12 november 2022: zie ook dit artikel: https://kanker-actueel.nl/oncolytische-virussen-geven-uitstekende-resultaten-in-aanpak-van-kanker-clemens-dirven-en-casper-van-eyck-vertellen-in-op1-over-hun-nieuwste-vinding-waarmee-patient-met-hersentumor-is-genezen.html

7 november 2022: Bron: Future oncology Published Online:14 Jun 2022

Uit de eerste resultaten van deze fase I studie blijkt de combinatie van immuuntherapie met ezabenlimab, een anti-PD medicijn met een gemoduleerd oncolytisch virus met de naam Vesiculair Stomatitis Virus (VSV-GP) (code: BI 1831169) voor hoopvolle resultaten te zorgen bij kankerpatiënten met vergevorderde uitgezaaide kanker met solide tumoren.

Dat schrijft Boehringer Ingelheim op een van hun websites, waar ik helaas geen toegang toe heb. Er worden nog geen resultaten in cijfers weergegeven omdat de studie nog loopt en ook in Europa kunnen patiënten nog worden aangemeld om mee te doen. Contact: Boehringer Ingelheim Tel: 1-800-243-0127 clintriage.rdg@boehringer-ingelheim.com

Hier het studieprotocol van deze eerste veiligheidsstudie: A Study to Test Different Doses of BI 1831169 Alone and in Combination With Ezabenlimab in People With Different Types of Advanced Cancer (Solid Tumors).




Figure 1. 1456.1 study design.

*Protocol amendment is planned following determination of the cRP2D to add expansion cohorts to part 2.

**For patients without document objective progression at EOT.

C: Cycle; cRP2D: Recommended combination therapy phase II dose; CT: Computed tomography; D: Day; EOT: End of treatment; exp: Expansion; FUP: Follow-up; FU-PD: Follow-up progressive disease; it.: Intratumoral; iv.: Intravenous; mRP2D: Recommended monotherapy phase II dose; PD: Progressive disease; pts: Patients.


Als u klikt op de titel van onderstaand abstract kunt u heel veel informatie over het Vesiculair Stomatitis Virus (VSV-GP) lezen.

Doel van deze veiligheidsstudie die is verdeeld in twee gedeeltes:

Er is behoefte aan nieuwe behandelingen voor mensen met kanker. Immuuntherapie is een soort geneesmiddel dat de natuurlijke afweer van het lichaam, het immuunsysteem, helpt om kankercellen te vernietigen. Er zijn verschillende soorten immuuntherapieën, zoals oncolytische virussen (OV's) en immuuncheckpointremmers (ICI's). Oncolytische virussen (OV's) zijn virussen die kunnen helpen kankercellen te vernietigen terwijl normale cellen ongedeerd blijven. Ze werken door te repliceren in kankercellen; dit zorgt ervoor dat de tumorcellen op een bepaald moment kapot barsten en meer van het virus vrijgeven, dat vervolgens nabijgelegen kankercellen infecteert en het immuunsysteem van het lichaam activeert.
Immuuncheckpointremmers (ICI's) (anti-PD medicijnen) kunnen mogelijk samenwerken met OV's om dit effect te versterken.
VSV-GP is een type OV waarvan is aangetoond dat het kankercellen effectief vernietigt in dierstudies. Deze first-in-human studie zal VSV-GP op zichzelf en in combinatie met een ICI genaamd ezabenlimab onderzoeken voor de behandeling van kanker in een laat stadium of kanker die zich heeft verspreid naar meerdere delen van het lichaam.

Hier beschrijven we de achtergrond en het ontwerp van dit lopende onderzoek dat tot doel heeft uit te vinden of VSV-GP alleen of in combinatie met ezabenlimab effectief is tegen kanker, de geschikte dosis en of er bijwerkingen optreden.

Published Online:https://doi.org/10.2217/fon-2022-0439

Abstract

Patients with advanced, recurrent or metastatic cancer have poor prognosis despite treatment advancements. Vesicular stomatitis virus (VSV)-glycoprotein (GP; BI 1831169) is a chimeric VSV with its neurotropic glycoprotein G replaced by the non-neurotropic GP of the lymphocytic choriomeningitis virus. This live, recombinant oncolytic virus has demonstrated preclinical efficacy as a viral-based immunotherapy due to its interferon-dependent tumor specificity, potent oncolysis and stimulation of antitumor immune activity. Co-administration of the immune checkpoint inhibitor, ezabenlimab (BI 754091), alongside VSV-GP may synergistically enhance antitumor immune activity. Here, we describe the rationale and design of the first-in-human, phase I, dose-escalation study of VSV-GP alone and in combination with the immune checkpoint inhibitor ezabenlimab in patients with advanced, metastatic or relapsed and refractory solid tumors (NCT05155332).

