On April 28, 2025 Edgewood Oncology, a clinical-stage biotechnology company focused on delivering BTX-A51 to patients with hematologic malignancies and genetically-defined solid tumors, reported the presentation of new preclinical data presented by Dana-Farber Cancer Institute and Hebrew University-Hadassah Medical School in support of an ongoing investigator-sponsored Phase 1 study of BTX-A51 in liposarcoma (LPS) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 25-30, 2025, in Chicago (Press release, Edgewood Oncology, APR 28, 2025, View Source [SID1234652229]).

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BTX-A51 is a first-in-class, small molecule kinase inhibitor that co-targets casein kinase 1 alpha (CK1a) and cyclin-dependent kinases 7 and 9 (CDK7 and CDK9), three master regulators of cancer cell survival and transcriptional control.

The presentation, "Therapeutic potential of combined targeting of casein kinase 1 alpha (CK1a) and CDK7/9 with the inhibitor BTX-A51 in human liposarcomas," highlights new mechanistic and efficacy data in patient-derived cell lines and xenograft models. One of the most significant findings from the presentation is that CK1a is an essential gene for the growth of liposarcomas based on genome-scale RNAi perturbation analysis. The study also used RNAi knockdown and targeted small molecules to confirm that inhibition of CK1a, CDK7, and CDK9 has synergistic impacts on LPS cell survival. As a single agent, BTX-A51 blocked MDM2 and induced P53 expression, stimulating potent apoptosis in LPS models while significantly inhibiting tumor growth in patient-derived xenografts at well tolerated dose levels.

"Well-differentiated and dedifferentiated liposarcomas (WD/DDLPS) remain among the most challenging soft tissue sarcomas to treat," said Geoffrey I. Shapiro, M.D., Ph.D., Professor of Medicine, Harvard Medical School, and director of the Early Drug Development Center at Dana-Farber Cancer Institute. "This study identifies novel, targetable vulnerabilities in LPS and offers a compelling justification for the clinical evaluation of BTX-A51 in this patient population."

BTX-A51 is currently being evaluated in an open-label, investigator-sponsored Phase 1 pilot study at Dana-Farber Cancer Institute in patients with metastatic and/or recurrent liposarcomas characterized by Murine Double Minute Clone 2 (MDM2) amplifications. Additional details about the study can be found at clinicaltrials.gov under the identifier NCT06414434.

"These findings strengthen the rationale for BTX-A51’s mechanism of action and support its potential across a spectrum of genetically defined cancers," said David N. Cook, Ph.D., Chief Executive Officer of Edgewood Oncology. "We’re encouraged by the strength of these preclinical findings, which further support the ongoing clinical advancement of BTX-A51."

Additional Details about the Study
Through computational and experimental methods, including DepMap screening, siRNA silencing, and small-molecule inhibitor profiling, the study confirmed that CK1α, CDK7, and CDK9 are essential for LPS survival. CK1a knockdown by itself was shown to be toxic to LPS cell lines and CDK9 inhibition alone suppressed LPS cell growth and induced apoptosis by downregulating MDM2 and activating p53. When CK1α depletion and CDK9 inhibition were combined, the potency of the individual approaches was amplified. In addition, combining CDK7 and CDK9 inhibitors synergistically inhibited LPS cell lines. These observations led to the evaluation of BTX-A51, which inhibits all three kinases with nanomolar potency. BTX-A51 robustly reduced MDM2 expression and induced expression of p53 and PUMA. The compound also lowered MCL1 expression and sensitized cells to apoptotic signaling through BIM and PUMA, as confirmed by BH3 profiling. In vivo studies in two LPS PDX models demonstrated that BTX-A51 is well tolerated and inhibits tumor growth under clinically relevant dosing conditions.

On April 28, 2025 Delcath Systems, Inc. (NASDAQ: DCTH), an interventional oncology company focused on the treatment of primary and metastatic liver cancers, reported that the U.S. Food and Drug Administration (FDA) has completed its 30-day review of the Company’s Investigational New Drug (IND) application for a Phase 2 clinical trial evaluating HEPZATO in combination with standard of care (SOC) for liver-dominant metastatic breast cancer (mBC) (Press release, Delcath Systems, APR 28, 2025, View Source [SID1234652228]). With the FDA’s review complete, Delcath is now cleared to initiate patient enrollment in the U.S.

