On April 18, 2023 Turn Biotechnologies, a cell rejuvenation company developing novel mRNA medicines for untreatable, age-related conditions, reported immunology data that demonstrate its ERA technology enhances T cell performance against tumor cells (Press release, Turn Biotechnologies, APR 18, 2023, View Source [SID1234630281]).

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The findings are expected to improve the efficacy of CAR-T cell therapies.

Data will be shared at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held at the Orange County Convention Center in Orlando, Florida, from April 14 to 19.

The Turn Bio data will be shared on a poster, "Transient Epigenetic Reprogramming Enhances T-Cell Proliferation and Tumor Clearance," to be presented by Mustafa Turkoz, PhD, Turn Bio Immunology. An abstract of the poster was published in the AACR (Free AACR Whitepaper) journal "Cancer Research" on March 31.

Presentation details:

Title: "Transient Epigenetic Reprogramming Enhances T Cell Proliferation and Tumor Clearance".
Location: Section 23, Board number 27, in the Orange County Convention Center, during the CAR-T Cell Therapy session.
Date and Time: Tuesday, April 18, 2023, at 9 a.m. Eastern Time.
The AACR (Free AACR Whitepaper) Annual Meeting is one of the most important cancer meetings in the world, attracting key stakeholders in all areas of cancer research to connect, collaborate, and expand the frontiers of integrative cancer science and medicine. Last year’s meeting attracted more than 20,000 scientists, clinicians, other health care professionals, survivors, patients, and advocates.

On April 18, 2023 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the presentation of new preclinical data supporting the intracranial activity NVL-655 (Press release, Nuvalent, APR 18, 2023, View Source [SID1234630280]). NVL-655 is a brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) designed to maintain activity against ALK and ALK mutations that confer resistance to currently approved therapies, and to avoid neurological adverse events and dose-limiting toxicities associated with TRK inhibition.

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The data result from a collaboration with Yonsei University College of Medicine and will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, taking place April 14-19 in Orlando, Florida. The poster will also be available on the Nuvalent website at www.nuvalent.com following the presentation.

"Brain penetrance is a critical medical need for ALK TKIs due to the high incidence of brain metastases in ALK-positive non-small cell lung cancer (NSCLC), both at initial diagnosis and upon progression with currently available therapies. Treatment-emergent ALK resistance mutations as well as the structural similarity between the ALK and TRK kinases pose additional challenges for development of brain penetrant TKIs," said Professor Byoung Chul Cho, M.D., Ph.D., Yonsei University College of Medicine. "Careful design of highly potent ALK-selective compounds is needed to inhibit treatment-resistant ALK-driven disease while avoiding neurological effects associated with inhibition of TRK in the brain."

Professor Cho continued, "The potent preclinical efficacy of NVL-655 in a challenging patient-derived model of treatment-resistant intracranial ALK NSCLC was consistent with its design as a brain-penetrant ALK-selective TKI with activity against the G1202R mutation, and supportive of a differentiated preclinical profile for NVL-655 compared with approved and other investigational ALK TKIs."

The YU-1077 patient-derived cell line was developed from a patient with alectinib-resistant NSCLC harboring an EML4-ALK fusion with the G1202R resistance mutation. Cell viability and ALK signaling assays confirmed potent in vitro activity of NVL-655 and limited sensitivity to first- and second-generation ALK TKIs, consistent with prior relapse on alectinib and the G1202R resistance mutation. A mouse model of drug-resistant lung cancer that had metastasized to the brain was established through intracranial injection of YU-1077 cells. Upon treatment with NVL-655, intracranial efficacy was confirmed via MRI.

"This study marks the first utilization of a patient-derived model to assess the preclinical intracranial activity of NVL-655 and represents an enhancement in physiological relevance over our previous preclinical experiments," said Henry Pelish, Ph.D., Senior Vice President of Drug Discovery at Nuvalent. "The resulting data are an important addition to the growing body of preclinical evidence demonstrating NVL-655’s differentiated ability to target ALK and display intracranial activity against brain tumors bearing resistance mutations."

NVL-655 has previously demonstrated preclinical efficacy in a cell line model of intracranial disease, as well as broad preclinical activity across diverse ALK resistance mutations and tumor types while maintaining strong selectivity for ALK over TRKB. NVL-655 is currently being investigated in the ALKOVE-1 study (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors.

AACR Presentation Overview:
Title: Preclinical intracranial activity of NVL-655 in an alectinib-resistant patient-derived model harboring EML4-ALK fusion with G1202R mutation
Authors: Jii Bum Lee1*, Mi Ra Yu1*, Mi Ran Yun1, You Won Lee1, Seung Yeon Oh1, Eun Ji Lee1, Anupong Tangpeerachaikul2+, Henry E. Pelish2, Byoung Chul Cho1
Permanent Abstract: 4022
Session Category: Experimental and Molecular Therapeutics
Session Title: Tyrosine Kinase and Phosphatase Inhibitors 1
Session Date and Time: Tuesday April 18, 2023 from 9:00 a.m. – 12:30 p.m. ET
Location: Orange County Convention Center, Poster Section 20
1Yonsei University College of Medicine, Seoul, Republic of Korea 2Nuvalent Inc., Cambridge, MA, USA
*Equal contributions
+Presenter

Summary of Presentation:
In the YU-1077 intracranial tumor model derived from a patient with alectinib-resistant lung cancer, NVL-655 showed potent preclinical efficacy, consistent with its design as a brain-penetrant ALK TKI with activity against the G1202R mutation.

