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DRUG:

Adstiladrin (nadofaragene firadenovec-vncg)

i
Other names: rAd-IFN/Syn3, SCH 721015/SCH 209702, Ad-IFNalpha/Syn3, rAd-IFN, TR002, FE 999326
Company:
FKD Therapies, Ferring, Royalty
Drug class:
IFNα stimulant
2d
Single-cell RNA sequencing analysis identifies acute changes in the tumor microenvironment induced by interferon α gene therapy in a murine bladder cancer model. (PubMed, Front Immunol)
This single-cell analysis builds upon our understanding of the impact of Ad-IFNα on tumor cells and other compartments of the microenvironment. These data will help identify mechanisms to improve patient selection and therapeutic efficacy of Nadofaragene firadenovec.
Preclinical • Journal • PD(L)-1 Biomarker • IO biomarker • Gene therapy
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IFNA1 (Interferon Alpha 1)
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PD-L1 expression • PD-1 expression
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Adstiladrin (nadofaragene firadenovec-vncg)
7d
Enrollment closed
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Adstiladrin (nadofaragene firadenovec-vncg)
9d
ABLE-41: ADSTILADRIN Early Utilization and Outcomes in the Real World Setting (clinicaltrials.gov)
P=N/A, N=400, Recruiting, Ferring Pharmaceuticals | N=800 --> 400
Enrollment change
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Adstiladrin (nadofaragene firadenovec-vncg)
14d
INFINITE: Efficacy & Safety of RAd-IFN Administered with Celecoxib & Gemcitabine in Patients with Malignant Pleural Mesothelioma (clinicaltrials.gov)
P3, N=53, Active, not recruiting, Ferring Ventures Limited | Trial completion date: Nov 2024 --> Apr 2026 | Trial primary completion date: Nov 2023 --> Mar 2024
Trial completion date • Trial primary completion date • Combination therapy
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MSLN (Mesothelin) • EFEMP1 (EGF Containing Fibulin Extracellular Matrix Protein 1)
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gemcitabine • Adstiladrin (nadofaragene firadenovec-vncg) • celecoxib oral
21d
New P1/2 trial
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Adstiladrin (nadofaragene firadenovec-vncg)
25d
Enrollment open • Combination therapy
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Keytruda (pembrolizumab) • gemcitabine • docetaxel • Adstiladrin (nadofaragene firadenovec-vncg)
29d
Enrollment open
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Adstiladrin (nadofaragene firadenovec-vncg)
1m
Minimal Residual Disease Detection with Urine-derived DNA Is Prognostic for Recurrence-free Survival in Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer Treated with Nadofaragene Firadenovec. (PubMed, Eur Urol Oncol)
P2; Urinary MRD testing after nadofaragene firadenovec induction provided statistically significant prognostication of recurrence among phase 2 trial participants.
Journal • Minimal residual disease
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HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • ARID1A (AT-rich interaction domain 1A) • ELF3 (E74 Like ETS Transcription Factor 3)
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HER-2 mutation
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UroAmp
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Adstiladrin (nadofaragene firadenovec-vncg)
2ms
Clinical use of nadofaragene firadenovec-vncg. (PubMed, Ther Adv Urol)
Implementation of these recommendations will ensure efficient real-world use of nadofaragene firadenovec and the development of useful training materials and relevant standard operating procedures to help support a clinic's treatment for patients with BCG-unresponsive NMIBC with CIS. Video Abstract https://vimeo.com/user17898099/review/953723559/e18af7ec43.
Review • Journal
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IFNA1 (Interferon Alpha 1)
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Adstiladrin (nadofaragene firadenovec-vncg)
3ms
The Evolution of Nadofaragene Firadenovec: A Review and the Path Forward. (PubMed, Bladder Cancer)
Nadofaragene leverages the cytotoxic, anti-angiogenic, and immune-modulatory roles of interferon to effectively treat NMIBC that is resistant to BCG. Ongoing studies of resistance mechanisms and prognostic biomarkers have been promising; these will ultimately improve patient selection and allow for the modulation of factors in the tumor or immune microenvironment to further increase therapeutic response.