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The Phase 2 trial will evaluate the safety and efficacy of HEPZATO in combination with SOC versus SOC alone in patients with liver-dominant HER2-negative mBC following the failure of previous treatments. The SOC options will be the physician’s choice of eribulin, vinorelbine or capecitabine. Approximately 90 patients will be enrolled in this randomized, controlled trial. The study will take place at more than 20 sites across the United States and Europe, with patient enrollment expected to begin in the fourth quarter of 2025. The trial’s primary endpoint, hepatic progression-free survival, is anticipated to be announced by the end of 2028, while results for overall survival, a secondary endpoint, are expected in 2029.

Company management estimates that approximately 7,000 patients annually in the United States are affected by HER2-negative metastatic breast cancer with liver metastases and are candidates for third line treatment. This population includes patients with a significant burden of liver metastases, which are likely to be the primary cause of mortality. By focusing on this demographic, Delcath intends to offer a novel therapeutic option to those patients with limited treatment alternatives.

"This randomized Phase 2 trial marks an important milestone as we expand the clinical investigation of HEPZATO into patients with liver-dominant metastatic breast cancer," said Gerard Michel, Chief Executive Officer of Delcath Systems, Inc. "We are excited to bring new hope to patient populations in indications beyond metastatic uveal melanoma and to further demonstrate the potential of HEPZATO to address unmet needs in oncology. This study underscores our commitment to broadening the applications of HEPZATO and the underlying hepatic delivery system, positioning us as a platform technology that can offer directed treatment options for a variety of liver-dominant cancers."

On April 28, 2025 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a leader in the field of masked, conditionally activated biologics, reported new preclinical data in collaboration with Moderna on an mRNA encoded masked IL-12 molecule (Press release, CytomX Therapeutics, APR 28, 2025, View Source [SID1234652227]). The data will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in Chicago, IL on April 25-30, 2025.

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"We are excited to share new preclinical data at AACR (Free AACR Whitepaper), establishing proof of concept for an mRNA encoded masked molecule in the treatment of cancer," said Marcia Belvin, Ph.D. SVP, Chief Scientific Officer of CytomX Therapeutics. "IL-12 has shown promising anti-tumor activity, but its clinical use has been limited due to its inflammatory toxicity and narrow therapeutic window. By combining CytomX’s proprietary PROBODY masking technology and Moderna’s mRNA technology, we have created an mRNA therapeutic encoding a masked IL-12, designed to be selectively activated within the tumor microenvironment (TME), with limited systemic activity. The data presented at AACR (Free AACR Whitepaper) show proof of concept for this unique technology combination, a key initial goal of the CytomX-Moderna collaboration."

Details for the poster presentation are as follows:
Presentation Title: An mRNA-encoded masked IL-12 improves systemic tolerability while maintaining anti-tumor efficacy in preclinical studies
Poster Number: 3127/12
Section 24
Session Date and Time: April 28, 2025, 2:00 pm – 5:00 pm CT

On April 28, 2025 Crown Bioscience, a global contract research organization (CRO) headquartered in the United States and a part of JSR Life Sciences and Japan-based JSR Corporation, reported at AACR (Free AACR Whitepaper) 2025 its cutting-edge 3D bone marrow niche (BMN) in vitro models to advance hematological cancer research (Press release, Crown Bioscience, APR 28, 2025, View Source [SID1234652226]). Providing both the physical environment (cell-cell interactions), and the growth factor cocktail that hematological cancer cells require to thrive and proliferate, this innovative model provides a dynamic platform for studying liquid malignancies such as acute myeloid leukemia (AML) and multiple myeloma (MM).

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The system incorporates key cellular components—stromal cells and endothelial cells—within biofunctional hydrogels seeded with patient-derived tumor cells, optionally supplemented with autologous immune cells. By accurately capturing the essential tumor microenvironment, the niche provides a physiologically relevant system that offers insight into tumor behavior, immune evasion, and drug resistance, outperforming classic suspension assays when it comes to cell viability, assay versatility, and clinical predictivity.

"Crown Bioscience is proud to unveil this high-content imaging-based 3D BMN platform that offers a unique and robust high-throughput drug screening in primary patient cells that allows testing of malignancies and toxicities at scale," said Ludovic Bourré, Vice President, Research and Innovation, Crown Bioscience. "Until now, bone marrow research has lagged behind solid tumor research due to lack of relevant in vitro models. With these BMN technological advances, we are now able to help researchers understand how cancer survives therapies once it reaches the bone marrow. This allows them to guide the selection of drug candidates with fewer off-target or bone marrow-related side effects and to overcome drug resistance mechanisms."

