On March 7, 2024 Debiopharm (www.debiopharm.com), a privately-owned, Swiss-based biopharmaceutical company aiming to establish tomorrow’s standard-of-care to cure cancer and infectious diseases, reported the first patient dosed in the expansion of its open-label, non-randomized, multicenter Phase 1 study evaluating Debio 0123, an oral, potent, highly selective and brain-penetrant WEE1 inhibitor, as a monotherapy in patients with recurrent or progressive solid tumors (Press release, Debiopharm, MAR 7, 2024, View Source [SID1234640947]). The expansion of this Phase 1 study, NCT05109975, is to characterize the safety, tolerability, and initial signs of antitumor activity of Debio 0123 when administered as monotherapy. Two out of the three expansion arms of the study will be using biomarkers to pre-select patients with different solid tumors while the third arm will be treating patients with recurrent serous endometrial carcinoma. Currently, sites are open for enrollment in the United States, Spain, and Switzerland.

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"Part of our strategy of utilizing OMICs* approaches to identify specific biomarkers and identify patient populations that will respond to Debio 0123 due to synthetic lethality will allow us to enroll patients who are most likely to benefit from treatment, thereby taking a truly precision medicine approach" expressed Dr. Victor Rodriguez-Freixinos, Medical Director, Debiopharm.

Uterine serous carcinoma (USC) is an uncommon, but aggressive subtype of endometrial cancer. It represents approximately 10% of all endometrial cases, which translates to more than 6,000 newly diagnosed patients each year in the United States 1-2. Despite representing a small proportion of endometrial cancer cases, uterine serous carcinoma accounts for an alarming 39% of endometrial cancer-related deaths. Features highlighting the gravity of USC include the high rates of deep myometrial invasion, as well as metastatic spread to lymph nodes and peritoneal surfaces 1. These features largely affect the 5-year overall survival but compared with more common endometrial cancer, the prognosis for USC is generally poor and the risk of relapse is high 3. Similar to USC, epithelial ovarian cancer (EOC) is known for its poor prognosis due to the aggressive clinical course and the tendency to metastasize. However, EOC accounts for about 90% of all ovarian cancers and affects more than 17,000 American women each year, of which about 30% survive for 5 years after diagnosis 4-5.

"This study’s population is mainly female, burdened by fatal malignancies like Uterine Serous Carcinoma, Epithelial Ovarian Cancer and fallopian tube cancer which are well-known hard-to-treat cancers. These patients need new treatment options, as the current standard of care is insufficient in assuring long-term progression free survival." Dr. Manish R. Sharma, Principal Investigator at the START Midwest, Michigan.

The Debio 0123 program originates from a growing awareness of DDR inhibition in fighting life-threatening cancers. Maximizing efficacy, while preserving safety are key elements that Debiopharm is eager to assess throughout the clinical development of Debio 0123. With the successful realization of these requirements, Debio 0123 could become the first choice WEE1 inhibitor.

About Debio 0123

Debio 0123 is a brain-penetrant, highly selective WEE1 kinase inhibitor. WEE1 is a key regulator of the G2/M and S phase checkpoints, activated in response to DNA damage, allowing cells to repair their DNA before resuming their cell cycle. WEE1 inhibition, particularly in combination with DNA damaging agents, induces an overload of DNA breaks. In conjunction with abrogation of other checkpoints such as G1, the compound pushes the cells through cycle without DNA repair, promoting mitotic catastrophe and inducing apoptosis of cancer cells. Currently in research for solid tumors in monotherapy and combination, Debio 0123 is being developed to respond to high unmet needs of patients living with the burden of difficult-to-treat cancers.

About DNA-Damage Response (DDR)

When cells have damaged DNA, they need to undergo a repair process called DDR to be able to survive. Cancer cells use their hyperactive DDR response to divide and grow uncontrollably, which promotes cancer expansion. Inhibition of DDR, particularly in combination with other anticancer agents, induces an overall arrest in the uncontrollable cancer cell cycle. This ultimately activates a self-destruction program in cancer cells. DDR inhibitors such as Debiopharm’s WEE1 and USP1 inhibitors, are being tested in either clinical or preclinical studies.

On March 7, 2024 BostonGene, a leading provider of AI-driven molecular and immune profiling solutions, reported the publication of the manuscript, "Multi-omic Profiling of Follicular Lymphoma Reveals Changes in Tissue Architecture and Enhanced Stromal Remodeling in High-Risk Patients" in Cancer Cell, a premier peer-reviewed scientific journal that publishes high-impact results in cancer research and oncology (Press release, BostonGene, MAR 7, 2024, View Source [SID1234640946]).

