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Rondo Therapeutics Publishes Preclinical Data on RNDO-564, a Novel CD28 x Nectin-4 Co-Stimulatory Bispecific Antibody for the Treatment of Bladder Cancer

On April 8, 2025 Rondo Therapeutics, a privately held biopharmaceutical company pioneering the development of next-generation T cell-engaging bispecific antibodies for the treatment of solid tumors, reported the publication detailing the discovery and preclinical development of RNDO-564, a CD28 x Nectin-4 bispecific antibody in the Journal for ImmunoTherapy of Cancer (JITC) (Press release, Rondo Therapeutics, APR 8, 2025, View Source [SID1234651847]).

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CD28 co-stimulatory bispecific antibodies are designed to boost T cell-mediated tumor killing and overcome T cell exhaustion in the solid tumor microenvironment. The publication describes the identification of a diverse panel of CD28-targeting binders with a range of potencies. Utilizing this panel, RNDO-564 was designed with optimal potency to elicit robust, safe, and durable tumor killing activity both in vitro and in vivo.

The full article, titled "A Potency-optimized CD28-activating Bispecific Antibody for the Targeted Treatment of Nectin-4 Positive Cancers," is available online at JITC.

Key findings for RNDO-564

Elicits robust Nectin-4 and signal-1 dependent T-cell mediated killing of Nectin-4-expressing tumor cells.
Enhances T-cell function in settings with mixed Nectin-4 positive and negative target cells.
Restores tumor cell killing function of serially stimulated T cells in vitro.
Fully eliminates established tumors in in vivo mouse model as monotherapy and in combination with a checkpoint inhibitor.
Preliminary tolerability studies in non-human primates demonstrate safety and support clinical evaluation of RNDO-564.
Demonstrates robust cytotoxic activity against bladder cancer cells that are resistant to antibody drug conjugates.
"The data serve as proof-of-concept for Rondo’s immune engager platform for solid tumors," said Starlynn Clarke, Senior Director of Preclinical Biology of Rondo Therapeutics. "We are excited about the clinical potential of CD28 T-cell engagers as a new modality for solid tumors, as they address the limitations of CD3 T-cell engagers, ADCs, and checkpoint inhibitors."

Rondo’s immune-engager platform delivers bispecific antibody therapeutics tailored to specific tumor targets, indications, and treatment regimens, offering a transformative alternative to traditional "one size fits all" strategies, unlocking the potential for durable responses in patients with solid tumors.

City of Hope Study Demonstrates Proof of Concept for Targeted New Approach to Treat Pancreatic Cancer

On April 8, 2025 Researchers at City of Hope, one of the largest and most advanced cancer research and treatment organizations in the U.S. with its National Medical Center named top 5 in the nation for cancer by U.S. News & World Report, have identified a new molecular target for treating pancreatic cancer, reported a Gastroenterology study published today (Press release, City of Hope, APR 8, 2025, View Source [SID1234651846]).

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest human cancers worldwide because it evades most treatments. With few therapeutic options, 90% of these patients don’t survive beyond five years. Now an innovative new approach offers the potential for transforming the genetic culprit behind PDAC’s stubborn resistance to treatment into a therapeutic ally.

Led by Mustafa Raoof, M.D., M.S., City of Hope assistant professor of surgery, cancer genetics and epigenetics, scientists focused on transcription-replication conflicts (TRCs), which occur when the mechanisms responsible for gene expression and genome duplication collide. The clash disrupts cells’ ability to read and copy genes, leading to replication stress, a frequent phenomenon in pancreatic cancer. The added stress causes cells to make errors copying their DNA, enabling cancer to gain a foothold and spread.

"Transcription-replication conflicts are an important vulnerability of pancreatic cancer," said Dr. Raoof, senior author of the new study. "Our study is the first to confirm proof of concept for whether exploiting this chink in cancer’s armor could provide an effective therapeutic target for patients."

In an earlier study, Dr. Raoof and his colleagues had identified high levels of TRCs as a unique weakness in pancreatic cancers that are driven by a common gene mutation. Building upon this research, his team used an experimental drug developed at City of Hope called AOH1996 as a tool to target TRCs and measure clinical responses.

