On April 29, 2025 Bayer reported initiation of a Phase I clinical trial with 225Ac-GPC3 (BAY 3547926), an investigational targeted alpha radiopharmaceutical being developed to treat tumors expressing Glypican-3 (GPC3) in patients with advanced hepatocellular carcinoma (HCC) (Press release, Bayer, APR 29, 2025, View Source [SID1234652345]). Oncofetal protein GPC3 is a membrane-associated proteoglycan which is overexpressed in 70-75% of HCC lesions making it an attractive target for targeted radionuclide therapy.1,2 The first-in-human, dose escalation study (NCT06764316) will evaluate the safety, tolerability and preliminary efficacy of BAY 3547926 alone, and as a combination therapy in patients with advanced HCC.

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"Hepatocellular carcinoma continues to be a devastating disease for millions of patients and a pressing unmet need in cancer care. The launch of the Phase I trial using the 225Ac-GPC3 radionuclide therapy marks an important milestone in our commitment to develop new medicines targeting cancer cells with high effect size and precision to improve the lives of people living with cancer," said Dominik Ruettinger, M.D., Ph.D., Global Head of Research and Early Development for Oncology at Bayer’s Pharmaceuticals Division. "Through continued research innovation we can unlock the full potential of targeted alpha therapies which is an emerging class of targeted radionuclide therapy and a strategic focus area for Bayer’s precision oncology development portfolio."

Liver cancer, including hepatocellular carcinoma, is the third leading cause of cancer-related deaths in the world with almost 900,000 new cases annually.3 It is the most rapidly growing cause of cancer deaths in the US accounting for approximately 2% of new cases and 5% of cancer deaths.4 Despite recent scientific advancements, many doctors are not satisfied with the therapeutic benefits from the currently available treatments.

Targeted alpha therapy (TAT) has the potential to address high unmet medical need across various cancer types. Bayer’s growing TAT portfolio combines alpha particle-emitting radionuclides with different targeting moieties. 225Ac-GPC3 is the third TAT program in clinical development and the first investigational targeted radiopharmaceutical for Bayer in HCC. The newly disclosed targeted alpha conjugate joins 225Ac-Pelgifatamab and 225Ac-PSMA-Trillium, which are currently in Phase I clinical trials in patients with advanced metastatic castration resistant prostate cancer.

On April 28, 2025 Bayer introduced 225Ac-GPC3 in an oral presentation during the "New Drugs on the Horizon" session at the AACR (Free AACR Whitepaper) (American Association of Cancer Research) Annual Meeting, showcasing preclinical characterization of the asset including the low uptake and fast clearance from normal organs as well as induction of tumor regression in in vivo models. Recognition in this special symposium highlights the company’s commitment for precision oncology development portfolio.

1

Kolluri A and Ho M (2019), The Role of Glypican-3 in Regulating Wnt, YAP, and Hedgehog in Liver Cancer. Front. Oncol. 9:708. doi: 10.3389/fonc.2019.00708.
2

Yongle Wu, Hui Liu, Huiguo Ding, GPC-3 in hepatocellular carcinoma: current perspectives, Journal of Hepatocellular Carcinoma 2016:3, 63-67.
3

Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, Freddie Bray BSc, MSc, PhD; Mathieu Laversanne MSc; Hyuna Sung PhD; Jacques Ferlay ME; Rebecca L. Siegel MPH; Isabelle Soerjomataram MD, MSc, PhD; Ahmedin Jemal DVM, PhD.
4

SEER Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer. National Cancer Institute. Bethesda, MD, View Source

About BAY 3547926
BAY 3547926 is an investigational targeted alpha radiopharmaceutical being developed to treat tumors expressing Glypican-3 (GPC3) in patients with advanced hepatocellular carcinoma (HCC). It is composed of a GPC3 targeting high affinity antibody radiolabeled with actinium-225 (225Ac). 225Ac-GPC3 delivers highly potent alpha-particles to the GPC3-expressing cancer cells, with the potential to inducing DNA double-strand breaks, reducing cancer cell viability which may potentially cause anti-tumor activity.

About Targeted Alpha Therapy
Targeted alpha therapy (TAT) is an emerging class of radionuclide therapy that can be used against a variety of tumors. It delivers alpha particle radiation directly to the tumor inside the body, either via its bone-seeking property (radium-223) or by combining alpha radionuclides, such as actinium-225, with specific targeting moieties.

