On May 06, 2024 Ferring Pharmaceuticals reported the final 60-month follow-up data from the Phase 3 study of ADSTILADRIN (nadofaragene firadenovec-vncg) were presented at the American Urological Association (AUA) 2024 Annual Meeting (Press release, Ferring Pharmaceuticals, MAY 6, 2024, View Source [SID1234642710]). The study demonstrated an 80% overall survival rate and 49% cystectomy-free survival rate at Month 60 in adult patients with high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors (±Ta/T1), and in patients with high-grade Ta/T1 without CIS. These data, which are the longest follow-up of efficacy and safety data reported for a novel agent for BCG-unresponsive NMIBC, were simultaneously published ahead of print and will be included in the July issue of The Journal of Urology.

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ADSTILADRIN is the first and only intravesical non-replicating adenoviral vector-based gene therapy approved by the U.S. Food and Drug Administration (FDA) in patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. The mechanism of action of ADSTILADRIN is designed to deliver the human interferon-alfa 2b gene (IFNα2b) directly into the bladder to enable secretion of interferon alfa-2b protein with a single treatment every three months.

"ADSTILADRIN represents a novel treatment option for BCG-unresponsive NMIBC with a convenient quarterly dosing pattern for patients," said Vikram M. Narayan, Assistant Professor at Emory University Department of Urology, Director of Urologic Oncology at Grady Memorial Hospital, who presented the five-year results at AUA. "Oftentimes, disease recurrence and progression can lead to bladder removal surgery, so it is important that ADSTILADRIN allowed bladder preservation in nearly half of the patients in the CIS cohort and two-thirds of those in the Ta/T1 cohort after five years."

About the Phase 3 ADSTILADRIN Data and Final Five-Year Analysis in BCG-Unresponsive NMIBC
These new data are part of the final five-year follow-up analysis from the Phase 3 study which included two cohorts: patients with CIS ± Ta/T1 (CIS cohort) and patients with high-grade Ta/T1 without CIS (papillary disease [PD cohort]). Patients with NMIBC who fully met the criteria of being BCG-unresponsive, as defined by the 2018 FDA Guidance for Industry, were enrolled in the study.

Patients with NMIBC CIS±Ta/T1 and high-grade Ta/T1 papillary disease (without CIS) received ADSTILADRIN 75 mL intravesical instillation (3×1011 viral particles) once every three months for up to 12 months (quarterly dosing), or until unacceptable toxicity or recurrent high-grade (HG) NMIBC. Retreatment in patients who did not achieve a complete response at three months after a single dose was not allowed, per the protocol. Three clinical trials in the existing multi-year ADSTILADRIN studies program that were previously announced include retreatment.

At 12 months after initial treatment, patients had a biopsy of five sites (dome, trigone, right and left lateral wall, and posterior wall) in the bladder. Patients with no evidence of high-grade recurrence continued receiving ADSTILADRIN once every three months at the discretion of their treating physician, entering an additional four-year treatment and monitoring phase.

Data Show ADSTILADRIN is a Well-Tolerated and Novel Treatment Option for BCG-unresponsive NMIBC
Median follow-up was 50.8 months (IQR 39.1-60.0), with 26.8% receiving five instillations and 7.6% receiving treatment for 57 months. Among patients who were high-grade recurrence free (HGRF) at Month 3, 13 patients were followed and remained HGRF at month 57. The Kaplan-Meier (KM)-estimated probability of remaining HGRF for at least 57 months was 13.2% and 32.7% in the CIS and PD cohorts, respectively.

The overall survival at 60 months was 76.3% in the CIS cohort and 85.9% in the PD cohort. The cystectomy-free survival rate at Month 60 was 43.2.% and 58.7% in the CIS and PD cohorts, respectively. Clinical progression to muscle invasion was rare in the trial population and seen in only 3.3% of all patients (four with CIS and one with Ta/T1) over the five-year follow-up period.

Most treatment emergent adverse events (TEAEs) experienced by patients were transient Grade 1 or 2 (66% of all patients studied), and <4% of patients experienced Grade 3 TEAEs with the most common being discharge around the catheter during instillation, fatigue, bladder spasm, urgency to urinate, chills, dysuria, pyrexia, and urinary incontinence. There were no Grade 4 or 5 TEAEs, no treatment-related deaths, and no new safety signals reported with long-term follow-up.

