A Phase I/II, Open-label Study to Evaluate the Safety and Anti-tumor Effects of NV1020 Administered Repeatedly Via Hepatic Artery Infusion Prior to Second-line Chemotherapy, in Patients With Colorectal Adenocarcinoma Metastatic to the Liver

This study is an open-label study. It has two stages. Stage 1 is a dose escalation phase of the study to determine and evaluate the safety and tolerability of repeated treatments with a genetically engineered herpes simplex virus NV1020 administered locoregionally to the liver.
Stage 2 is to evaluate the dose found in Stage 1 to be "optimally tolerated". Stage 2 is to assess the efficacy of the optimally tolerated dose of NV1020 by itself and in combination with second-line chemotherapy.
Assignment to Stage 1 or Stage 2 of the study is determined by when the patient enters the study.

Start Date01 Jul 2004

Sponsor / Collaborator

MediGene AG

NCT00012155 / CompletedPhase 1IIT

A Phase I, Open-Label, Dose-Escalating Study Of The Safety, Tolerability, And Anti-Tumor Activity Of A Single Intrahepatic Arterial Injection Of Genetically Engineered Herpes Simplex Virus, NV1020, In Subjects With Adenocarcinoma Of The Colon With Metastasis To The Liver

RATIONALE: Gene therapy may make the body build an immune response to kill tumor cells.
PURPOSE: Phase I trial to study the safety of NV1020 in patients who have colon cancer that has spread to the liver and has not responded to previous chemotherapy.

Start Date01 Oct 2000

Sponsor / Collaborator

Memorial Sloan Kettering Cancer Center

[+1]

100 Clinical Results associated with NV-1020

100 Translational Medicine associated with NV-1020

100 Patents (Medical) associated with NV-1020

153

Literatures (Medical) associated with NV-1020

02 Nov 2023·NatureQ1 · CROSS-FIELD

Clinical trial links oncolytic immunoactivation to survival in glioblastoma

Q1 · CROSS-FIELD

Article

Author: Rodig, Scott J ; Wechuck, James ; Malinowski, Seth W ; Barone, Francesca ; Chen, Ethan ; Wen, Patrick Y ; Suvà, Mario L ; Krisky, David ; Zeng, Yu ; Batchelor, Tracy ; Masud, Nafisa ; Kovarsky, Daniel ; Soni, Himanshu ; Landivar, Ana Montalvo ; Tabakov, Dmitry ; Triggs, Daniel ; Nakashima, Hiroshi ; Kittelberger, Kara ; Bi, Wenya Linda ; Shin, Nara ; Liu, Junfeng ; Santos, Andres ; Stopa, Brittany ; Halloran, Patrick ; Fell, Geoffrey ; Piranlioglu, Raziye ; Gonzalez Castro, L Nicolas ; Ito, Hirotaka ; Ling, Alexander L ; Tikhonova, Ekaterina ; Grant, James ; Prabhu, Michael C ; Miheecheva, Natalia ; Yilmaz, Ayse S ; Torio, Erickson ; Manzanera, Andrea ; Reardon, David A ; Chiocca, E Antonio ; Gorbacheva, Alisa ; Tirosh, Itay ; Ligon, Keith ; Dumont, Sydney D ; Aguilar-Cordova, Estuardo ; Frenkel, Felix ; Chukwueke, Ugonma ; Mo, Xiaokui ; Zhang, Abigail ; Aguilar, Laura K ; Carlisle, Anne ; Lee, Eudocia Quant ; Shono, Naoyuki ; Shumskiy, Artemy ; Solomon, Isaac H ; Peruzzi, Pierpaolo ; Nowicki, Michal O ; Matheny, Chris ; Wucherpfennig, Kai W ; Nayak, Lakshmi ; Woods, Jared K ; Bernstock, Joshua D ; Tak, Paul P

Abstract:

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM)1,2. Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110—an oncolytic herpes virus (oHSV)3. In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue4. These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318).

