected technologies all target STAT3 inhibition. We believe our oligonucleotide technologies are unique, highly differentiated, and superior to other STAT3 inhibitors currently under development," said Scopus chairman Joshua R. Lamstein in a statement. Alan Horsager, Ph.D., the president and chief executive officer of the newly launched Duet Therapeutics, will present at the 14th Annual RNA Consortium Meeting on September 10. His participation is significant, as he will be presenting on the topic "Clinical Development of CpG-STAT3 Inhibitors" as part of the Clinical Translation of Oligonucleotide Therapeutics virtual session. Dr. Horsager joined Scopus in July after his role as the director of LA Biospace at Cal State LA. Before that, he co-founded and served as a senior executive of two biotechnology firms and functioned as a research assistant professor at the University of Southern California. A major topic in Horsager's presentation on September 10 will be the Duet Platform, which reflects the strengths of both Duet and Olimmune and is comprised of three distinctive complementary CpG-STAT3 inhibitors: RNA silencing (CpG-STAT3siRNA, DUET-01), antisense (CpG-STAT3ASO, DUET-02), and protein degradation (CpG-STAT3decoy, DUET-03). DUET-01 is currently in a Phase I clinical trial as a monotherapy for B-cell non-Hodgkin lymphoma. DUET-02, which is set to commence in 2022, will INDs in two separate indications for genitourinary and head and neck cancers. Details for DUET-03 have yet to be finalized. "It is a privilege to play a key role in integrating and developing Duet's drug candidates. Based on the large body of scientific data, we firmly believe our oligonucleotide platform has enormous potential to address one of the society's most significant unmet medical needs — unprecedented treatments, and potential cures, for many different types of cancer," noted Dr. Horsager. The biotechnology market welcomed the developments and sent shares in Scopus BioPharma up by 18 percent on September 3 following the news, placing the company's per share value at $5.90.

合作寡核苷酸免疫疗法并购siRNA

2021-09-03

·BioSpace

Scopus BioPharma’s Subsidiary — Duet Therapeutics — to Present at the 14th Annual RNA Consortium MeetingAlan Horsager, Ph.D., President and Chief Executive Officer of Duet, to Present on Clinical Development of CpG-STAT3 Inhibitors

NEW YORK, Sept. 03, 2021 (GLOBE NEWSWIRE) -- Scopus BioPharma Inc. (Nasdaq: “SCPS”), a clinical-stage biopharmaceutical company developing transformational therapeutics for serious diseases with significant unmet medical need, today announced that Alan Horsager, Ph.D., President and Chief Executive Officer of Duet Therapeutics, will present at the 14th Annual RNA Consortium Meeting, to be held virtually on Friday, September 10, 2021. Duet Therapeutics is a wholly-owned subsidiary of Scopus. Dr. Horsager is also President — Immuno-Oncology of Scopus. Dr. Horsager’s presentation will be part of the Clinical Translation of Oligonucleotide Therapeutics session. Dr. Horsager will present on Clinical Development of CpG-STAT3 Inhibitors. Duet Therapeutics was recently launched by Scopus BioPharma to integrate the immunotherapy assets of Scopus and Olimmune, creating the Duet Platform. The Duet Platform is comprised of three distinctive complementary CpG-STAT3 inhibitors: • RNA silencing CpG-STAT3siRNA (“DUET-01”) • Antisense CpG-STAT3ASO (“DUET-02”) • DNA-binding inhibitor CpG-STAT3decoy (“DUET-03”) The Duet Platform enables and facilitates development of STAT3 inhibitors which are highly selective for a multitude of different solid tumors and hematological malignancies. Current and potential indications for the Duet Platform include: B-cell non-Hodgkin lymphoma, T-cell non-Hodgkin lymphoma, genitourinary (e.g., prostate, kidney and bladder) and head & neck cancers. Duet’s CpG-STAT3 inhibitors are also being evaluated as combination therapies with checkpoint inhibitors and CAR-Ts. About Scopus BioPharma Scopus BioPharma Inc., both directly and through subsidiaries, is a clinical-stage biopharmaceutical company developing transformational therapeutics for serious diseases with significant unmet medical need. The company’s lead drug candidate is a novel, targeted immuno-oncology RNA therapy for the treatment of multiple cancers. This drug candidate is highly distinctive, encompassing both RNA therapy and immunotherapy by synthetically linking siRNA to an oligonucleotide TLR9 agonist, creating the potential for targeted gene silencing with simultaneous TLR stimulation and immune activation in the tumor microenvironment. Additional STAT3-targeting immunotherapy drug candidates include bi-functional antisense and protein degradation therapies. In addition, the company is developing additional drug candidates that target the endocannabinoid system, including MRI-1867 for the treatment systemic sclerosis. The company also seeks to identify additional compelling technologies for potential acquisition, in-licensing and/or other similar transactions. Receive updates by following Scopus BioPharma on Twitter here. Forward-Looking Statements This press release may include forward-looking statements that involve risks and uncertainties. Forward-looking statements are statements that are not historical facts. Such forward-looking statements are subject to risks (including those set forth in the company’s Form 10-K for the fiscal year ended December 31, 2020, as amended, filed with the U.S. Securities and Exchange Commission (“SEC”)) and uncertainties which could cause actual results to differ from the forward-looking statements. The company expressly disclaims any obligations or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in the company’s expectations with respect thereto or any change in events, conditions or circumstances on which any statement is based. Investors should realize that if our underlying assumptions for the projections contained herein prove inaccurate or that known or unknown risks or uncertainties materialize, actual results could vary materially from our expectations and projections. Further, there can be no assurance that the company will identify and/or consummate any transaction relating to any additional technologies. Contacts Rodd Leeds/David Waldman Crescendo Communications, LLC Tel: (212) 671-1020 Email: SCPS@crescendo-ir.com Hugh Burns/Delia Cannan/Nicholas Leasure Reevemark Tel: (212) 433-4600 Email: scopus@reevemark.com

合作寡核苷酸免疫疗法并购siRNA

100 项与 DUET-02 相关的药物交易

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