Actinium-225 is an alpha particle–emitting radionuclide with a 9.9-day half-life. Alpha particles deposit highly ionizing radiation over a short range. This localized delivery of the radioactive payload induces irreparable DNA double-strand breaks, often resulting in cell death. At the same time, because the energy travels a short range, damage to nearby normal tissues is much reduced.

On April 29, 2025 AbCellera (Nasdaq: ABCL) reported new data on its PSMA x CD3 T-cell engagers (TCEs), presented as a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)Ⓡ (AACR) (Free AACR Whitepaper) 116th Annual Meeting at the McCormick Place Convention Center in Chicago, Illinois, taking place April 25 to 30, 2025 (Press release, AbCellera, APR 29, 2025, View Source [SID1234652344]).

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Targeting prostate-specific membrane antigen (PSMA) with a CD3 TCE could provide an effective treatment option for metastatic castration-resistant prostate cancer (mCRPC). In its poster presentation at AACR (Free AACR Whitepaper), AbCellera demonstrated that its PSMA x CD3 TCEs show promising preclinical activity, including:

Potent in vitro tumor-cell killing, with one molecule showing ~10x higher EC50 than benchmark
Sustained in vitro activity across four rounds of serial T-cell killing
Preclinical in vivo efficacy, with significant tumor growth inhibition in a xenograft mouse model
Potential for enhanced potency when combined with costimulatory PSMA x CD28 bispecifics
"The preclinical data package presented at AACR (Free AACR Whitepaper) is the first demonstration that our novel CD3-binders can be used to generate molecules with potent anti-tumor efficacy in vivo," said Adam Clarke, Ph.D., SVP, Discovery at AbCellera. "The poster underscores the strength of our TCE platform strategy, which is to combine diverse CD3- and tumor-binding antibodies and use empirical testing to engineer optimized therapeutic candidates. In addition, the data strongly support the use of costimulation to further increase anti-tumor activity."

On April 29, 2025 Cellworks Group Inc., a leader in Personalized Therapy Decision Support and Best-in-Class PTRS, reported compelling results from a new study demonstrating the ability of the Cellworks Platform to identify patients with high microsatellite instability (MSI-H) who may not respond to immune checkpoint inhibitors (ICIs), despite MSI-H status (Press release, Cellworks, APR 29, 2025, View Source [SID1234652343]). Results from the study were showcased in a poster presentation titled, Use of Biosimulation to Predict Immune Checkpoint Inhibitor Resistance in Patients with High Microsatellite Instability as part of the AACR (Free AACR Whitepaper) Annual Meeting 2025 taking place April 25-30, 2025 at the McCormick Place Convention Center in Chicago.

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While immune checkpoint inhibitors (ICIs) such as pembrolizumab are considered a standard-of-care for MSI-H cancers, MSI-H status alone is not a definitive predictor of treatment success. In this study, Cellworks applied its unique mechanistic Computational Biology Model (CBM) to biosimulate patient-specific responses to ICIs. The computational biosimulation process in the study uncovered molecular signatures of resistance in MSI-H patients who were predicted to have poor response to ICIs, providing a deeper understanding of why some MSI-H patients fail to benefit from immunotherapy.

Key Findings

Efficacy Scores Significantly Higher in MSI-H Patients. MSI-H patients demonstrated significantly higher pembrolizumab efficacy scores compared to microsatellite stable (MSS) patients in both STAD (average ES: 20.5 vs. 3.2, p < 0.001) and CRC (average ES: 13.4 vs. 2.4, p < 0.001).
Large Subset of MSI-H Patients Predicted to Have Low ICI Response. Despite being MSI-H, 59% of STAD and 81% of CRC patients were identified as low pembrolizumab responders.
Molecular Drivers of Resistance Identified. In MSI-H patients classified as low pembrolizumab responders, higher rates of NOTCH2, EGFR, and EZH2 amplifications, along with TP53 loss-of-function mutations, were identified. In MSI-H/ES-L CRC patients, MYC amplification was significantly enriched (p < 0.05).
"These findings highlight the power of using patient-specific drug response methods to move beyond MSI-H status and identify critical molecular drivers of immune checkpoint inhibitor resistance," said Dr. James Wingrove, Chief Development Officer at Cellworks and presenting author of the study. "By identifying patients unlikely to respond to ICIs, we can help oncologists personalize treatment strategies and improve outcomes for MSI-H patients who may otherwise receive ineffective therapies."