31 May 2023·Science translational medicineQ1 · MEDICINE

Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas

Q1 · MEDICINE

Article

Author: Kitamura, Yohei ; Wakimoto, Hiroaki ; van Schaik, Thijs A ; Shah, Khalid ; Chen, Kok-Siong ; Fisher, David ; Farzani, Touraj Aligholipour ; Franco, Arnaldo ; Borges, Paulo ; Jahan, Nusrat ; Kuroda, Shinji ; Kanaya, Nobuhiko ; Boland, Genevieve ; Ichinose, Toru ; Seddiq, Waleed ; Lopez Vazquez, Maria

Oncolytic virus therapy has shown activity against primary melanomas; however, its efficacy in brain metastases remains challenging, mainly because of the delivery and immunosuppressive nature of tumors in the brain. To address this challenge, we first established PTEN-deficient melanoma brain metastasis mouse models and characterized them to be more immunosuppressive compared with primary melanoma, mimicking the clinical settings. Next, we developed an allogeneic twin stem cell (TSC) system composed of two tumor-targeting stem cell (SC) populations. One SC was loaded with oncolytic herpes simplex virus (oHSV), and the other SC was CRISPR-Cas9 gene-edited to knock out nectin 1 (N1) receptor (N1 KO ) to acquire resistance to oHSV and release immunomodulators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Using mouse models of brain metastatic BRAF V600E /PTEN −/− and BRAF V600E/wt /PTEN −/− mutant melanomas, we show that locoregional delivery of TSCs releasing oHSV and GM-CSF (TSC-G) activated dendritic cell– and T cell–mediated immune responses. In addition, our strategy exhibited greater therapeutic efficacy when compared with the existing oncolytic viral therapeutic approaches. Moreover, the TSCs composed of SC-oHSV and SC N1KO –releasing GM-CSF and single-chain variable fragment anti–PD-1 (TSC-G/P) had therapeutic efficacy in both syngeneic and patient-derived humanized mouse models of leptomeningeal metastasis. Our findings provide a promising allogeneic SC-based immunotherapeutic strategy against melanomas in the CNS and a road map toward clinical translation.

25 May 2023·International journal of molecular sciences

Human Monocytes Are Suitable Carriers for the Delivery of Oncolytic Herpes Simplex Virus Type 1 In Vitro and in a Chicken Embryo Chorioallantoic Membrane Model of Cancer.

Article

Author: von Einem, Jens ; Palù, Giorgio ; Reale, Alberto ; Parolin, Cristina ; Kochanek, Stefan ; Krutzke, Lea ; Calistri, Arianna ; Cadamuro, Massimiliano ; Vitiello, Adriana

Oncolytic viruses (OVs) are promising therapeutics for tumors with a poor prognosis. An OV based on herpes simplex virus type 1 (oHSV-1), talimogene laherparepvec (T-VEC), has been recently approved by the Food and Drug Administration (FDA) and by the European Medicines Agency (EMA) for the treatment of unresectable melanoma. T-VEC, like most OVs, is administered via intratumoral injection, underlining the unresolved problem of the systemic delivery of the oncolytic agent for the treatment of metastases and deep-seated tumors. To address this drawback, cells with a tropism for tumors can be loaded ex vivo with OVs and used as carriers for systemic oncolytic virotherapy. Here, we evaluated human monocytes as carrier cells for a prototype oHSV-1 with a similar genetic backbone as T-VEC. Many tumors specifically recruit monocytes from the bloodstream, and autologous monocytes can be obtained from peripheral blood. We demonstrate here that oHSV-1-loaded primary human monocytes migrated in vitro towards epithelial cancer cells of different origin. Moreover, human monocytic leukemia cells selectively delivered oHSV-1 to human head-and-neck xenograft tumors grown on the chorioallantoic membrane (CAM) of fertilized chicken eggs after intravascular injection. Thus, our work shows that monocytes are promising carriers for the delivery of oHSV-1s in vivo, deserving further investigation in animal models.

News (Medical) associated with NV-1020

15 Mar 2024

·www.prnewswire.com

ImmVira's oncolytic product MVR-T3011 IT Intratumoral Injection Receives FDA Fast Track Designation for HNSCC Treatment