First, the laboratory tested AOH1996 on a mouse model for pancreatic cancer and on small, lab-grown versions of human organs called organoids. The scientists discovered that the drug slowed tumor growth, damaged tumor cells without harming healthy tissue and boosted mouse survival from a median of 14 days to three weeks.

Next, the team tested the approach on two patients whose pancreatic tumors had resisted earlier treatments (NCT05227326). The patients experienced up to a 49% shrinkage in their liver metastases after taking the pill twice a day for two months.

Overall, the experimental approach was most effective at killing cancer cells with high replication stress, a common phenomenon that occurs when the KRAS gene goes awry in 95% of patients with pancreatic cancer.

"While the KRAS mutation has suggested a strong therapeutic target, pinpointing it in human PDAC has been difficult until now," said Dr. Raoof. "With inhibitors to mutant KRAS entering clinical trials, resistance is expected. It’s crucial for us to develop new approaches that target dependency on KRAS."

Targeting TRCs enabled the scientists to pinpoint only pancreatic cancer cells that experienced high levels of replication stress.

"Transcription-replication conflicts are more prevalent in cancer cells than normal cells," Dr. Raoof said. "Therapies that interfere with how cells manage their DNA during replication could open up new ways to treat cancer, offering hope for patients who have not benefited from other approaches."

Though excited by the study’s early results, Dr. Raoof emphasized caution in interpreting its findings. Due to the trial’s small size, scientists will need to pursue larger clinical and biomarker discovery studies to realize the full potential of therapeutic targeting of TRCs.

A respected birthplace for biotech, City of Hope created the technology that led to the development of synthetic human insulin. City of Hope later contributed to the development of "smart" cancer drugs like Herceptin, Rituxan and Avastin.

City of Hope’s Linda Malkas, Ph.D., discovered and developed AOH1996, which is exclusively licensed to the biotechnology company RLL, LLC.

Last year City of Hope received a historic $150 million gift to fund pancreatic cancer research from two entrepreneur-philanthropists: A. Emmet Stephenson Jr. and his daughter, Tessa Stephenson Brand. The donation’s mission is to accelerate leading-edge research into effective pancreatic cancer treatments through scientific partnerships with the world’s top researchers, regardless of institutional affiliation.

The Gastroenterology study entitled, "Therapeutic Targeting of Oncogene-induced Transcription-Replication Conflicts in Pancreatic Ductal Adenocarcinoma" was supported by grants from the National Comprehensive Cancer Network and the 2020 Pancreatic Cancer Action Network Career Development Award in Memory of Skip Viragh (20-20-RAOO) to the Raoof laboratory, as well as by the National Cancer Institute of the National Institutes of Health (P30CA033572) and NCCN Foundation.

New Study in the Scientific Journal “Cancer Cell” Supports CEL-SCI’s Strategy to Seek Early Approval for Multikine in Head and Neck Cancer Based on Pre-Surgical Tumor Responses

On April 8, 2025 CEL-SCI Corporation (NYSE American: CVM) reported that a study titled "Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies" by Li Housaiyin et. al., Cancer Cell (2025) provides support for CEL-SCI’s approach aimed at seeking early regulatory approval for Multikine* (Leukocyte Interleukin, Injection) as a neoadjuvant in the treatment of newly diagnosed previously untreated locally advanced head and neck cancer based on early tumor responses (Press release, Cel-Sci, APR 8, 2025, View Source [SID1234651845]).

The concept that tumor responses predict survival has been acknowledged for many cancer types and has led to accelerated approval of many cancer drugs. The study in Cancer Cell, which had 41 evaluable patients, gives further support that this is also true in the neoadjuvant pre-surgical immunotherapy treatment of head and neck cancer.

"The data from both our completed Multikine neoadjuvant Phase 3 study and the study published in Cancer Cell show that newly diagnosed locally advanced head and neck cancer patients who were treated with immune therapies before surgery and had tumor responses, were also likely to have better overall survival. This is quite logical—when a person’s tumor shrinks in response to immunotherapy treatment before the tumor is removed by surgery—their survival outcome is expected to be better," stated CEL-SCI CEO Geert Kersten. "We believe that the recent greater availability of peer-reviewed published data specific to neoadjuvant therapy and early tumor response in head and neck cancer supports our development and regulatory efforts."