Researchers can realize significant benefits with the BMN models including:

The use of more predictive ex vivo data to increase accuracy in cancer cell response

The ability to screen compounds for hematological toxicity earlier in the drug development process

Enhanced translational insight for more informed in vivo studies, helping to reduce animal use and speed up drug development

Enabling the creation of more effective, targeted treatments through adhesion-mediated drug resistance modeling

Unlocking new potential in stem cell, hematological malignancy, and bone-marrow-specific oncology studies
The introduction of the BMN platform seamlessly integrates into Crown Bioscience’s expertise in 3D organoid-like cell cultures, drug resistance models, and AML mouse models and bridges a gap between in vitro and in vivo models.

Bourré said, "This is a very exciting advancement for researchers and with this offering that integrates into Crown Bioscience’s existing solutions, we’re able to continually foster innovation and accelerate drug development."

Crown Bioscience will be presenting a poster at AACR (Free AACR Whitepaper), with details below.

3D Bone Marrow Niche: Scalable and Physiologically Relevant Ex Vivo Drug Screening Platform for Acute Myeloid Leukemia and Multiple Myeloma
Session Category: Experimental and Molecular Therapeutics
Session Title: Drug Discovery Assay Technologies
Session Date and Time: April 29 at 2:00PM CT
Location: Poster section 16
Poster Board Number: 21
Published Abstract Number: 5493

On April 28, 2025 Coherus BioSciences, Inc. ("Coherus," NASDAQ: CHRS), reported data from its ongoing Phase 1 clinical trial evaluating CHS-114, a selective, cytolytic anti-CCR8 antibody, as monotherapy and in combination with toripalimab in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) evaluating two pharmacologically active doses of CHS-114 for dose optimization (Press release, Coherus Biosciences, APR 28, 2025, View Source [SID1234652225]). These data are being presented at the 2025 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 25-30, 2025, in Chicago, Illinois.

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The data showed a confirmed partial response in a heavily pretreated PD-1 refractory patient, a > 50% depletion in CCR8+ Treg, and an increase in CD8+ T cells, consistent with anti-tumor activity and demonstrating proof of mechanism. Importantly, the safety profile was consistent with advanced disease and the known safety profile of toripalimab. These data support continued evaluation of CHS-114 in combination with other therapies, including toripalimab. Results support advancement and ongoing enrolment in Part 3 of the study evaluating CHS-114 with toripalimab in HNSCC (n = 40).

CHS-114 is an afucosylated CCR8 monoclonal antibody and is the only known selective molecule designed to exclusively target human CCR8 with no off-target binding and preferentially kills CCR8+ Tregs within the tumor microenvironment while preserving CD8+ effector T cells and Tregs in normal tissue.

"The data to date demonstrate a robust depletion of Treg cells in tumors, with a manageable safety profile, and a patient with a meaningful clinical response, which is highly encouraging," said Rosh Dias, M.D., Coherus’ Chief Medical Officer. "Furthermore, the profound increase in CD8+ T cells, making these tumors immunologically hot, is exciting as it supports CHS-114 being combined with several treatment modalities including T Cell Engagers. Head and neck cancer is an important strategic focus for Coherus, but CHS-114 has the potential, based on its mechanism of action, to treat many solid tumors, including non-small cell lung cancer and other large, underserved immuno-oncology indications, like colorectal cancer. We look forward to sharing further head and neck and gastric cancer data in the first half of next year."

"One of the biggest challenges in oncology has been finding a treatment that depletes Treg cells and relieves immune suppression in the tumor without causing collateral autoimmune disease or affecting antitumor T cells," said Douglas Adkins, M.D., Professor of Medicine, Director, Section of Head and Neck and Thyroid Medical Oncology, Division of Medical Oncology, Washington University School of Medicine. "These early clinical results are exactly what we’ve been hoping for and demonstrate CHS-114’s ability to remodel the tumor microenvironment in favor of anti-tumor activity. I am looking forward to exploring this treatment combination for solid tumor patients, even beyond head and neck."

Results from Phase 1b dose expansion trial evaluating CHS-114 monotherapy and with toripalimab in HNSCC

This open-label Phase 1b clinical trial evaluated CHS-114 as a single-agent and in combination with toripalimab in 21 patients with advanced solid tumors including HNSCC. Patients received either CHS-114 alone or in combination with toripalimab (240 mg) q3w. The primary endpoint of the study was to determine dose limiting toxicities (DLTs) and treatment emergent adverse events (TEAEs), with the goal of identifying two recommended doses for expansion. Key secondary endpoints included objective response rate (ORR) based on investigator review per RECIST v1.1 as well as pharmacokinetics and pharmacodynamics (PK/PD).