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Follicular lymphoma (FL), an often incurable malignancy, stems from developmentally blocked germinal center B cells. Throughout its progression, FL tumor B cells undergo significant genetic changes and extensively remodel the lymphoid microenvironment to promote survival and immune evasion. The dynamic interaction between tumor B cells and the tumor microenvironment are thought to influence the diverse clinical behaviors observed among FL patients, ranging from an indolent disease to a more aggressive clinical course characterized by progression after therapy, histologic transformation, and premature death from lymphoma. Despite the urgent need, current clinical tools inadequately predict disease behavior, underscoring the necessity for risk stratification methods, particularly for early relapsers.

The study, led by researchers at the National Institute of Allergy and Infectious Diseases and National Cancer Institute in collaboration with BostonGene, employed a multi-modal approach to comprehensively examine cell-intrinsic and -extrinsic factors governing disease progression and therapeutic outcomes in FL patients enrolled in a prospective clinical trial. Utilizing BostonGene’s advanced end-to-end bioinformatics and proprietary software, the researchers identified several tumor-specific features and microenvironmental patterns associated with early relapse, the most high-risk subgroup of FL patients.

The research’s key findings included identifying unique histological patterns such as stromal desmoplasia and follicular growth pattern alterations observed before first progression and relapse in FL patients. Additional results provide a comprehensive characterization of the genomic and transcriptomic landscapes of tumor B cells, uncovering diverse genetic lesions and alterations in pathways associated with immune escape, apoptosis resistance, and extracellular matrix remodeling. Utilizing single-cell resolution profiling, the research revealed distinct populations of B cells, T cells, myeloid cells, and stromal cells within FL lymph nodes, shedding light on their spatial distribution within the tumor microenvironment. Moreover, the researchers established a correlation between gene signatures linked to poor prognosis and extracellular matrix remodeling with cellular communities identified in FL lymph nodes, offering potential therapeutic targets for high-risk patients.

"The insights garnered from this study signal a pivotal moment in refining treatment strategies for follicular lymphoma patients," said Nathan Fowler, MD, Chief Medical Officer at BostonGene. "By unraveling the intricate molecular and cellular dynamics steering disease progression, we advance toward implementing precision medicine paradigms that can reshape the standard of care."

Research reported in this press release was supported by the National Institute of Allergy and Infectious Diseases and National Cancer Institute, parts of the National Institutes of Health, under award numbers Z01 AI000545, ZIA BC011914, Z01 SC004024, and Z01 BC011006. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

On March 7, 2024 Johnson & Johnson (NYSE: JNJ) reported that it has successfully completed the acquisition of Ambrx Biopharma, Inc., a clinical-stage biopharmaceutical company with a proprietary synthetic biology technology platform to design and develop next-generation antibody drug conjugates (ADCs), in an all-cash merger transaction for a total equity value of approximately $2.0 billion, or $1.9 billion net of estimated cash acquired, as announced on January 8, 2024 (Press release, Johnson & Johnson, MAR 7, 2024, View Source [SID1234640945]). The transaction will be accounted for as a business combination.

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"We’re pleased to welcome Ambrx’s talented scientific team and proprietary ADC platform to Johnson & Johnson. We look forward to continuing the development of ARX517, which represents a potential first- and best-in-class PSMA-targeting ADC for the treatment of metastatic castration-resistant prostate cancer," said Yusri Elsayed, MD, MHSc, PhD, Global Therapeutic Area Head, Oncology, Johnson & Johnson Innovative Medicine. "This significant opportunity sets the stage for advancing next generation ADCs with the aim of delivering differentiated solid tumor therapies that improve patients’ lives."

The acquisition presents a distinct opportunity for Johnson & Johnson to design, develop and commercialize targeted oncology therapeutics. Ambrx’s proprietary ADC technology incorporates the advantages of highly specific targeting monoclonal antibodies securely linked to a potent chemotherapeutic payload to achieve targeted and efficient elimination of cancer cells without the prevalent side effects typically associated with chemotherapy.

"The Ambrx team has developed a promising pipeline and ADC platform that will be a strong complement and strategic fit to our oncology innovation strategy," said Biljana Naumovic, Worldwide Vice President, Oncology, Johnson & Johnson Innovative Medicine. "ADCs are transforming the solid tumor treatment paradigm by leveraging antibody-antigen interactions to release cytotoxic payload directly to tumor cells. This acquisition underscores our ambition to deliver enhanced, precision biologics to transform the treatment of cancers, including prostate cancer."