CEL-SCI’s 212-patient Confirmatory Registration Study, which has received the FDA’s go-ahead, is designed to verify the statistically significant efficacy and safety results from the Company’s previously completed Phase 3 randomized controlled Multikine trial.

During the Multikine Phase 3 clinical trial, the 5-year survival rate of the target patient population for the confirmatory study increased to 73% when patients were treated with Multikine before surgery vs 45% for control patients who received only the standard of care treatments [Log rank p=0.0015 and a hazard ratio of 0.35 (0.18, 0.65; Wald p=0.0012)].

As a neoadjuvant therapy, Multikine is given to patients right after diagnosis, prior to surgery. In the Phase 3 study, pre-surgery objective early tumor response to treatment with Multikine was confirmed by pathology at surgery. There were 45 objective early responders, of which 5 were complete pathological responders, whose tumors completely disappeared in the Multikine treated group, within the 3-weeks of Multikine treatment. There were zero responders reported in the control group pre-surgery. Pre-surgical responders exhibited a 306% overall survival prolongation and had a significantly lowered death rate -vs- non-responders 22.2% vs 54.1% (2-sided Fisher Exact Test, p <0.0001) in support of pre-surgical response being prognostic.

AbCellera to Participate at Upcoming Investor Conferences in May and June

On April 8, 2025 AbCellera (Nasdaq: ABCL) reported that the Company will participate in the following investor conferences (Press release, AbCellera, APR 8, 2025, View Source [SID1234651844]):

Bloom Burton & Co. Healthcare Investor Conference, May 5-6
Goldman Sachs 46th Annual Global Healthcare conference, June 9-11

Visit AbCellera’s Investor Relations website for additional information.

DATROWAY® Approved in the EU for Patients with Previously Treated Metastatic HR Positive, HER2 Negative Breast Cancer

On April 8, 2025 Astrazeneca and Daiichi Snakyo reported that DATROWAY (datopotamab deruxtecan) has been approved in the European Union (EU) for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received endocrine therapy and at least one line of chemotherapy in the advanced setting (Press release, AstraZeneca, APR 8, 2025, View Source [SID1234651843]).

DATROWAY is a specifically engineered TROP2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

The approval by the European Commission follows the positive opinion of the Committee for Medical Products for Human Use of the European Medicines Agency and is based on results from the TROPION-Breast01 phase 3 trial.

In TROPION-Breast01, DATROWAY significantly reduced the risk of disease progression or death by 37% compared to investigator’s choice of chemotherapy (hazard ratio [HR]=0.63; 95% confidence interval [CI]: 0.52-0.76; p<0.0001) in patients with HR positive, HER2 negative metastatic breast cancer as assessed by blinded independent central review (BICR). Median progression free survival (PFS) was 6.9 months in patients treated with DATROWAY versus 4.9 months with chemotherapy. A confirmed objective response rate (ORR) of 36% was observed in the DATROWAY arm compared to an ORR of 23% observed in the chemotherapy arm. The median duration of response (DoR) was 6.7 months (95% CI: 5.6-9.8) in the DATROWAY arm compared to 5.7 months (95% CI: 4.9-6.8) in the chemotherapy arm. The final overall survival (OS) results of the trial did not achieve statistical significance (median OS of 18.6 months in the DATROWAY arm versus 18.3 months in the chemotherapy arm [HR 1.01; 95% CI: 0.83-1.22]) and may have been affected by subsequent ADC treatment.

"With the majority of breast cancer cases historically considered HR positive, HER2 negative, additional treatment options are needed to improve outcomes for patients with metastatic disease that continues to progress following endocrine-based therapy and initial chemotherapy," said Barbara Pistilli, MD, Head of the Breast Cancer Unit in the Medical Oncology Department of Gustave Roussy Cancer Center, Villejuif, France. "The approval of DATROWAY in the EU will provide these patients with a new treatment option that can help slow the progression of this disease."