"This study demonstrates the importance of looking beyond MSI status to understand immune checkpoint inhibitor resistance at a molecular level," said Dr. Michael Castro, Chief Medical Officer at Cellworks. "Our biosimulation revealed that MSI-H patients with low predicted response to pembrolizumab frequently harbored alterations such as NOTCH2, EGFR, and EZH2 amplifications, as well as TP53 loss-of-function mutations in STAD, and MYC amplifications in CRC. Identifying these resistance-associated biomarkers can help guide clinicians in selecting more effective, personalized treatment strategies for MSI-H patients who may not benefit from ICIs alone."

Study Design

Cellworks developed a mechanistic Computational Biology Model (CBM) that can be personalized based on a patient’s tumor-based genomic profile, revealing signaling pathway dysregulation and patient-specific drug response. Output from the model was used to identify MSI-H patients who may have a poorer response to ICIs. Computational biosimulation was performed using real-world retrospective cohorts of 423 STAD patients and 534 CRC patients (TCGA). MSI measurements were provided by TCGA. Efficacy scores based on biosimulated composite cell growth in response to disease and therapy were generated on all patients for pembrolizumab. Molecular rationales for ICI resistance were identified for MSI-H patients with low pembrolizumab efficacy scores.

The Cellworks Platform

The Cellworks Platform performs computational biosimulation of protein-protein interactions, enabling in silico modeling of tumor behavior using comprehensive genomic data. This allows for the evaluation of how personalized treatment strategies interact with the patient’s unique tumor network. Multi-omic data from an individual patient or cohort is used as input to the in silico Cellworks Computational Biology Model (CBM) to generate a personalized or cohort-specific disease model.

The CBM is a highly curated mechanistic network of 6,000+ human genes, 30,000 molecular species and 600,000 molecular interactions. This model along with associated drug models are used to biosimulate the impact of specific compounds or combinations of drugs on the patient or cohort and produce therapy response predictions, which are statistically modeled to produce a qualitative therapy response score for a specific therapy. The Cellworks CBM has been tested and applied against various clinical datasets with results provided in over 125 presentations and publications with global collaborators.

On April 29, 2025 Ensoma, a genomic medicines company advancing the future of medicine through one-time, in vivo therapies designed to precisely and durably engineer the hematopoietic system to treat chronic diseases, reported it will present preclinical data and manufacturing advancements at the American Society of Gene & Cell Therapy (ASGCT) (Free ASGCT Whitepaper) 28th Annual Meeting, hosted May 13-17 in New Orleans (Press release, Ensoma, APR 29, 2025, View Source [SID1234652342]).

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The company’s poster presentations will highlight key programs that leverage its in vivo HSC engineering platform. Ensoma combines a unique delivery system with an advanced gene engineering toolkit, offering the potential for durable, transformative therapies to address chronic diseases, improve patient access and significantly reduce treatment burden. The platform uses virus-like particles (VLPs) that preferentially bind to HSCs, efficiently deliver DNA to the nucleus and de-target the liver. With a 35-kilobase cargo capacity, these VLPs carry a diverse range of genomic engineering constructs, including control elements that enable specific cargo expression in targeted cells, from single base edits to large multi-gene insertions.

"We look forward to presenting preclinical data at ASGCT (Free ASGCT Whitepaper) that underscore the potential of our in vivo HSC engineering platform to address complex genetic disorders and cancer," said Robert Peters, Ph.D., chief scientific officer of Ensoma. "Exciting new findings from our non-human primate studies reinforce the precision and effectiveness of our VLPs, showcasing their ability to safely deliver genetic therapies with targeted biodistribution and expression. With this strong progress, Ensoma remains on track to initiate our first clinical trial in the second half of 2025—marking a major step toward bringing this groundbreaking therapy to patients."

"Building on this momentum, our novel adenovirus production process is a significant milestone for Ensoma, ensuring the scalable and high-quality production of VLPs needed for clinical trials," said Dan Leblanc, chief technology officer of Ensoma. "This robust suspension manufacturing process is delivering consistent product yield and quality to support the clinical use of EN-374 for the treatment of X-CGD. It’s incredibly rewarding to see our platform move closer to delivering potentially transformative therapies to patients."