Review • Journal
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IFNA1 (Interferon Alpha 1) • IFNA2 (Interferon Alpha 2)
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Adstiladrin (nadofaragene firadenovec-vncg)
3ms
New P2 trial • Combination therapy
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Keytruda (pembrolizumab) • gemcitabine • docetaxel • Adstiladrin (nadofaragene firadenovec-vncg)
4ms
Enrollment open
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Adstiladrin (nadofaragene firadenovec-vncg)
4ms
New P3 trial
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Adstiladrin (nadofaragene firadenovec-vncg)
5ms
Intravesical instillation-based mTOR-STAT3 dual targeting for bladder cancer treatment. (PubMed, J Exp Clin Cancer Res)
The bi-specific siRNA strategy, encapsulated in an adenovirus, could be a promising tool to augment cancer treatment efficacy and overcome conventional therapy limitations associated with "undruggability." Hence, we propose that dual targeting of mTOR and STAT3 is an advantageous strategy for intravesical therapy using adenoviruses.
Journal
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CD8 (cluster of differentiation 8) • STAT3 (Signal Transducer And Activator Of Transcription 3)
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Adstiladrin (nadofaragene firadenovec-vncg) • cretostimogene grenadenorepvec (CG0070)
5ms
Safety and Efficacy of FE 999326 Administered Intravesically to Japanese Subjects With High-grade, BCG Unresponsive, Non-muscle Invasive Bladder Cancer (NMIBC) (clinicaltrials.gov)
P3, N=24, Recruiting, Ferring Pharmaceuticals | Trial completion date: Dec 2028 --> Dec 2029 | Trial primary completion date: Dec 2024 --> Oct 2025
Trial completion date • Trial primary completion date
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Adstiladrin (nadofaragene firadenovec-vncg)
8ms
Urinary minimal residual disease detection predicts recurrence in BCG-unresponsive NIMBC and quantifies molecular response to nadofaragene firadenovec (AUA 2024)
uMRD enables quantitative assessment of molecular response to drug treatment. uMRD-determined pre-treatment disease burden assessment can support stratification of control and intervention arms in future treatment trials.
Minimal residual disease
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HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • ARID1A (AT-rich interaction domain 1A) • ELF3 (E74 Like ETS Transcription Factor 3) • SOX4 (SRY-Box Transcription Factor 4)
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HER-2 mutation
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UroAmp
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Adstiladrin (nadofaragene firadenovec-vncg)
9ms
ABLE-41: ADSTILADRIN Early Utilization and Outcomes in the Real World Setting in the United States (clinicaltrials.gov)
P=N/A, N=800, Recruiting, Ferring Pharmaceuticals | Trial completion date: Dec 2026 --> Dec 2025 | Trial primary completion date: Dec 2026 --> Dec 2025
Trial completion date • Trial primary completion date • Real-world evidence • Real-world
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Adstiladrin (nadofaragene firadenovec-vncg)
11ms
ABLE-41: Nadofaragene firadenovec-vncg early use and outcomes in a real-world setting in the United States. (ASCO-GU 2024)
The estimated follow-up period is 24 months, until study discontinuation, or withdrawal. Final results from this large, prospective, multi-institutional, real-world registry providing early use and outcomes of nadofaragene firadenovec are expected December 2026.
Clinical • Real-world evidence • Real-world
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Adstiladrin (nadofaragene firadenovec-vncg)
11ms
Urinary minimal residual disease detection predicts recurrence in BCG-unresponsive NIMBC and quantifies molecular response to nadofaragene firadenovec. (ASCO-GU 2024)
uMRD enables quantitative assessment of molecular response to drug treatment. uMRD-determined pre-treatment disease burden assessment can support stratification of control and intervention arms in future treatment trials.
Minimal residual disease
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HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • ARID1A (AT-rich interaction domain 1A) • ELF3 (E74 Like ETS Transcription Factor 3) • SOX4 (SRY-Box Transcription Factor 4)
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HER-2 mutation
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UroAmp
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Adstiladrin (nadofaragene firadenovec-vncg)
12ms
Novel immunotherapeutic options for BCG-unresponsive high-risk non-muscle-invasive bladder cancer. (PubMed, Cancer Med)
Three drugs-pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec-vncg-have been FDA approved for the treatment of BCG-unresponsive NMIBC in patients who are ineligible for or decline RC. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR-NMIBC is essential for the discovery of new targets and the development of effective treatments.
