On October 23, 2024 Repare Therapeutics Inc. ("Repare" or the "Company") (Nasdaq: RPTX), a leading clinical-stage precision oncology company, reported updated data highlighting the benefits of its individualized schedule for the management of anemia in the Phase 1 MYTHIC clinical trial treating patients with the combination of lunresertib, a first-in-class PKMYT1 inhibitor, and camonsertib, a potential best-in-class oral small molecule ATR inhibitor (lunre+camo) (Press release, Repare Therapeutics, OCT 23, 2024, View Source [SID1234647356]).

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Lunre+camo in the MYTHIC clinical trial (NCT04855656) previously demonstrated promising clinical activity in molecularly selected patients across multiple tumor types. In this analysis, Repare followed patients for approximately nine months at the recommended Phase 2 dose (RP2D) to assess the effectiveness of an individualized schedule. The analysis demonstrated a successful approach to mitigating mechanism-based anemia while maintaining clinical benefit. Further, Repare observed no thrombocytopenia of any grade nor serious neutropenia in these patients.

Dr. Martin Højgaard of Rigshospitalet, Denmark presented this data in a poster titled, "Individualized schedule improves rates and severity of anemia in patients treated with lunresertib, a PKMYT1 inhibitor, and camonsertib, an ATR inhibitor, in the Phase I MYTHIC study (NCT04855656)" at the 36th EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) (ENA) Symposium on Molecular Targets and Cancer Therapeutics, being held October 23-25, 2024 in Barcelona, Spain.

"This individualized schedule in heavily pretreated patients with advanced cancers from our MYTHIC clinical trial met its goal of maintaining antitumor activity while reducing rates of grade 3 anemia," said Maria Koehler, MD, PhD, Executive Vice President and Chief Medical Officer of Repare. "We believe that these data demonstrate a favorable and differentiated tolerability profile versus both current and emerging therapies. We look forward to sharing efficacy data from the gynecological cancer expansion cohort of the MYTHIC clinical trial in December 2024."

Key Clinical Trial Findings:

The individualized schedule mitigated mechanism-based anemia based on entry hemoglobin observed in a minority of patients
Overall clinical benefit was maintained after schedule change with generally maintained radiographic regressions and molecular responses:
– Despite the change in schedule, deepening of target lesion regression was noted in some patients
– After 9 weeks on therapy, there was no observed impact on Progression Free Survival (PFS) in patients who started on or switched to the schedule of 2 weeks on / 1 week off of treatment
Dose optimization meaningfully reduced Grade 3 anemia (22.6% vs. 51.4%, previously) in all patients:
– Baseline marrow function was the key reason for Grade 3 anemia as opposed to exposure to therapy
– Baseline hemoglobin, prior therapies, and treatment intensity (weekly vs. 2 weeks on / 1 week off) predicted Grade 3 anemia frequency with lunre+camo
– Anemia reduction was greatest in patients with baseline hemoglobin less than 11g/dL (Grade 3 anemia at week 12: 34% vs. 68%, previously; overall risk reduction: 58%)
– Red blood cell transfusions (13% vs. 43%, previously), dose interruptions (13% vs. 23%) and dose reductions (6% vs. 17%) were also reduced with the new schedule
– Other Grade 3 events were already uncommon (<5% incidence) and remained consistently low, regardless of schedule

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.