Poster Presentations at ASGCT (Free ASGCT Whitepaper) 28th Annual Meeting:

Title: In Vivo Engineering of Hematopoietic Stem Cells with Virus-like Particles to Generate Multi-Lineage CAR Immune Cell Therapy for Cancer (1783)
Poster Presentation Time/Date: 5:30-7:30 p.m. CT, Thursday, May 15
Location: Poster Hall I2
Presenter: Chirayu Chokshi, Ph.D., Ensoma

Data Summary: Ensoma will present updated data from its preclinical HER2 CAR program. An HSC-targeted VLP encoding lineage-specific regulatory elements to direct CAR expression resulted in robust generation of HSC-derived CAR-M, NK and T cells in vivo. This lineage-restricted, multi-cellular CAR therapy mediated tumor control and microenvironment remodeling, supporting Ensoma’s technology as a highly differentiated approach to addressing solid tumors.

Title: Novel In Vivo Gene Therapy Approach to Hematopoietic Stem Cell (HSC) Engineering Creates Durable HSC-Derived Neutrophils to Treat X-Linked Chronic Granulomatous Disease (1780)
Poster Presentation Time/Date: 5:30-7:30 p.m. CT, Thursday, May 15

Location: Poster Hall I2

Presenter: Sravya Kattula, Ph.D., Ensoma

Data Summary: Ensoma will present updated preclinical data from its X-CGD program with EN-374, which highlights the use of its VLP platform to efficiently modify HSCs in vivo and restore neutrophil function. In this preclinical study in a CGD mouse model, EN-374 provided durable gene correction in neutrophils to restore CYBB protein expression and activity. This study sets the foundation for Ensoma’s in vivo HSC gene therapy to reach the clinic and be applied to a range of genetic disorders that thus far have only been addressed with ex vivo gene therapies.

Title: Acute Safety and Biodistribution Profile of Hematopoietic Stem Cell (HSC) Targeting Virus-like Particles Based on Helper-dependent Adenovirus Serotype 5/35++ in Non-human Primates (1779)
Poster Presentation Time/Date: 5:30-7:30 p.m. CT, Thursday, May 15
Location: Poster Hall I2
Presenter: Patrick Au, Ph.D., Ensoma

Data Summary: Ensoma will present data from a non-human primate study evaluating the safety, biodistribution and transgene expression profiles of its HSC-targeting VLPs. Results showed favorable tolerability without any clinical signs of toxicity and a well-characterized biodistribution, supporting the continued development of Ensoma’s VLP-based platform as a safe and effective solution for in vivo HSC engineering.

Title: Development and Scale-up of a Novel Adenovirus Production Process (2016)
Poster Presentation Time/Date: 6:00-7:30 p.m. CT, Tuesday, May 13
Location: Poster Hall I2
Presenter: Chapman Wright, Ph.D., Ensoma

Data Summary: Ensoma will present the establishment of a novel, serum-free suspension manufacturing process for large-scale, high-efficiency VLP manufacturing. The presentation will address adaptation of an adherent cell line to a serum-free suspension cell culture, followed by a design-of-experiment strategy for efficient development of a clinical-scale production process.

On April 29, 2025 Shorla Oncology (‘Shorla’), a U.S.-Ireland specialty pharmaceutical company, reported that the U.S. Food and Drug Administration has granted approval for 100 mg/10mL multi-dose vial of TEPYLUTE, a ready-to-dilute formulation of thiotepa to treat breast and ovarian cancer, that eliminates the need for reconstitution and may reduce preparation time and errors offering more scheduling flexibility for their patients (Press release, Shorla Oncology, APR 29, 2025, View Source [SID1234652341]).

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"We are pleased to offer another viable treatment option for patients with breast and ovarian cancer," said Sharon Cunningham, Chief Executive Officer and Co-Founder of Shorla Oncology. "Once opened, our 100mg vial of TEPYLUTE is stable for 14 days when properly stored, giving providers the flexibility they need when preparing and administering this very important treatment.

TEPYLUTE is a ready to dilute formulation of a well-established, standard of care oncology drug thiotepa that has been manufactured as freeze-dried powder since the 1950s.

"This is a huge win for providers because TEPYLUTE avoids the need for complicated and time-consuming reconstitution," said Orlaith Ryan, Chief Technical Officer and Co-Founder of Shorla Oncology.

We are excited to bring TEPYLUTE to the US Market. It provides consistent dosing accuracy and allows for "just in time" preparation, which benefits everyone, especially patients." said Rayna Herman, Chief Commercial Officer, Shorla Oncology.

The American Cancer Society estimates that more than 300,000 women will be diagnosed with breast cancer in the U.S in 2025.2 About 20,890 women will be diagnosed with ovarian cancer in the U.S. in 2025.