"These positive five-year follow-up data from our Phase 3 trial continue to demonstrate the efficacy and safety of ADSTILADRIN for NMIBC patients who no longer respond to BCG therapy," said Pierre-Yves Berclaz, M.D., Ph.D., Executive Vice President and Chief Science and Medical Officer, Ferring Pharmaceuticals. "This first-of-its-kind study adds to the body of evidence from our 24-month and 36-month data results and makes ADSTILADRIN the only novel agent with five-year data. With ADSTILADRIN, Ferring has pioneered gene therapy for NMIBC, representing a critical advancement that offers patients renewed hope for more time without disease progression and radical treatment. We look forward to enlarging the body of evidence for ADSTILADRIN with our expanded clinical trial program, which we announced earlier this year."

If you are a healthcare provider interested in the ADSTILADRIN clinical trial program, please visit www.abletrials.com.

About ADSTILADRIN
ADSTILADRIN (nadofaragene firadenovec-vncg) is the first and only FDA-approved intravesical non-replicating gene-therapy for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. It is a non-replicating adenovirus vector-based therapy containing the gene interferon alfa-2b, administered locally as a monotherapy by catheter directly into the bladder once every three months. The vector enters the cells of the bladder wall, releasing the active gene and causing the bladder’s cell walls to secrete high and transient local expression of interferon alfa-2b protein, a naturally-occurring protein the body uses to fight cancer. This approach essentially turns the bladder wall cells into interferon microfactories, enhancing the body’s own natural defenses against the cancer.

ADSTILADRIN has been studied in a clinical trial program that includes 157 patients with high-grade, BCG-unresponsive NMIBC who had been treated with adequate BCG previously and did not see benefit from additional BCG treatment (full inclusion criteria published on clinicaltrials.gov: NCT02773849).1

About Non-Muscle Invasive Bladder Cancer (NMIBC)
NMIBC is a form of bladder cancer that is present in the superficial layer of the bladder and has not invaded deeper into the bladder or spread to other parts of the body.2 In the United States, bladder cancer is the seventh most common cancer, fourth among men,3-4 and it is estimated that there will be approximately 83,190 new cases of bladder cancer in the U.S. in 2024.5 Historically, 75% of bladder cancer presents as NMIBC.6 In patients with high-risk NMIBC, intravesical BCG remains the first-line standard-of-care. However, more than 50% of patients who receive initial treatment with BCG will experience disease recurrence and progression within one year, with many developing BCG-unresponsive disease.5 Current treatment options for BCG-unresponsive patients are very limited, and National Comprehensive Cancer Network (NCCN) guidelines recommend cystectomy (partial or complete removal of the bladder).7

INDICATION
ADSTILADRIN is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS: ADSTILADRIN is contraindicated in patients with prior hypersensitivity reactions to interferon alfa or to any component of the product.

WARNINGS AND PRECAUTIONS:

Risk with delayed cystectomy: Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.
Risk of disseminated adenovirus infection: Persons who are immunocompromised or immunodeficient may be at risk for disseminated infection from ADSTILADRIN due to low levels of replication-competent adenovirus. Avoid ADSTILADRIN exposure to immunocompromised or immunodeficient individuals.
DOSAGE AND ADMINISTRATION: Administer ADSTILADRIN by intravesical instillation only. ADSTILADRIN is not for intravenous use, topical use, or oral administration.

USE IN SPECIFIC POPULATIONS: Advise females of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during ADSTILADRIN treatment and for 3 months after the last dose.

ADVERSE REACTIONS: The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination urgency), creatinine increased, hematuria (blood in urine), phosphate decreased, chills, pyrexia (fever), and dysuria (painful urination).

You are encouraged to report negative side effects of prescription drugs to FDA. Visit www.FDA.gov/medwatch or call 1-800-332-1088. You may also contact Ferring Pharmaceuticals at 1-888-FERRING.

Please click to see the full Prescribing Information.

On May 06, 2024 BostonGene, a leading provider of AI-driven molecular and immune profiling solutions, and the Medical College of Wisconsin, reported the manuscript "Transcriptomic-Based Microenvironment Classification Reveals Precision Medicine Strategies for PDAC” has published online and in print in Gastroenterology, the premier journal in the field of gastrointestinal disease (Press release, BostonGene, MAY 6, 2024, View Source [SID1234642709]). BostonGene’s artwork was also chosen for the cover of the May publication. The journal highlights original research, reviews and expert insights in adult and pediatric gastroenterology and hepatology, covering clinical, translational and basic aspects of the digestive system, liver, pancreas and nutrition. The study identified four distinct tumor microenvironment (TME) subtypes, unveiling a promising path forward in the fight against PDAC and underscoring the importance of considering TME features in personalized therapeutic strategies.