Plain language summary

There is a need to develop new treatments for people living with cancer. Immunotherapy is a type of medicine that works by helping the body’s natural defenses, known as the immune system, to destroy cancer cells. There are different types of immunotherapies such as oncolytic viruses (OVs) and immune checkpoint inhibitors (ICIs). OVs are viruses that may help destroy cancer cells while leaving normal cells unharmed. They work by replicating within cancer cells; this causes them to burst and release more of the virus which then infects nearby cancer cells and activates the body’s immune system. ICIs may be able to work together with OVs to amplify this effect. Vesicular stomatitis virus (VSV)-glycoprotein (GP) is a type of OV that has been shown to effectively destroy cancer cells in animal studies. This first-in-human study will investigate VSV-GP on its own and in combination with an ICI called ezabenlimab for the treatment of late-stage cancer or cancer that has spread to multiple parts of the body. Here, we describe the background and design of this study in progress which aims to find out if VSV-GP alone or in combination with ezabenlimab is effective against cancer, the suitable dose and if any side effects occur.

Trial Registration Number: NCT05155332 (ClinicalTrials.gov)

Tweetable abstract

Click to tweetThe 1456.1study (NCT05155332) is a first-in-human, phase I dose-escalation study investigating the oncolytic virus VSV-GP alone and in combination with the immune checkpoint inhibitor ezabenlimab in patients with solid tumors.

Rationale for VSV-GP combination therapy with ICIs

Although VSV-GP induces a substantial antitumor immune response, this may also be a limitation of its virotherapeutic potential. VSV-GP induces upregulation of PD-L1, which can protect tumor cells from an immune response by binding to its negative regulating receptor PD-1 on T cells [25,28]. However, administering an ICI such as the PD-1 inhibitor ezabenlimab (BI 754091) in combination with VSV-GP may counteract this tumor evasion effect by restoring T-cell activity and, in the context of viral oncolysis and exposure of activated T cells to tumor and viral antigens, may represent an opportunity to synergistically enhance the antitumor efficacy locally and systemically through a sustained antitumor T-cell effector function [28]. Although ezabenlimab may augment VSV-GP’s immune modulatory properties via blockade of the PD-1/PD-L1 signaling pathway, VSV-GP may also overcome known limitations associated with ICIs.

Treatment with ICIs such as anti-PD-1 or anti-PD-L1 antibodies has become a standard of care treatment for many advanced, recurrent or metastatic cancers, with extension of patient survival [29]. However, only a subset of patients respond to therapy, with the majority of patients exhibiting primary resistance to ICI blockade [30]. This was shown to be associated with a lack of infiltrating T cells, described as an immunologically ‘cold’ tumor environment [31].

Oncolytic virotherapy, by creating a highly inflamed TME with increased T cells and other immune cell infiltrates activated by viral and tumor antigens and pro-inflammatory cytokines, may convert a ‘cold’ tumor environment into an immunologically ‘hot’ environment, leading to a better response to PD-1 inhibitors [31]. A similar concept has been investigated with other OVs in combination with ICIs, confirming that OVs can change the antitumor immune cell makeup, making the tumor more susceptible to ICI therapy [30,32–35]. The potential synergistic effect of VSV-GP in combination with ezabenlimab on antitumor activity will be explored in this first-in-human clinical study.

Phase I study

Herein we report the design and methods for the phase I study of BI 1831169 (VSV-GP) as a monotherapy and in combination with ezabenlimab in patients with advanced or metastatic solid tumors (NCT05155332). The study will be conducted at sites in Europe and North America. Patients are currently being recruited and the study is estimated to complete in August 2025.


Supplementary data

An infographic accompanies this paper. To view or download this infographic in your browser please click here: https://www.futuremedicine.com/doi/suppl/10.2217/fon-2022-0439

Author contributions

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).

Acknowledgments

Boehringer Ingelheim International GmbH was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Financial & competing interests disclosure

The 1456.1 study was supported and funded by Boehringer Ingelheim International GmbH. The authors did not receive payment related to the development of the manuscript. M Porosnicu’s effort was partly supported by NIH/NCI U01 CA215848. M Porosnicu received clinical research support from Boehringer Ingelheim, AstraZeneca, Eli Lilly, Astellas and Sanofi-Aventis. M Porosnicu is a consultant for Boehringer Ingelheim.A-M Quinson is an employee of Boehringer Ingelheim. K Crossley is an employee of Boehringer Ingelheim. S Luecke is an employee of Boehringer Ingelheim. UM Lauer worked as a consultant for Boehringer Ingelheim, ViraTherapeutics and MSD/Themis Bioscience and as an advisor for Novartis, Amgen and Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

D Else of MediTech Media provided writing and editorial support which was contracted and funded by Boehringer Ingelheim International GmbH (BI).

Open access

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/





 

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