These results—together with broad ALK mutational coverage, brain penetrance, and sparing TRK—further support NVL-655’s preclinical profile that is differentiated from that of FDA/EMA-approved and other investigational ALK TKIs.
About NVL-655

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with the solvent front G1202R mutation or compound mutations G1202R / L1196M ("GRLM"), G1202R / G1269A ("GRGA"), or G1202R/L1198F ("GRLF"). NVL-655 has been optimized for CNS penetrance to improve treatment options for patients with brain metastases. NVL-655 has been observed in preclinical studies to selectively inhibit wild-type ALK and its resistance variants over the structurally related tropomyosin receptor kinase (TRK) family to potentially avoid TRK-related CNS adverse events seen with dual TRK/ALK inhibitors and drive more durable responses for patients. NVL-655 is currently being investigated in the ALKOVE-1 study (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive NSCLC and other solid tumors.

On April 18, 2023 DELFI Diagnostics, Inc., a pioneering developer of a new class of high-performance, accessible liquid biopsy tests for early cancer detection and monitoring, reported proof-of-concept data demonstrating how DELFI’s platform can be used for monitoring the treatment of patients with advanced cancer without requiring any prior genomic information about the patient’s tumor (Press release, Delfi Diagnostics, APR 18, 2023, View Source [SID1234630279]). The data were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting and builds on earlier studies showing the potential of using DELFI’s technology for treatment monitoring.

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The DELFI-Tumor Fraction (DELFI-TF) score tracked mutant-allele fraction scores (MAFs) in side-by-side assessments, and also identified cancer signals in patients with clinical disease burden who had false negative MAF assays. Today, MAF assays are a common clinical measure of tumor burden. Researchers demonstrated that the DELFI-TF score and MAF results were equally predictive of clinical outcomes, and that changes in DELFI-TF scores over time anticipated later changes in radiologic assessments of disease response.

"Legacy liquid biopsy approaches to cancer treatment monitoring rely either on prior knowledge about the genomic makeup of a patient’s tumor or deep sequencing looking for expected alterations. Each approach is high cost, and subject to various types of errors and failures," said Peter Bach, MD, DELFI’s Chief Medical Officer. "These proof of concept findings show that the whole-genome fragmentation analysis that underlies the DELFI-TF assay could be used to measure tumor burden, patient prognosis, and treatment response without the need for tumor tissue."

Researchers from DELFI and the Netherlands Cancer Institute, and the University Medical Center Utrecht looked at 174 patients undergoing therapy for metastatic colorectal cancer and collected a total of 692 blood samples at various time points before and after treatment. They found that the DELFI-TF score predicted survival outcomes in the overall study population, regardless of the patient’s BRAF or RAS status, two genes that are commonly mutated in CRC. Patients whose change in DELFI-TF was below the median over time showed both longer progression-free survival (HR = 2.03, 95% CI: 1.247-3.318) and overall survival (HR = 3.05, 95% CI: 1.58 – 5.90).

The study builds on prior work demonstrating the potential of the DELFI platform to monitor patients with metastatic cancer undergoing treatment with immunotherapy. In that study, presented at ESMO (Free ESMO Whitepaper) in 2022, researchers showed that the DELFI-TF score was as effective as imaging at tracking progression and progression-free survival. The work was awarded "Best Poster" in the Translational Research, Tumor Agnostic session.

"This is another example of the power of DELFI’s unique platform to provide high quality results using low-cost methods and a common wet-lab process that is used in all our applications and products in development," said Nicholos Dracopoli, PhD, DELFI Co-Founder and Chief Scientific Officer.

Also at AACR (Free AACR Whitepaper), DELFI and other researchers using the DELFI platform presented data describing the platform’s strong performance in a training set that will be used to develop DELFI’s first lung cancer screening product. Researchers also shared promising initial data on the DELFI platform’s ability to detect early stage ovarian cancer.

On April 18. 2023 NeoPhore Limited, a small molecule neoantigen immuno-oncology company, reported that it has signed a strategic collaboration agreement with Professor Chris Lord’s lab at The Institute of Cancer Research, London (Press release, NeoPhore, APR 18, 2023, View Source [SID1234630278]). The collaboration will use NeoPhore’s proprietary small molecule inhibitors of DNA mismatch repair (‘MMR’) to investigate single agent activity against tumours with defined genetic backgrounds.

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Building on the seminal discoveries and ongoing research of its scientific founders and collaborators, NeoPhore is developing a pipeline targeting novel proteins in the DNA mismatch repair pathway to treat cancer. The Company’s first-in-class MMR modulators induce neoantigen expression and increase immunogenicity in solid tumours that become exquisitely sensitive to immunotherapy.