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Pancreatic ductal adenocarcinoma (PDAC) has long been notorious for its aggressive nature and genetic complexity, making it difficult for doctors to predict how patients will respond to treatment and for scientists to develop effective predictive biomarkers and targeted therapies. To address these unmet needs, Ben George, MD, at the Medical College of Wisconsin (MCW) in collaboration with BostonGene, led a study utilizing a transcriptomic profiling platform to classify the TME of PDAC based on functional gene expression signatures. This innovative approach analyzed data from publicly available PDAC datasets and was further validated in a clinically annotated, independent cohort of PDAC patients from the LaBahn Pancreatic Cancer Program, part of the MCW Cancer Center.

"For a long while, the scientific community believed that pancreatic cancer was not responsive to immunotherapy, which uses a person’s own immune system to fight cancer. We’ve since made new discoveries that show that pancreatic cancer that spreads to the lungs is biologically distinct, prognostically favorable, and potentially responsive to immunotherapy compared to those that spread to the liver," said Ben George, MD, William F. Stapp Endowed Chair; Professor of Medicine and Medical Director, Cancer Clinical Trials Program at the Medical College of Wisconsin. "Together with BostonGene, we hope to further characterize the biologically distinct PDAC subtypes and investigate how different treatments can modify the TME of pancreatic cancers. Our goal is to design prospective clinical trials, which will be made available through the MCW Cancer Center, to test various immunomodulatory strategies based on these four subtypes."

As part of the collaboration, BostonGene utilized an artificial intelligence (AI)-driven algorithm to reconstruct the transcriptomic data and identified four distinct TME subtypes: immune-enriched (IE), immune-enriched with fibrosis (IE/F), fibrotic (F) and immune-depleted (D). Importantly, patients with immune-enriched subtypes, IE and IE/F, demonstrated a more favorable prognosis and showed potential responsiveness to immunotherapy than those classified as F and D.

"We’re excited to unveil our latest research, which sheds light on the intricate tumor microenvironment of PDAC," said Ben George. "These results pave the way for transcriptomic-based immunotherapeutic strategies in PDAC, bringing us closer to personalized treatment approaches for this challenging disease."

"Our findings not only define a subgroup of PDAC patients who may benefit from immunotherapeutic interventions but also sets the stage for prospective clinical trials to validate the predictive utility of these transcriptomic TME PDAC subtypes," said Nathan Fowler, MD, Chief Medical Officer at BostonGene.

On May 06, 2024 ArteraAI, the developer of multimodal artificial intelligence-based prognostic and predictive cancer tests, reported the validation of its first multimodal artificial intelligence (MMAI) digital pathology-based post-radical prostatectomy biomarker for stratifying risk of metastasis and identifying differential absolute benefit for the addition of hormone therapy to salvage radiation therapy in radical prostatectomy patients with biochemical recurrence (BCR) (Press release, Artera, MAY 6, 2024, View Source [SID1234642708]).

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Researchers successfully trained and validated the model for patients who experience BCR after radical prostatectomy surgery, which is strongly associated with the risk of the disease spreading. The data was presented by Dr. Todd Morgan from Michigan Medicine as an oral presentation at the 2024 AUA Annual Meeting, on Sunday, May 5, 2024.

A radical prostatectomy is the removal of the prostate in a patient with prostate cancer and has served as a primary treatment for this disease for many years. However, about 20-40% of patients who undergo the procedure eventually develop BCR, which is an indicator of the cancer returning. In this event, salvage radiotherapy is usually recommended and clinicians are also faced with the decision of whether to further intensify the treatment by combining the salvage radiotherapy with hormone therapy.

"There is a continued need to optimize treatment for men with BCR post-radical prostatectomy to avoid both over- and under-treatment," said Morgan, urological surgeon and Chief of Urologic Oncology at Michigan Medicine. "In the near future, clinicians and patients may be able to use this digital pathology-based biomarker to better understand the risk of further disease progression and inform the treatment plan for these patients in particular."