Review • Journal • PD(L)-1 Biomarker • IO biomarker
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FGFR (Fibroblast Growth Factor Receptor) • IDO1 (Indoleamine 2,3-dioxygenase 1)
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Keytruda (pembrolizumab) • Adstiladrin (nadofaragene firadenovec-vncg) • valrubicin
1year
UPDATED EFFICACY AND SAFETY OF ORAL ERDAFITINIB IN PATIENTS WITH BACILLUS CALMETTE-GUÉRIN–UNRESPONSIVE, HIGH-RISK NON-MUSCLE–INVASIVE BLADDER CANCER WITH FGFR3/2 ALTERATIONS IN THOR-2 COHORT 2 (SUO 2023)
Treatment options for patients with bacillus Calmette-Guérin (BCG)-unresponsive CIS who refuse/are ineligible for radical cystectomy include pembrolizumab, intravesical chemotherapy, or nadofaragene firadenovec. Data from this trial provide first evidence of occurrence of FGFR alterations in CIS and demonstrate the promising and durable efficacy of an FGFR inhibitor such as erdafitinib in patients with BCG-unresponsive CIS with FGFR alterations. Safety data were consistent with the known safety profile of erdafitinib.
Clinical
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FGFR3 (Fibroblast growth factor receptor 3)
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Keytruda (pembrolizumab) • Balversa (erdafitinib) • Adstiladrin (nadofaragene firadenovec-vncg)
1year
Novel Combination Therapy Using Interferon Gene Therapy and Gemcitabine in Murine Bladder Cancer Cell Lines (SUO 2023)
Funding: Research is supported in part by A.I. Virtanen Institute for Molecular Sciences (Kuopio, Finland) and MD Anderson CCSG program (P30 016672).; Introduction: Interferon alpha (IFNα) gene therapy with Nadofaragene firadenovec is emerging as a promising therapeutic option for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Combination therapy with IFNα or -β and Gemcitabine led to superior cell cycle arrest and apoptosis in murine BLCA cell lines. The observed differences between the effects of IFNα and IFNβ merit further investigation to optimize intravesical gene therapy. Future in-vitro and in-vivo experiments using human and murine BLCA models are ongoing to direct future clinical development of intravesical gene therapy.
Preclinical • Combination therapy • Gene therapy
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IFNA1 (Interferon Alpha 1) • ANXA5 (Annexin A5) • IFNB1 (Interferon Beta 1)
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gemcitabine • Adstiladrin (nadofaragene firadenovec-vncg)
1year
EFFICACY OF INTRAVESICAL NADOFARAGENE FIRADENOVEC FOR PATIENTS WITH BCG-UNRESPONSIVE CARCINOMA IN SITU OF THE BLADDER: 36-MONTH FOLLOW-UP FROM A PHASE 3 TRIAL (SUO 2023)
Intravesical nadofaragene firadenovec, administered once every three months, demonstrated a sustained durability of response in patients with BCG-unresponsive CIS±Ta/T1 papillary disease. Nadofaragene firadenovec represents a novel treatment option for BCG-unresponsive NMIBC with a favorable benefit-to-risk ratio. *All patients had passed 36 months at data cutoff on 09 September 2021.
Clinical • P3 data
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Intron A (interferon α-2b) • Adstiladrin (nadofaragene firadenovec-vncg)
1year
Real-world evidence • Enrollment open • Real-world
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Cxbladder • UroVysion™ Bladder Cancer Kit (UroVysion Kit)
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Adstiladrin (nadofaragene firadenovec-vncg)
1year
Interferon gene therapy with nadofaragene firadenovec for bladder cancer: from bench to approval. (PubMed, Front Immunol)
Ongoing research focuses on improving patient selection, identifying biomarkers for response prediction, exploring alternative vectors for enhanced transfection efficiency, and developing combination strategies targeting resistance mechanisms. The approval of nadofaragene firadenovec marks a significant milestone in the field of gene therapy for bladder cancer, and future developments hold promise for further enhancing its efficacy and impact.
Review • Journal • Gene therapy
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IFNA1 (Interferon Alpha 1)
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Adstiladrin (nadofaragene firadenovec-vncg)
1year
New trial
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Cxbladder • UroVysion™ Bladder Cancer Kit (UroVysion Kit)
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Adstiladrin (nadofaragene firadenovec-vncg)
over1year
Nadofaragene Firadenovec: First Approval. (PubMed, Drugs)
In December 2022, nadofaragene firadenovec received its first global approval in the USA for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumours in adults. This article summarizes the milestones in the development of nadofaragene firadenovec leading to this first approval for this indication.