"Treating metastatic HR positive, HER2 negative breast cancer presents challenges, particularly treatment resistance and disease progression that occur following endocrine-based therapy and initial chemotherapy," said Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc. "DATROWAY represents the second antibody drug conjugate approved for breast cancer based on Daiichi Sankyo’s DXd technology and the third medicine to be approved in the EU from our oncology pipeline, underscoring our commitment to creating new medicines for patients with cancer."

"Though the HR positive breast cancer treatment landscape has evolved in the last several years, disease progression on front-line therapies remains a common and complex challenge for patients with metastatic disease," said Dave Fredrickson, Executive Vice President, Oncology Hematology Business Unit, AstraZeneca. "With today’s approval of DATROWAY, patients in the EU with HR positive, HER2 negative breast cancer now have a new and needed alternative to conventional chemotherapy."

Grade 3 or higher adverse events from a pooled safety analysis of two clinical studies, including 443 patients who received DATROWAY (6 mg/kg) for a median duration of 6.2 months (range: 0.7-28.5), were stomatitis (7.9%), fatigue (4.3%), anemia (3.2%), AST increased (2.7%), vomiting (1.6%), ALT increased (1.6%), nausea (1.4%), urinary tract infection (1.4%), COVID-19 (1.1%), decreased appetite (1.1%), neutropenia (1.1%) and pneumonia (1.1%). Grade 5 adverse events occurred in 0.7% of patients due to interstitial lung disease/pneumonitis, dyspnea and sepsis.

About TROPION-Breast01
TROPION-Breast01 is a global, randomized, multicenter, open-label phase 3 trial evaluating the efficacy and safety of intravenous DATROWAY (6 mg/kg) once per 21-day cycle versus investigator’s choice of single-agent chemotherapy (eribulin, capecitabine, vinorelbine or gemcitabine) in adult patients with unresectable or metastatic HR positive, HER2 negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have progressed on and are not suitable for endocrine therapy per investigator assessment and have received at least one prior line of chemotherapy for unresectable or metastatic disease.

Following disease progression or discontinuation of DATROWAY or chemotherapy, patients had the option to receive a subsequent treatment at the discretion of their physician. Crossover between trial arms was not permitted.

The dual primary endpoints of TROPION-Breast01 are PFS as assessed by BICR and OS. Key secondary endpoints include ORR, DoR, investigator-assessed PFS, disease control rate, time to first subsequent therapy and safety. The PFS data and additional results for key secondary endpoints of TROPION-Breast01 were published in the Journal of Clinical Oncology and OS results were presented at a Virtual Plenary session hosted by the European Society for Medical Oncology in February 2025.

TROPION-Breast01 enrolled 732 patients in Africa, Asia, Europe, North America and South America. For more information visit ClinicalTrials.gov.

About Hormone Receptor Positive, HER2 Negative Breast Cancer
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.1 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.1 In Europe, approximately 557,000 cases of breast cancer are diagnosed annually.2 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.3

Approximately 70% of diagnosed cases are considered what has been historically called HR positive, HER2 negative breast cancer (measured as HER2 score of IHC 0, IHC 1+ or IHC 2+/ISH-).3 Endocrine therapy is widely given consecutively in the early lines of treatment for metastatic HR positive breast cancer.4 However, after initial treatment, further efficacy from endocrine therapy is often limited.4

About DATROWAY
DATROWAY (datopotamab deruxtecan) is a TROP2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, DATROWAY is one of six DXd ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. DATROWAY is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

DATROWAY is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic HR positive, HER2 negative breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease based on the results of the TROPION-Breast01 trial.

About the DATROWAY Clinical Development Program
A comprehensive global clinical development program is underway with more than 20 trials evaluating the efficacy and safety of DATROWAY across multiple cancers, including non-small cell lung cancer, triple negative breast cancer and HR positive, HER2 negative breast cancer. The program includes eight phase 3 trials in lung cancer and five phase 3 trials in breast cancer evaluating DATROWAY as a monotherapy and in combination with other anticancer treatments in various settings.