For the study, researchers aimed to develop a novel biomarker for patients with BCR post-radical prostatectomy using multimodal deep learning on digital histopathology to stratify the risk of distant metastasis. Data from two Phase 3 randomized trials, NRG/RTOG 9601 and 0534, were used for development and validation. Clinical and histopathological data were available for 1,855 of the 2,573 eligible patients (72.1%). The training cohort included 1,322 men and the validation cohort included 533 men. Digitized images of prostatectomy tumor samples were utilized to develop an MMAI model to estimate the risk of distant metastasis and identify benefits from adding hormone therapy to salvage radiation therapy.

"We’re thrilled to have had the opportunity for our data to be presented at AUA," said Andre Esteva, Co-founder and CEO of ArteraAI. "These data exemplify how ArteraAI plans to extend its platform in the future for patients who have undergone a radical prostatectomy."

Prior to this research, no AI-based models had been developed in cohorts of radical prostatectomy patients. This is the first MMAI digital pathology-based post-radical prostatectomy biomarker that has successfully been trained and validated using data from Phase 3 clinical trials of men post-prostatectomy to show prognostic capability for all tested endpoints as well as differential absolute benefit for the addition of hormone therapy to salvage radiation therapy.

For more information on ArteraAI, visit Artera.ai.

On May 06, 2024 Biocytogen Pharmaceuticals (Beijing) Co., Ltd. ("Biocytogen", HKEX: 02315), a global biotechnology company focused on the discovery of novel antibody-based therapeutics, reported a TCR-mimic antibody evaluation and potential licensing agreement with BioCopy AG ("BioCopy"), a research-based biotechnology company headquartered in Basel, Switzerland (Press release, Biocytogen, MAY 6, 2024, View Source [SID1234642707]).

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The agreement grants BioCopy access to fully human TCR-mimic antibodies targeting an intracellular antigen generated by Biocytogen’s proprietary RenTCR-mimicTM mice. BioCopy will conduct an evaluation and retain the option to license these antibodies for the development of novel cancer therapies.

"We are glad to provide BioCopy with our TCR-mimic antibodies," said Dr. Yuelei Shen, President and CEO of Biocytogen. "Our in vivo matured TCR-mimic antibodies demonstrated favorable affinity and excellent specificity. Combined with BioCopy’s expertise in TCR-mimic antibody screening and engager development, we are optimistic that our collaboration will generate novel drugs that benefit cancer patients."

BioCopy will use Biocytogen’s TCR-mimic antibodies and test them against promising intracellular tumor associated antigens. Here, BioCopy will use its automated end-to-end platform for the optimization of multispecific biotherapeutics to further develop these TCR-mimic antibodies into next-generation oncological drugs.

About Biocytogen’s TCR-mimic Antibody Discovery Platform

Biocytogen’s TCR-mimic platform focuses on the discovery of fully human antibodies to intracellular targets that are presented on the cell surface by MHC class I molecules. Leveraging proprietary RenTCR-mimicTM (HLA/RenMab) mice and specialized immunization protocols, Biocytogen’s platform is designed to generate TCR-mimic antibodies that are highly specific for peptide/HLA complexes and not HLA itself. Using a high-throughput antibody screening platform, Biocytogen swiftly identifies TCR-mimic antibodies with higher specificity and affinity than endogenous TCRs derived from patients to overcome tumor immune escape. Currently, antibody hits for multiple intracellular targets, including TAAs, cancer-testis antigens, mutated protein antigens, and viral protein antigens, are being evaluated in vivo and in vitro. Fully human antibody sequences obtained from the TCR-mimic platform can empower the development of T cell engagers, bispecific/multispecific antibodies, and CAR-T therapies.

On May 06, 2024 Arsenal Biosciences, Inc. (ArsenalBio), a clinical stage programmable cell therapy company focused on engineering advanced CAR T-cell therapies for solid tumors, reported the presentation of four abstracts at the American Society of Gene + Cell Therapy (ASGCT) (Free ASGCT Whitepaper) annual meeting in Baltimore, Md., May 7-11, 2024 (Press release, ArsenalBio, MAY 6, 2024, View Source [SID1234642706]). These data highlight the portfolio of solutions ArsenalBio is developing to address unmet need in solid tumor cancers, including those currently being studied as potential treatments for ovarian cancer (NCT05617755) and kidney cancer (NCT06245915).