Professor Chris Lord is Professor of Cancer Genomics and Deputy Head of the Division of Breast Cancer Research at The Institute of Cancer Research (ICR), as well as the Deputy Leader of the Breast Cancer Now Toby Robins Research Centre and the Cancer Research UK Gene Function Team at the ICR.

Professor Chris Lord, Lead Researcher on the project from the ICR, said: "We are excited about this new collaboration with NeoPhore. Identifying new ways of treating cancer is central to much of what we do here at the ICR and this project will focus on exactly that. Our hope is that by working with NeoPhore, we can find new vulnerabilities in cancer cells that can be targeted by drugs that NeoPhore has discovered."

Dr. Matthew Baker, Chief Executive Officer of NeoPhore, stated: "We are excited to collaborate with Prof. Chris Lord who is a prominent and respected researcher in the field. Access to his team’s scientific expertise will allow us to investigate new mechanisms of action of the MMR pathway in a variety of solid tumours. We believe that this impactful collaboration has the potential to broaden the use of MMR inhibitors beyond neoantigen generation. Ultimately the results of the collaboration have the potential to provide significant patient benefit in a variety of solid tumour indications."

This is the 4th collaboration agreement NeoPhore has signed since 2017, having entered collaborations with University of Turin, St George’s University of London and Memorial Sloan Kettering Cancer Center (MSKCC).

On April 18, 2023 Pyramid Biosciences, Inc., a privately-held, clinical-stage biotechnology company focused on developing transformative medicines for patients with cancer, and its partner GeneQuantum Healthcare (Suzhou) Co. Ltd, a privately-held biotechnology company based in China, reported data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 highlighting the preclinical efficacy and safety profile of GQ1010, a potential best-in-class antibody drug conjugate (ADC) targeting trophoblast cell surface antigen 2 (TROP2), across several in vitro and in vivo models (Press release, Pyramid Biosciences, APR 18, 2023, View Source [SID1234630277]).

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The poster presentation highlights several preclinical studies which showcase the differentiating attributes of GQ1010. Specifically, in a mouse syngeneic MC38 colon cancer model, the combination of GQ1010 plus anti-PD-1 therapy showed compelling synergistic tumor growth inhibition, which was superior to DS-1062 plus anti-PD-1. In this study, the GQ1010 combination reported 5 of 6 animals achieved a complete response, compared to zero of 6 animals with the DS-1062 combination.

In addition, GQ1010 showed more potent in vitro cytotoxicity and a superior bystander effect versus DS-1062, and increased in vivo tumor growth inhibition with GQ1010 monotherapy compared head-to-head with either DS-1062 or TRODELVY across multiple cancer models.

Safety findings with GQ1010 in a non-human primate (NHP) study indicated a differentiated profile and highest non-severe toxic dose (HNSTD) of greater than 30 mg/kg, which may translate to a wider therapeutic window in human studies relative to more advanced TROP2 ADCs in development. Plasma stability studies showed 98% retention of drug-to-antibody ratio (DAR) for GQ1010, attributable to its unique, irreversible cleavable linker chemistry.

"These preclinical findings are driven by GQ1010’s unique ADC design, which utilizes site-specific enzymatic conjugation technology and a novel linker-payload which confer potent cytotoxicity and better stability in the plasma," said Qin Gang, Ph.D., CEO of GeneQuantum Healthcare. "The preclinical differentiation seen with GQ1010 provides further validation of the capabilities of the GeneQuantum platform to produce best-in-class bioconjugates, as was also observed in a Phase 1a study of the HER2-directed ADC, GQ1001."

"TROP2 is a highly validated target in oncology, and TROP2-directed therapies are an important potential treatment option for a large number of cancers," remarked Brian Lestini, MD PhD, CEO of Pyramid Biosciences. "However, despite the TROP2 agents currently approved or in development, there remains significant unmet need for therapies that improve efficacy while reducing the potential for serious toxicities and optimizing therapeutic index and combinability. Preclinical data demonstrates the potential for GQ1010’s unique ADC chemistry to provide a superior, best-in-class clinical profile and improve patient outcomes. Based on this preclinical data, we are excited to be moving GQ1010 into clinical development."

The AACR (Free AACR Whitepaper) annual meeting poster presentation details are as follows:
Title: Preclinical characterization of GQ1010, a next generation Trop2 ADC with the best-in-class potential against diverse Trop2 positive solid tumors
First Author: Yajun Sun
Session: PO.ET02.06 – Antibody Drug Conjugates
Abstract #: 1549

About TROP2
TROP2 is a cell surface glycoprotein that is highly expressed in a variety of tumors including breast, lung, pancreatic, ovarian, and prostate cancer, and plays a role in tumor cell proliferation. Currently TRODELVY (Gilead) is the only approved TROP2 ADC, with indications in triple-negative breast cancer, hormone-receptor positive breast cancer, and urothelial cancer. Clinical data have also been previously reported for TROP2 ADCs in development by Daiichi-Sankyo and Merck & Co.