SHENZHEN, China, March 15, 2024 /PRNewswire/ -- ImmVira has recently announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for oncolytic virus product MVR-T3011 IT (intratumoral injection) for the treatment of recurrent or metastatic head and neck squamous cell cancer with disease progression after platinum-based chemotherapy and at least one prior line of anti-PD1/PDL1 therapy. Fast track designation is intended to facilitate the development and expedite the review of drugs targeting serious conditions with unmet medical needs. The Fast Track designation was sought based on the promising potential of MVR-T3011 IT to meet the unmet medical needs associated with HNSCC. Supporting evidence for this request was derived from Phase I/II trials conducted in both the United States and China, focusing on evaluating the efficacy, safety, and durability of response in patients with HNSCC. HNSCC has become a growing public health concern, with increases in incidence rates as of 2023 statistics. Approximately 32% of patients face recurrence after curative therapy, and 3-10% present with metastatic disease at the time of diagnosis, emphasizing the aggressive nature and severity of this cancer. While immune checkpoint inhibitors such as PD-1/PD-L1 blockers have transformed HNSCC treatment, their benefits are confined to a modest 15-20% of patients. This treatment gap underscores the critical need for innovative therapies. Clinical data indicates that MVR-T3011 IT demonstrated the potential to overcome immunosuppression, and delivered favorable outcomes in terms of tumor shrinkage and control in patients who failed ICI treatments. "Attaining Fast Track designation from the FDA marks a pivotal milestone and underscores MVR-T3011 IT's capacity to address the substantial unmet needs of HNSCC patients," said Grace Guoying Zhou, Chairwoman and CEO of ImmVira. "We are encouraged by the FDA's decision as it reflects the need for FDA approved and widely available treatments for these patients. This designation will allow us to work closely with the FDA to quickly advance MVR-T3011 IT, to make a meaningful difference for patients who require new treatment options." About MVR-T3011 MVR-T3011, ImmVira's proprietary 3-in-1 oHSV, is a novel genetic engineered oHSV which aims to achieve the most favorable profile of attenuated HSV-1 with replication potency in tumor cells and highly restricted replication in normal cells. Its incorporation of two latest and well-validated exogenous genes, PD-1 antibody and IL-12, further enhances immune responses in the tumor microenvironment. About ImmVira ImmVira is a biotechnology company focused on developing and synthesizing biological vector delivery platform. The company has constructed a fully integrated OVPENS (Open Vector+ Potent, Enabling, Novel & Safe) platform with solid science, technology and CMC know-how, and three derivative subplatforms including Oncolytic Virus, Cancer Vaccine and Biosynthetic Exosome, to support ongoing R&D, clinical studies and commercialization of best-in-class mono and combo therapies driven by clinical benefits in oncology and non-oncology fields. SOURCE ImmVira

Fast TrackImmunotherapyClinical Study

10 Nov 2023

·www.prnewswire.com

MVR-T3011 IV, Global First Intravenous Oncolytic Product, Successfully Concludes Phase I Clinical Study in the U.S. with Outstanding Safety Results

SHENZHEN, China, Nov. 9, 2023 /PRNewswire/ -- On November 9, 2023, ImmVira announced the successful completion of Phase I clinical study conducted on late-stage patients with various tumor types for our intravenous oncolytic product, MVR-T3011 IV, in the United States. This milestone was marked by the product's exceptional safety results and preliminary efficacy for certain indications. Concurrently, a series of comprehensive pharmacokinetics/pharmacodynamics (PK/PD) and immune responses research were also conducted, generating valuable firsthand data to guide the forthcoming Phase II clinical study. As of October 31, 2023, 17 patients (17/18, 94.4%) experienced Treatment-Emergent Adverse Events (TEAEs), with 16 patients (16/18, 88.89%) reporting drug-related Treatment-Related Adverse Events (TRAEs). Notably, all of these adverse events were of grade 1 or 2 severity, and no TRAEs of grade 3 or higher were observed. TEAEs with an incidence of over 20% included abdominal pain (4/18, 22.2%), urinary tract infection (5/18, 27.28%), nausea (6/18, 33.3%), hypokalaemia (4/18, 22.2%) and hypotension (6/18, 33.3%). 7 patients (7/18, 38.89%) experienced Serious Adverse Events (SAEs), none of which were drug-related. Overall, MVR-T3011 IV showed great safety profile at Phase I clinical study. Currently, there are 12 evaluable patients. According to RECIST 1.1, patients with endometrial, appendiceal, and gallbladder cancer demonstrated a significant reduction in tumor burden. The maximum reduction exceeded 15% compared to the baseline. Simultaneously, Company is conducting a series of clinical exploratory studies in China for multiple tumor types. By combining PK/PD data from Phase I clinical study in both the U.S. and China, our goal is to devise a development strategy for a registrational Phase II clinical study targeting real unmet clinical needs. Chairwoman and CEO Dr. Grace Guoying Zhou said that, "The development of intravenously administered oncolytic virus products has long been a challenging bottleneck. Oncolytic viruses must overcome numerous hurdles, such as neutralization by antibodies or the risk of cytokine storms, in order to effectively reach tumor sites with a sufficient number of viruses to achieve anti-tumor effects. With the successful Phase I clinical study results of MVR-T3011 IV, global first clinical-stage intravenous oHSV product, our company is now fully confident and committed to expediting clinical explorations in colorectal cancer, non-small cell lung cancer, and other indications, including combination treatments with immune checkpoint inhibitor or chemotherapy. Our goal is to bring the benefits of intravenous oncolytic virotherapy to cancer patients as swiftly as possible." About MVR-T3011 MVR-T3011, ImmVira's proprietary 3-in-1 oHSV, is a novel genetically engineered oHSV, which aims to achieve the most favorable profile of attenuated HSV-1 with replication potency in tumor cells and highly restricted replication in normal cells. Its incorporation of two latest and well-validated exogenous genes, PD-1 antibody and IL-12, further enhances immune responses in the tumor microenvironment. About ImmVira ImmVira is a biotechnology company focused on developing and synthesizing biological vector delivery platform. The company has constructed a fully integrated OVPENS (Open Vector+ Potent, Enabling, Novel & Safe) platform with solid science, technology and CMC know-how, and three derivative subplatforms including Oncolytic Virus, Cancer Vaccine and Biosynthetic Exosome, to support ongoing R&D, clinical studies and commercialization of best-in-class mono and combo therapies driven by clinical benefits in oncology and non-oncology fields. SOURCE ImmVira