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"We continue to advance the science of CAR T-cell therapy and to develop new tools to improve the potency and persistence of our fundamental integrated circuit T cell technology"

"We continue to advance the science of CAR T-cell therapy and to develop new tools to improve the potency and persistence of our fundamental integrated circuit T cell technology," said Nick Haining, B.M., B.Ch., ArsenalBio’s Co-Founder and Chief Scientific Officer. "The entry into the clinic with our second T cell medicine just five years into our company’s journey is a testament to the rigorous nature of our approach, the robustness of our data, and the urgency of our purpose – to address the unmet need for safe and effective treatments for solid tumor cancers."

The following abstracts will be presented as poster presentations during the ASGCT (Free ASGCT Whitepaper) annual meeting.

Abstract 811: Development of AB-2100, a PSMA-inducible anti-CA9 CAR T cell therapy intended for the treatment of ccRCC
Date and Time: May 8, 2024 at 12:00 p.m.
Presenter: Mark Landon, M.S.

AB-2100 is designed to treat relapsed/refractory clear cell renal cell carcinoma (ccRCC). It is an autologous integrated circuit T (ICT) cell product, generated by inserting a DNA cassette into a safe harbor locus within the T cell. It is designed to use three mechanisms to attack tumors while sparing healthy tissues: a logic gate requiring the presence of two antigens in the tumor microenvironment; a synthetic pathway activator (SPA) that enhances antitumor activity; and shRNAs that armor it against immunosuppression. These T cell functions were tested in xenograft models to study the specificity of the logic gate in addressing tumors expressing CA9 as well as both PSMA and CA9 (as the CAR T cells are designed to do). This approach was shown to be successful in overcoming the suppressive mechanisms of the tumor microenvironment and addressing ccRCC expressing both PSMA and CA9 in xenograft models.

Abstract 782: Development of a microscopy-based IF/ISH assay for detection of ICT cells in patients treated with AB-1015
Date and Time: May 8, 2024 at 12:00 p.m.
Presenter: Nickolas Attanasio

AB-1015 is an autologous, genetically modified integrated circuit T (ICT) cell product in clinical development for the treatment of ovarian cancer. It integrates an "AND" logic gate designed to limit off-tumor toxicity through a requirement for dual tumor antigen recognition. To better understand the performance characteristics of AB-1015 ICT cells in human tissue, a custom multiplex immunofluorescence (mIF) assay was developed using the RNAScope platform to detect CD3 protein and mRNA transcripts of both the PrimeR and CAR portion of the circuit by in situ hybridization (ISH). After validation in xenograft models, the assay was used to detect ICTs in one on-trial tumor biopsy sample of an AB-1015 patient.

Abstract 839: Single-cell, pooled CRISPR screening reveals T cell intrinsic regulators of exhaustion in context of chronic antigen stimulation
Date and Time: May 8, 2024 at 12:00 p.m.
Presenter: Glenn Wozniak, Ph.D.

T cell exhaustion from chronic antigen stimulation and an immunosuppressive tumor microenvironment limits the efficacy of T cell therapies used to treat solid tumors. This research used CRISPR/Cas9-based screening, paired with deep sequencing, to identify intrinsic genetic perturbations that can prevent T cell exhaustion. By developing pools of genetically engineered CAR T cells each designed to achieve up- or down-regulation of a single target gene and subjecting the pools to chronic antigen stimulation to replicate hallmarks of T cell exhaustion, we can understand the function of individual genetic changes on T cell function. Our results demonstrated the potential for pooled CRISPR screening to measure complex phenotypes and provided data to direct the development of future advanced CAR T cell therapies.

Abstract 814: Development of logic-gated "Payload" module in CAR T cells aimed at increasing local concentration of a secreted pro-inflammatory module in an antigen-dependent manner
Date and Time: May 8, 2024 at 12:00 p.m.
Presenter: Gavin Shavey, M.S.

This experiment aimed to study whether the logic-gated secretion of a pro-inflammatory module (Payload) could provide an ICT-extrinsic enhancement to the success of these therapies by supporting activation of the endogenous immune system to aid in the anti-tumor response. The study evaluated the ability of a variety of supplemented cytokines to enhance both the ICT and the bystander immune cells anti-tumor function in vitro by engineering and testing 30+ cytokine variants to be secreted as Payloads. Incorporation of such Payloads into ICT cells resulted in significant augmentation of anti-tumor activity. We showed Payloads can enhance the function of both ICT and bystander immune cells without signs of increased transformation risk and can increase capacity for tumor clearance in vivo at significantly lower dosage.

For more information about ArsenalBio, visit www.arsenalbio.com.