As of the data cutoff date of January 24, 2025:

CHS-114 monotherapy demonstrated Treg cell depletion (range of decrease: 52-97%), and significant increase in CD8+ T cells in the tumor, establishing proof of mechanism and confirming the doses are pharmacologically active.
CHS-114 with toripalimab had promising antitumor activity in HNSCC that warrants continued exploration.
CHS-114 administration leads to a substantial increase in CD8+ T cells in the tumor microenvironment, providing a strong rationale for combining with toripalimab and other drugs such as T cell engagers and bispecifics.
A confirmed partial response was achieved in the high dose cohort of CHS-114 in combination with toripalimab in a heavily pre-treated PD-1 refractory patient (PD-L1 low), demonstrating CHS-114 in combination with toripalimab can potentially overcome PD-1 resistance.
CHS-114 with and without toripalimab had a manageable safety profile in HNSCC patients, with TEAEs consistent with advanced disease and the known safety profile of toripalimab.
Two CHS-114 doses were selected for dose optimization based on safety, peripheral CCR8+ Treg depletion, PK and biomarker data.
These results support continued evaluation of CHS-114 in combination with other drugs including toripalimab, with broad potential applications in many solid tumors with a high density of CCR8+ Treg cells. A second-line HNSCC dose optimization study of CHS-114 in combination with toripalimab in HNSCC and gastric cancer patients is ongoing, with anticipated results in the first half of 2026 The current study design is expected to address the regulatory requirements under Project Optimus1 and support the recommendation of a phase 2 dose by early 2026.

AACR 2025 Presentation Details

Title: Phase 1 study of anti-CCR8 antibody CHS-114 with and without anti-PD-1 antibody toripalimab in patients with advanced solid tumors
Lead Author: Francis Worden, M.D., University of Michigan
Abstract #: CT038
Poster Session: Phase 0 and Phase 1 Clinical Trials
Poster Section 49: Poster board 17
Date and Time: Monday, April 28, 2025, 9:00 a.m. – 12:00 p.m. CDT

Conference Call Information for Investors and Analysts

Coherus Chief Development Officer, Dr. Theresa LaVallee, and Chief Medical Officer, Dr. Rosh Dias, will host a presentation and discussion of new clinical data from the Phase 1 study with CHS-114 with and without anti-PD-1 antibody toripalimab with study investigator, Dr. Douglas Adkins of Washington University.

When: Monday, April 28, 2025, starting at 4:30 p.m. Eastern Time

Investors and analysts are invited to listen into a live audio webcast of the presentation. To access the conference call, please pre-register through the following link to receive dial-in information and a personal PIN to access the live call: View Source

Please dial in 15 minutes early to ensure a timely connection to the call.

Webcast: View Source

An archived webcast will be available on the "Investors" section of the Coherus website at View Source

About the CHS-114 Phase 1 Study

The Phase 1 study (NCT05635643) is a dose escalation, dose optimization, and expansion study evaluating CHS-114 as a monotherapy and in combination with toripalimab, a next-generation PD-1 inhibitor. Arm 1a (first-in-human dose escalation) enrolled 20 patients with advanced solid tumors including 2 patients with HNSCC and evaluated multiple dose levels (5-1200 mg) of CHS-114 monotherapy. Arm 1b evaluated two pharmacologically active doses of CHS-114 monotherapy in 12 HNSCC patients with paired tumor biopsies. Arm 2 evaluated two pharmacologically active doses of CHS-114 with toripalimab in 7 patients. Arm 3 is evaluating two pharmacologically active doses of CHS-114 with toripalimab in 40 patients with second-line HNSCC. Primary objectives are to optimize the CHS-114 dose(s) for expansion and evaluate the safety of CHS-114 with toripalimab. Secondary objectives were to evaluate the safety, PK, and antitumor activity of CHS-114 with and without toripalimab and assess biomarkers, including changes in regulatory T cells (Tregs) and CD8+ T cells in paired tumor biopsies and other immune biomarkers.

About CHS-114

CHS-114, an afucosylated, cytolytic CCR8 monoclonal antibody, is designed to selectively target human CCR8 and preferentially kill CCR8+ Tregs within the tumor microenvironment while preserving CD8+ effector T cells and Tregs in normal tissue. In preclinical studies, CHS-114 induced antibody-dependent cellular cytotoxicity (ADCC) and/or antibody-dependent cellular phagocytosis (ADCP) to deplete tumoral CCR8+ Tregs. In addition, treatment with CHS-114 alone reduced tumor growth in murine models, and enhanced antitumor activity was observed in combination with anti-PD-1 treatment. CHS-114 is currently being evaluated in combination with toripalimab in two Phase 1b clinical trials in patients with advanced solid tumors, including head and neck cancer (NCT05635643) and gastric cancer (NCT06657144).