Phase 1Clinical ResultImmunotherapyPhase 2

07 Jun 2023

·www.biospace.com

ImmVira presented latest encouraging clinical results of two proprietary products at ASCO 2023

SHENZHEN, China, June 6, 2023 /PRNewswire/ -- ImmVira submitted four abstracts covering latest results from Phase I/II clinical trials of MVR-T3011 IT (intratumoral injection) and MVR-T3011 IV (intravenous injection) in both U.S. and China with all selected to be published (1 chosen for poster discussion) at the 2023 American Society for Clinical Oncology Annual Meeting (ASCO 2023) taking place from June 2nd to 6th, 2023 in Chicago, IL. 1. Intratumoral product MVR-T3011 IT demonstrated clinical efficacy both as monotherapy and combination therapy 1） Phase I/IIa study of MVR-T3011 IT administered via intratumoral injection in China as monotherapy Being among the 22 China studies selected for Poster Discussions this year, MVR-T3011 IT clinical updates in China was also presented in a Poster discussion session on June 3rd (see below). As of January 18, 2023, among 90 patients who received MVR-T3011 IT monotherapy, the most frequent treatment-related adverse events ("TRAEs") were pyrexia and no dose-limiting toxicity ("DLT") events were reported. Recommended Phase II dose ("RP2D") was determined to be 1x108 PFU/ml. The confirmed objective response rate ("ORR") was 11% and disease control rate ("DCR") was 49% in 55 patients (with head and neck squamous cell carcinoma ("HNSCC"), sarcoma, melanoma, breast cancer, etc.) treated under RP2D evaluable for tumor response. 12 evaluable HNSCC patients who progressed after platinum-based chemotherapy and anti-PD-1/PD-L1 therapy achieved confirmed ORR of 25% and DCR of 50%, respectively. Meanwhile, 69.2% of patients were observed with increases in tumor-infiltrating CD8+ cell density in biopsy collected at 8 weeks after the first dose. In particular, 3 head and neck cancer patients with partial response ("PR") had notable increases in tumor-infiltrating CD8+ cell density in biopsy. Trial results showed that, MVR-T3011 IT had excellent safety pro clinical compliance. The drug didn't spread to blood, urine or saliva when injected intratumorally. Additionally, MVR-T3011 IT monotherapy demonstrated encouraging anti-tumor activity in advanced HNSCC patients, supporting further evaluation in Phase II studies. 2） Phase I/IIa study of MVR-T3011 IT administered via intratumoral injection in the U.S. as monotherapy and combination therapy combined with Pembrolizumab As of January 17, 2023, among 29 patients who received MVR-T3011 IT monotherapy or in combination with pembrolizumab, most frequent TRAEs were pyrexia, and no additional safety signals were observed in combination therapy. 12 advanced melanoma patients failing prior PD-1 or PD-1/CTLA-4 combination treatment received MVR-T3011 IT monotherapy. The confirmed ORR and DCR were 25.0% and 33.3%, respectively. 6 patients (including 5 with melanoma and 1 with mesothelioma) were re-challenged with MVR-T3011 IT combined with pembrolizumab after progression on monotherapy, among which 1 patient achieved PR after 4 months and ongoing PR had lasted for more than 8 months as of the data cutoff date. Meanwhile, remarkable increases in tumor-infiltrating CD8+ cell density in biopsy were observed in 66.7% of patients with PR or stable disease ("SD"). In particular, the increment of CD8+ cell density in 2 melanoma patients with PR was over 15 folds. Trial results showed that, MVR-T3011 IT monotherapy and combination therapy with pembrolizumab were safe and tolerable. MVR-T3011 may modify tumor microenvironment and overcome immune resistance. 