On March 7, 2024 3T Biosciences ("3T"), an immunotherapy company changing the future of treatment for solid tumors and other immune-mediated diseases, reported that it has entered into multiple additional collaborations with leading academic centers and principal investigators to further fuel 3T’s best-in-class 3T-TRACE (T-Cell Receptor Antigen and Cross-Reactivity Engine) pHLA target discovery platform (Press release, 3T Biosciences, MAR 7, 2024, View Source [SID1234640944]). These collaborations provide access to high quality patient samples and corresponding critical data to enable the identification of novel cancer targets of interest, including pancreatic, bladder, breast, head and neck, and colorectal cancers.

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Cancer immunotherapies have brought dramatic breakthroughs, but only for a minority of cancer patients. 3T’s platform aims to address this challenge by identifying novel shared T-cell receptor (TCR) targets of productive immune responses and comprehensively screening TCRs and TCR mimetics for specificity and off-target cross-reactivities. The platform identifies the most prevalent and immunogenic targets in solid tumors by uniquely combining high-diversity target libraries with active machine learning. This may lead to tumor-specific, safer therapies that can be delivered at higher doses.

3T is collaborating with multiple decorated academic investigators to partner in its mission to serve patients with solid tumors with high unmet need:

David Oh, M.D., Ph.D. and Larry Fong, M.D., at University of California, San Francisco – Focusing on bladder cancer patients treated with anti-PD(L)1.
Diether Lambrechts, Ph.D., at VIB-KU Leuven – Focusing on breast cancer, including triple-negative breast cancer, treated with checkpoint therapies.
Sabine Tejpar, M.D., Ph.D. at KU Leuven – Focusing on colorectal cancer, including MSS subtype where traditional immunotherapy methods have difficulty engaging immune responses.
Tao Dong, D.Phil., and Ricardo Fernandes, D.Phil., at Oxford University – Focusing on lung and breast cancer.
"At 3T, patients are at the center of everything we do," said Stefan Scherer, M.D., Ph.D., 3T’s president and chief executive officer. "By partnering with the world’s leading academic institutions, we are able to supercharge our discovery efforts in delivering novel therapeutics to patients by leveraging samples from patients themselves to further our understanding of the immune system’s response to cancer."

On March 7, 2024 Verismo Therapeutics, a clinical-stage CAR-T company developing the novel KIR-CAR platform technology, reported that it has activated a second clinical site for its STAR-101 Phase 1 clinical trial at The University of Texas MD Anderson Cancer Center (Press release, Verismo Therapeutics, MAR 7, 2024, View Source [SID1234640943]).

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STAR-101 is a multi-center clinical trial designed to evaluate Verismo Therapeutic’s lead candidate, SynKIR-110, for the treatment of mesothelin-overexpressing ovarian cancer, malignant pleural mesothelioma, and cholangiocarcinoma.

"This milestone marks the steady progress towards our goal of bringing SynKIR-110 to as many patients as possible," said Dr. Bryan Kim, Co-Founder and CEO of Verismo Therapeutics. "We are grateful for the opportunity to work with Dr. Mehmet Altan at MD Anderson to bring us closer to that goal."

Verismo achieved clearance from the FDA to initiate this multi-center clinical trial for SynKIR-110 and has partnered with the Hospital of the University of Pennsylvania as the first clinical site.

Verismo has previously announced that SynKIR-110 received Orphan Drug Designation and Fast Track Designation for the treatment of mesothelin-expressing mesotheliomas.

For more information about the STAR-101 clinical trial, please visit ClinicalTrials.gov NCT05568680.

About the KIR-CAR Platform
The KIR-CAR platform is a dual-chain CAR T cell therapy and has been shown in preclinical animal models to be capable of maintaining antitumor T cell activity even in challenging solid tumor environments. DAP12 acts as a novel costimulatory molecule for T cells using additional T cell stimulating pathways, further sustaining chimeric receptor expression and improving KIR-CAR T cell functional persistence. This continued T cell function and persistence can lead to ongoing regression of solid tumors in preclinical models, including those resistant to traditional CAR T cell therapies. The KIR-CAR platform is being investigated in combination with many additional emerging technologies, such as in vivo gene engineering, advanced cell manufacturing and reprogramming, combinational therapies, and even allogeneic cellular therapies to potentially provide the next-generation multimodal targeted immunotherapy for patients in need.