On October 23, 2024 TreeFrog Therapeutics reported a research collaboration with the University of Pittsburgh focused on the potential of tertiary lymphoid structures (TLS) in immuno-oncology, an exciting emerging field in cancer research (Press release, TreeFrog Therapeutics, OCT 23, 2024, View Source [SID1234647355]).

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Harnessing the pioneering research ongoing by Tullia Bruno, Ph.D, Assistant Professor in the Department of Immunology at the University of Pittsburgh and her team at UPMC Hillman Cancer Center, alongside the biotechnology expertise of TreeFrog Therapeutics and its proprietary C-Stem 3D cell encapsulation technology, the collaboration aims to break new ground in 3D immunology.

Tertiary lymphoid structures are ectopic lymphoid structures that develop in chronically infected organs, sites of inflammation, autoimmune diseases, and in transplants subjected to chronic rejection. In recent years, they have been described in solid tumors, where they act as crucial players in the body’s immune response to cancer. By deciphering the intricate mechanisms underlying TLS function and leveraging this knowledge, researchers aim to develop novel treatment approaches that harness the immune system’s inherent capacity to recognize and eliminate cancer cells.

"We are delighted to embark on this collaboration with Professor Bruno to apply our encapsulation technology to further understand and work with TLS, bringing new levels of control over the microenvironment of these amazing 3D immune structures. Research indicates that the presence of TLS in cancer may boost anti-tumor immunity and improve responses and prognosis, so I am excited to work with Professor Bruno and her team to explore synergies and opportunities of our 3D technology in this emerging field" said Maxime Feyeux, Chief Scientific Officer, TreeFrog Therapeutics.

"If we are able to recapitulate TLS using 3D technology, there are so many questions we could ask about their formation and modulation in a controlled manner. With 3D technology being a new frontier, this could help immensely as we work to better understand TLS biology, which could complement our work in patient samples and physiologically relevant murine models," commented Professor Bruno, Assistant Professor, Department of Immunology, University of Pittsburgh.

On October 23, 2024 Akamis Bio, a clinical-stage oncology company using a proprietary Tumor-Specific Immuno-Gene Therapy (T-SIGn) platform to deliver novel immunotherapeutic proteins, biomolecules and transgene combinations to treat solid tumors, reported the publication of data supporting the continued clinical development and intravenous route of administration of NG-350A, its lead program for the treatment of advanced metastatic cancers (Press release, Akamis Bio, OCT 23, 2024, View Source [SID1234647354]).

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NG-350A is a next-generation transgene-armed tumor gene therapy designed to drive intratumoral expression of a CD40 agonist monoclonal antibody resulting from selective replication in both primary and metastatic epithelial-derived solid tumors. Data from the first-in-human dose escalation FORTITUDE study in patients with metastatic/advanced epithelial tumors supports proof-of-mechanism for NG-350A, with strong evidence of tumor-selective delivery, replication and transgene expression. Additionally, this study demonstrates that intravenous delivery of NG-350A results in a superior overall pharmacokinetic and pharmacodynamic profile, with no apparent disadvantages versus intratumoral injection.

Blood sample analysis from patients showed sustained persistence of NG-350A up to seven weeks after intravenous dosing was completed (maximum follow up), particularly at higher dose levels. Further, a dose-dependent pattern was also seen with systemic delivery, resulting in four patients remaining positive for vector DNA in biopsies nearly two months after receiving the treatment. Transgene messenger RNA from replicating NG-350A was detected in nearly half the patients with intravenous treatment but only in one patient that had received intratumoral injection. Sustained increases in inflammatory cytokines were also observed following dosing, particularly with higher intravenous dose levels.

"These findings are highly supportive of our ongoing focus on intravenous administration of NG-350A to safely drive sustained transgene expression within the tumor microenvironment. Systemic delivery offers considerable advantages over current intratumoral approaches, particularly with transgene-containing viral vectors where the cargo needs to reach both the primary tumor and metastases throughout the body – an application for which direct injection or dependence on an abscopal effect is not viable," said Oliver Rosen, M.D., Chief Medical Officer at Akamis.

Dr. Rosen continued: "This study demonstrated that a T-SIGn therapeutic armed with targeted immunostimulatory proteins such as CD-40 agonists can be successfully delivered intravenously, resulting in a superior overall pharmacokinetic and pharmacodynamic profile compared to intratumoral administration. Our preliminary data suggest that the local expression of immunostimulatory therapies following intravenous administration can overcome toxicity that limits non-targeted systemic administration. We look forward to continuing to understand the potential of this treatment in upcoming proof-of-concept studies."