2. MVR-T3011 IV, global first intravenous oHSV product, showed assuring safety pro > As of December 16, 2022, a total of 15 patients (including 12 patients who received single ascending dose and 3 patients who received multiple ascending dose) received MVR-T3011 IV monotherapy with different dosages (1x106 PFU~3x108 PFU), all of which were Stage IV patients with chemotherapy history, including 9 patients who had received third-line or above treatment. Among them, 11 patients achieved SD, and the DCR was 73.3%. Notably, one colorectal cancer patient who progressed after irinotecan-based chemotherapy, anti-VEGF, and radiation therapy had long-term disease control with SD for over 4 months. Among these patients, three had Grade 3 treatment emergent adverse events ("TEAE") in the Common Criteria for the Evaluation of Adverse Events ("CTCAE") (hypertriglyceridemia, dyspnea, lymphopenia), only one case of Grade 3 TRAE (lymphopenia) was reported, and no≥ Grade 4 adverse event ("AE") was reported. No drug-related Serious Adverse Event ("SAE") or DLT occurred; maximum tolerated dose ("MTD") was not reached. Trial results showed that, MVR-T3011 IV is safe, well-tolerated, and unlikely to spread to close contacts. Encouraging preliminary efficacy and MVR-T3011 viral DNA in blood in a dose-dependent manner with additive effects from repeated doses support continued recruitment of patients to higher dose cohorts. In the meantime, MVR-T3011 IV's U.S. Phase I clinical data was also selected to be published at ASCO this year. We are expecting to report more intravenous clinical results in both U.S. and China in the future. About MVR-T3011 IT and MVR-T3011 IV MVR-T3011 IT and MVR-T3011 IV are two separate products developed on the same basis of MVR-T3011. MVR-T3011 IT is designed for intratumoral injection of solid tumors while MVR-T3011 IV is designed for intravenous injection and is also global first systemic administered oHSV in clinical stage. MVR-T3011, ImmVira's proprietary 3-in-1 oHSV, is a novel genetic engineered oHSV which aims to achieve the most favorable pro attenuated HSV-1 with replication potency in tumor cells and highly restricted replication in normal cells. In addition, MVR-T3011 carries two latest and well-validated exogenous genes, PD-1 antibody and IL-12, to further enhance immune responses of tumor microenvironment. About ImmVira ImmVira is a biotechnology company focused on developing and synthesizing biological vector delivery platform. The company has constructed a fully integrated OVPENS (Open Vector+ Potent, Enabling, Novel & Safe) platform with solid science, technology and CMC know-how, and three derivative subplatforms including Oncolytic Virus, Cancer Vaccine and Biosynthetic Exosome, to support ongoing R&D, clinical studies and commercialization of best-in-class mono and combo therapies driven by clinical benefits in oncology and non-oncology fields. View original content to download multimedia: SOURCE ImmVira

Clinical ResultASCOPhase 1Phase 2

100 Deals associated with NV-1020

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB04969

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	Phase 2	US	MediGene AG	01 Jul 2004
Colorectal Liver Metastases	Phase 2	US	MediGene AG	01 Jul 2004
Liver metastases	Phase 2	US	MediGene AG	01 Jul 2004
Liver Cancer	Phase 2	US	MediGene AG	01 Jul 2004

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2009	Phase 2	Liver metastases	22	NV1020	nuqcfuhjsd(fnfbqgvzji) = lbqnoddtug auemcpdcph (thdqiffxot, 36–90) View more	-	20 May 2009
ASCO2008	Phase 2	Colorectal Liver Metastases	22	NV1020	tmvahddeas(izxwirfejx) = yyaizswafa vupehwwomr (vqabvfdgjt, [30,65]) View more	-	20 May 2008
ASGCT2002	Not Applicable	Pancreatic Cancer	-	NV1020	fhqizzonai(lilosirhyq) = wwghigykku qokaywjgin (zbvftvzfkh )	-	01 May 2002

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