Review • Journal
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IFNA1 (Interferon Alpha 1)
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Adstiladrin (nadofaragene firadenovec-vncg)
over2years
Cases From The Community — Urologic Oncology Investigators Provide Perspectives on the Optimal Management of Urothelial Bladder Cancer (AUA 2022)
Ongoing and planned studies evaluating other novel approaches (eg, enfortumab vedotin, erdafitinib, nadofaragene firadenovec) for BCG-unresponsive NMIBC MODULE 2: The Role of Immune Checkpoint Inhibitors as Adjuvant and Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer (MIBC)rnrn1...Recent FDA approval of adjuvant nivolumab and identification of appropriate candidates for treatment 4...Current role of atezolizumab and pembrolizumab as first-line treatment for mUBC, importance of chemotherapy eligibility and PD-L1 status in selecting patients for this strategy 2. Key efficacy and safety data with maintenance avelumab after front-line chemotherapy for mUBC, appropriate incorporation into patient care 3...Preliminary data from the Phase I/II NORSE study of erdafitinib in combination with the investigational anti-PD-1 antibody cetrelimab for patients with previously untreated mUBC with FGFR3 or FGFR2 genetic alterations who are not eligible for cisplatin MODULE 4: The Selection and Sequencing of Therapy for Relapsed/Refractory mUBC 1...Emerging results from cohort 3 of the TROPHY U-01 trial combining sacituzumab govitecan and pembrolizumab 4...Optimal integration of enfortumab vedotin, sacituzumab govitecan and erdafitinib into therapy for progressive mUBCrnIncidence, severity and management of adverse events reported with enfortumab vedotin, sacituzumab govitecan or erdafitinib 6. Frequency of HER2 expression in UBC, mechanism of action of disitamab vedotin and available data and ongoing evaluation for patients with HER2-positive disease 7. Other promising agents and strategies under investigation for mUBC (eg, trastuzumab deruxtecan, futibatinib, infigratinib, cabozantinib) Target Audience This activity has been designed to meet the educational needs of medical and radiation oncologists, urologists and other allied healthcare professionals involved in the treatment of bladder cancer...RESEARCH TO PRACTICE CME PLANNING COMMITTEE MEMBERS, STAFF AND REVIEWERS — Planners, scientific staff and independent reviewers for Research To Practice have no relevant conflicts of interest to disclose. Supporters This activity is supported by educational grants from Astellas and Seagen Inc, AstraZeneca Pharmaceuticals LP, Gilead Sciences Inc, and Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC.
Clinical • PD(L)-1 Biomarker • IO biomarker
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HER-2 (Human epidermal growth factor receptor 2) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR3 (Fibroblast growth factor receptor 3)
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HER-2 positive • HER-2 expression
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Keytruda (pembrolizumab) • Opdivo (nivolumab) • cisplatin • Tecentriq (atezolizumab) • Enhertu (fam-trastuzumab deruxtecan-nxki) • Bavencio (avelumab) • Cabometyx (cabozantinib tablet) • Balversa (erdafitinib) • Truseltiq (infigratinib) • Lytgobi (futibatinib) • Aidixi (disitamab vedotin) • Trodelvy (sacituzumab govitecan-hziy) • Padcev (enfortumab vedotin-ejfv) • cetrelimab (JNJ-63723283) • Adstiladrin (nadofaragene firadenovec-vncg)
over2years
Patient-derived bladder tumor organoids for individualized preclinical characterization of Nadofaragene firadeneovec interferon gene therapy (AUA 2022)
Most recently, two organoids have been successfully established and expanded in suspension culture with 2-4% Matrigel supplementation, improving scalability and decreasing organoid doubling time. Conclusions : Patient-derived tumor organoids represent a novel preclinical model for evaluating the direct cytotoxicity of Nadofaragene firadenevec, and optimization of organoid growth in suspension culture improves capacity for real-time evaluation of individual tumor sensitivities to novel therapeutics.
Preclinical
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HER-2 (Human epidermal growth factor receptor 2) • EGF (Epidermal growth factor)
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Adstiladrin (nadofaragene firadenovec-vncg)
over2years
Adjuvant instillation therapy for non-muscle invasive bladder cancer - beyond BCG und mitomycin C (PubMed, Aktuelle Urol)
GemRIS is an implantable novel form of intravesical drug delivery of gemcitabine and is currently being investigated with cetrelimab, a checkpoint inhibitor, in patients with high-risk NMIBC and MIBC...Nadofaragene firadenovec (rAd-IFN-α/Syn3) is a recombinant adenovirus that induces release of interferon-alpha in the urothelium...N-803 is an interleukin (IL)-15 analogue, which has been investigated in a phase 1b study in combination with BCG and has shown durable complete response in all nine patients for 72 months. It was granted breakthrough designation status by the FDA in 2019.