NG-350A will now be studied in combination with chemoradiotherapy in FORTRESS, a multicenter open-label non-randomized Phase 1b trial of patients with locally advanced rectal cancer.

A link to the publication "First-in-human clinical outcomes with NG-350A, an anti-CD40 expressing tumor-selective vector designed to remodel immunosuppressive tumor microenvironments" can be found here.

About T-SIGn

Akamis Bio’s T-SIGn therapeutics are based on a replication competent, chimeric group B adenovirus backbone which has been adapted via directed evolution to home specifically to both primary and metastatic epithelial-derived solid tumor tissue following intravenous delivery. Once at the tumor site, T-SIGn therapeutics can drive the intratumoral expression of multiple transgene payloads, turning solid tumor cells into "drug factories" while leaving healthy tissue unaltered and intact. The intratumoral expression of immunologically active biomolecules and therapeutic proteins can result in the remodeling of the solid tumor microenvironment, triggering robust antitumor immune responses. T-SIGn therapeutics have the potential to be used in the monotherapy setting, as well as in combination with other immuno-oncology agents to target the key mechanisms that tumors use to evade the immune system.

On October 23, 2024 ImmPACT Bio USA, Inc. ("ImmPACT Bio"), a clinical-stage company developing transformative logic-gate-based chimeric antigen receptor (CAR) T-cell therapies for treating cancer and autoimmune diseases, reported that it will present new preclinical data about the potential of IMPT-601, a Claudin18.2/transforming growth factor beta (TGF-β) bispecific CAR T-cell therapy for the treatment of gastric cancer (Press release, ImmPACT-Bio, OCT 23, 2024, View Source;bispecific-car-t-cell-therapy-impt-601-for-gastric-cancer-at-the-sitc-39th-annual-meeting-302282396.html [SID1234647353]). These data were selected for an oral presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 39th Annual Meeting, to be held November 8-10, 2024 in Houston, TX.

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IMPT-601 is designed to overcome the suppressive tumor microenvironment by enhancing CAR T-cell infiltration, overcoming T-cell exhaustion, and reducing regulatory T-cell numbers through dual targeting of Claudin 18.2 and TGF-β.

Details for the presentation are as follows:
Title: Therapeutic Potential of IMPT-601, a Claudin18.2/TGF-β Bispecific CAR, Against Gastric Cancer
Abstract Number: 298
Presenter: Melanie L. Munguia, ImmPACT Bio
Session: Oral Abstract Session 2
Date and Time: Saturday, November 9, 2024, 3:25 – 4:45 PM CDT
Location: Exhibit Halls A B George R. Brown Convention Center

Abstracts and additional details can be found at the SITC (Free SITC Whitepaper) 39th Annual Meeting website.

On October 23, 2024 HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as "natural hotspots," reported it will present preclinical data from the Company’s mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) CARD11-BCL10-MALT1 (CBM) signalosome glue program highlighting its potential in NF-kB-driven solid tumors in a poster presentation at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (Press release, HotSpot Therapeutics, OCT 23, 2024, View Source [SID1234647352]).

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MALT1 is a component of the CBM protein complex, which serves as a key regulator of NF-kB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies and solid tumors. Leveraging the Company’s proprietary Smart AllosteryTM platform, HotSpot has developed a potential first-in-class small molecule signalosome glue designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NF-kB pathway, while sparing MALT1’s protease function.

"Our proprietary Smart Allostery platform has enabled the development of a MALT1 signalosome glue designed to selectively inhibit MALT1’s scaffolding function, a distinct activity profile that enables deep inhibition of the NF-kB pathway," said Geraldine Harriman, Ph.D., Chief Scientific Officer of HotSpot Therapeutics. "As the NF-kB signaling pathway is a well-characterized oncogenic driver, these preclinical data lend support for HST-1021’s potential utility for NF-kB-driven tumors, including as a precision oncology approach for solid tumors mediated by this pathway."

The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 CBM signalosome glue development candidate:

In contrast to MALT1 protease inhibitors, HST-1021 demonstrated robust inhibition of CBM signalosome activity.
In an NF-kB-driven nasopharyngeal carcinoma patient-derived xenograft model, HST-1021 demonstrated dose-dependent anti-tumor activity, supporting HST-1021’s potential for the treatment of NF-kB-driven solid tumors.

On October 23, 2024 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported four posters with clinical and preclinical data from RVU305 (MTA-cooperative PRMT5 inhibitor), WRN program, ONCO Prime, and RVU120 at the 2024 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium (ENA), October 23-25, Barcelona, Spain (Press release, Ryvu Therapeutics, OCT 23, 2024, View Source [SID1234647351]).