Journal
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IFNA1 (Interferon Alpha 1)
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mitomycin • cetrelimab (JNJ-63723283) • Adstiladrin (nadofaragene firadenovec-vncg) • Anktiva (nogapendekin alfa inbakicept-pmln) • GemRIS (gemcitabine-releasing intravesical system)
almost3years
Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance. (PubMed, Mol Ther Oncolytics)
In high-grade, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer, nadofaragene firadenovec, a non-replicating adenovirus administered locally to express the IFNα2b transgene, embodies a novel approach to deploy the therapeutic activity of type I IFNs while minimizing systemic toxicities...We found that constitutive activation of the type I IFN signaling pathway is a biomarker for resistance to both transcriptional response and direct cytotoxic effects of IFNα. We present several genes that discriminate between sensitive and resistant tumor cells, suggesting they should be explored for utility as biomarkers in future clinical trials of type I IFN-based anti-tumor therapies.
Journal
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IFNA1 (Interferon Alpha 1)
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Adstiladrin (nadofaragene firadenovec-vncg)
3years
PATIENT-DERIVED BLADDER TUMOR ORGANOIDS FOR INDIVIDUALIZED PRECLINICAL CHARACTERIZATION OF NADOFARAGENE FIRADENOVEC INTERFERON GENE THERAPY (SUO 2021)
Patient-derived tumor organoids represent a novel preclinical model for evaluating the direct cytotoxicity of nadofaragene firadenovec, and optimization of organoid growth in suspension culture improves capacity for real-time evaluation of individual tumor sensitivities to novel therapeutics. Current studies are evaluating baseline and post-treatment organoid gene expression profiles and developing organoid-based orthotopic murine xenograft disease models.
Preclinical
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HER-2 (Human epidermal growth factor receptor 2) • EGF (Epidermal growth factor)
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Adstiladrin (nadofaragene firadenovec-vncg)
over3years
[VIRTUAL] Phase III Trial of Intravesical Nadofaragene Firadenovec in Patients with High-Grade, BCG-Unresponsive, Non-muscle Invasive Bladder Cancer: Two Year Follow-up in the Ta/T1 Cohort (AUA 2021)
Nadofaragene firadenovec was well tolerated and demonstrates durability of response in pts with HG Ta/T1, BCG-unresponsive NMIBC in 24 mos follow-up after first intravesical treatment. Clinical trial information: NCT02773849.
Clinical • P3 data
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IFNA2 (Interferon Alpha 2)
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Intron A (interferon α-2b) • Adstiladrin (nadofaragene firadenovec-vncg)
over3years
[VIRTUAL] Efficacy of Intravesical Nadofaragene Firadenovec for Patients with Carcinoma in Situ (CIS), BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC): Longer-Term Follow-up from the Phase III Trial (AUA 2021)
Nadofaragene firadenovec instilled intravesically once every 3 mos demonstrates sustained durability of response with longer follow-up in pts with HG, BCG-unresponsive NMIBC. Clinical trial information: NCT02773849.
Clinical • P3 data
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IFNA2 (Interferon Alpha 2)
|
Intron A (interferon α-2b) • Adstiladrin (nadofaragene firadenovec-vncg)
over3years
[VIRTUAL] Anti-adenoviral Antibody Levels Predict Nadofaragene Firadenovec Response in BCG-unresponsive NMIBC: Results from a Phase 3 Trial (AUA 2021)
Secondary analysis of the prospective, multicenter phase 3 nadofaragene firadenovec trial in BCG-unresponsive NMIBC indicates a role for assaying baseline and on-treatment Ab titers. A combination of Ab titer and fold-change levels can potentially predict response to this novel therapeutic in a patient population with urgent unmet clinical need.
P3 data
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IFNA2 (Interferon Alpha 2)
|
Intron A (interferon α-2b) • Adstiladrin (nadofaragene firadenovec-vncg)
over4years
[VIRTUAL] A Phase III Study to Evaluate the Safety and Efficacy of Intravesical Nadofaragene Firadenovec for Patients with High-Grade, BCG Unresponsive Non-Muscle Invasive Bladder Cancer: Papillary Disease Cohort Results (AUA 2020)
Nadofaregene firadenovec was well tolerated and achieved an encouraging, durable HGRF survival in high-grade BCG-unresponsive NMIBC pts with PD. This demonstrates a clinically meaningful benefit in a pt population for whom to date non-surgical treatment options have remained limited. Clinical trial information: NCT02773849.
Clinical • P3 data
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IFNA2 (Interferon Alpha 2)
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Intron A (interferon α-2b) • Adstiladrin (nadofaragene firadenovec-vncg)