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"It is an exciting time for Ryvu’s pipeline as we advance a potentially best-in-class PRMT5 inhibitor, RVU305, through IND-enabling studies. We are pleased to highlight data from this program, with expected initiation of clinical development in Q4 2025, and other Ryvu projects at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium this year. We are especially proud of our ONCO Prime target discovery platform, which demonstrates the progress of our scientific efforts on novel synthetic lethal (SL) inhibitors targeting key oncogenic drivers such as KRAS and other mutations." – said Krzysztof Brzózka, Ph.D., Chief Scientific Officer.

Upcoming Events

R&D Update at ENA 2024: webinar on Friday, October 25 at 11:00 AM CET to discuss the data presented at the ENA Symposium. To join the webcast, please register here: View Source
RVU120 Program Progress and Data Update: webinar on Thursday, December 12, 10:00 AM CET to discuss the ongoing RVU120 Phase II studies.
Poster highlights:
Poster Title: Discovery of novel MTA-cooperative PRMT5 preclinical candidate as targeted therapeutics for MTAP-deleted cancers
Poster Number: 32
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

Ryvu has developed a potentially best-in-class MTA-cooperative PRMT5 inhibitor, RVU305, demonstrating favorable drug-like properties and effective PRMT5 inhibition dependent on MTA binding.

RVU305 exhibits robust antiproliferative activity in MTAP-null cancer models, including over 100% tumor growth inhibition (TGI) at several dose levels and multiple complete remissions (CRs) at several dose levels in a DoHH2 MTAP-deleted model.
Tolerability and selectivity towards MTAP-deleted cells was also demonstrated in in vitro and in vivo preclinical models.
Overall, the findings highlight the potential of RVU305 preclinical candidate as a promising therapeutic option for patients with MTAP-deleted cancers.
Poster Title: Exploring synthetic lethality and novel drug combinations in patient-derived cells
Poster Number: 417
Session date and time: Friday, October 25 (09:00-15:00 CEST)

Ryvu has developed a proprietary platform, ONCO Prime, to discover novel synthetic lethal (SL) inhibitors targeting key oncogenic drivers such as KRAS and other mutations.

Initial data are presented in colorectal cancer (CRC), but the platform has the potential to discover novel SL targets across all tumor types. ONCO Prime uses human intestinal stem cell (hISC)-derived cancer model cells, patient-derived xenografts (PDXs), and clinical samples to conduct genomic and functional analyses.
Ryvu generated isogenic cancer models and validated them through transcriptomic profiling of patient-derived xenografts (PDXs) and patient-derived cell cultures to ensure clinical relevance.
The data presented in this poster highlights the outcomes of chemical compound and CRISPR/Cas9 screenings, confirming the reliability and relevance of our model for identifying new therapeutic targets in oncology.
Poster Title: Discovery of WRN inhibitors as targeted therapy in the treatment of microsatellite unstable (MSI-H) tumors
Poster number: 107
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

Ryvu is developing a series of potent and selective WRN helicase inhibitors that demonstrate pronounced efficacy in tumors with high microsatellite instability (MSI-H).

Ryvu WRN inhibitors show nanomolar potency in viability assays in MSI-H cell lines, with excellent selectivity over microsatellite-stable (MSS) cells.
In in vivo studies, Ryvu inhibitor strongly suppressed tumor growth in an MSI-H model (SW48) while not impacting the MSS model (SW620).
The compounds exhibit favorable pharmacokinetics, achieving optimal exposure and target engagement, further enhancing their therapeutic potential in MSI-H cancers.
Poster Title: Phase I/II trial of RVU120, a CDK8/CDK19 inhibitor in patients with relapsed/refractory metastatic or advanced solid tumors
Poster Number: 34
Session date and time: Wednesday, October 23 (12:00-19:00 CEST)

RVU120 is being tested in patients with solid tumors in an ongoing Phase I/II clinical trial, AMNYS-51. RVU120 has demonstrated a manageable safety profile across multiple dose levels and dosing schedules in patients with advanced or metastatic solid tumors.

No dose-limiting toxicities (DLTs) were observed, and most treatment-emergent adverse events (TEAEs) were mild to moderate, with nausea and vomiting being the most common.
6/8 patients with adenoid cystic carcinoma achieve a longer duration of treatment on RVU120 compared with their most recent prior line of therapy. A reduction of 20% of target lesions was observed in 2 patients with adenoid cystic carcinoma.
The recommended phase 2 dose (RP2D) for the QOD schedule was identified as 250 mg and remains the primary dosing schedule in clinical studies, but a continuous dosing schedule was explored and could offer an alternative to patients: continuous every day administration (QD) of RVU120 at doses of 100 mg and 150 mg is considered safe and may improve tolerability of RVU120 compared with 250 mg every other day.