BI 1831169 / Boehringer Ingelheim - LARVOL DELTA

Newly identified oncolytic VSV-GP-specific CD8+ T cell epitopes for monitoring of anti-viral immune responses in the BALB/c mouse model. (PubMed, Mol Ther Oncol) - "Taken together, the 11 newly identified epitopes facilitate the monitoring of anti-viral CD8+ T cells, which will aid the preclinical development of novel VSV-GP variants. This epitope-specific monitoring also serves as proof of concept for the potential future application of anti-viral immunomonitoring in clinical trial settings."

Journal • Preclinical • Oncology • CD8

The Emerging Role of Oncolytic Virotherapy in Glioblastoma Management. (PubMed, Cancers (Basel)) - "Despite maximal resection, radiotherapy, and temozolomide, median survival is still 12-15 months because of tumor heterogeneity, diffuse infiltration, and therapeutic resistance...Several viral backbones have advanced to clinical testing, including adenovirus (DNX-2401), herpes simplex virus (G47Δ, G207), poliovirus (PVS-RIPO), measles virus (MV-CEA), reovirus (pelareorep), vaccinia virus (Pexa-Vec), and vesicular stomatitis virus (VSV-GP)...Advances in delivery, such as convection-enhanced infusion and blood-brain barrier modulation, are also under investigation. Despite obstacles, oncolytic virotherapy holds significant potential within multimodal GBM strategies."

Journal • Review • Brain Cancer • Glioblastoma • Glioma • Herpes Simplex • High Grade Glioma • Infectious Disease • Measles • Oncology • Solid Tumor

Latest insights into oncolytic viro-immunotherapy with vesicular stomatitis virus. (PubMed, Semin Immunol) - "To mitigate neurotoxicity and improve therapeutic efficacy, genetically-engineered strains, such as VSV-∆M51, VSV-mIFNβ, and VSV-GP, have been developed...Ongoing research continues to explore strategies for improving systemic delivery, minimizing off-target effects, and enhancing viral persistence within the tumor bed. Further investigation and clinical translation will determine the full potential of VSV-based viroimmunotherapy in cancer treatment."

Journal • Review • Oncology • IFNB1

A Study to Test How Well Different Doses of BI 1831169 in Combination With an Anti-PD1 Antibody Are Tolerated in Japanese People With Different Advanced Cancers (clinicaltrials.gov) - P1 | N=46 | Not yet recruiting | Sponsor: Boehringer Ingelheim

New P1 trial • Oncology • Solid Tumor

Interleukin-12 encoded by the oncolytic virus VSV-GP enhances therapeutic antitumor efficacy by inducing CD8+ T-cell responses with a long-lived effector cell phenotype. (PubMed, J Immunother Cancer) - "Taken together, we have demonstrated that oncolytic virotherapy using VSV-GP encoding IL-12 induces CD8+ T cell responses characterized by an LLEC phenotype, a cell population that is likely a crucial component of antitumor immunity."

Journal • CNS Disorders • Infectious Disease • Oncology • CD8 • IFNA1 • IL12A

Tailoring the Methods of Conjugation and Characterization for a Replication-Competent, Live, Viral Vector. (PubMed, Bioconjug Chem) - "Herein, we present a comprehensive series of steps for conjugation, purification, and characterization that are adapted from traditional biologics (e.g., monoclonal antibodies) and apply them to the replication-competent rhabdovirus VSV-GP-GFP. By confirming purity and quantifying the average degree of labeling (DoL), we tailored the label/particle ratio to generate tool viruses suitable for downstream applications in nonclinical and clinical development. These methods will enhance the development of viral vector therapies and hasten their delivery to patients in need."

Journal

Perfusion process with tangential flow filtration for oncolytic VSV-GP production. (PubMed, Front Bioeng Biotechnol) - "By optimizing the perfusion process, the titer reached up to 5.1 × 1010 TCID50 mL-1, which is 17-fold higher than in batch cultivation. Overall, this work presents perfusion cultivation as an efficient technology to improve the VSV-GP titer with virus retention."

Journal • Dental Disorders • Infectious Disease • Oncology • Stomatitis

1456-0001 study: A Study to Test Different Doses of BI 1831169 Alone and in Combination With an Anti-PD-1 Antibody in People With Different Types of Advanced Cancer (Solid Tumors) (clinicaltrials.gov) - P1 | N=190 | Recruiting | Sponsor: Boehringer Ingelheim | Trial primary completion date: May 2027 ➔ Dec 2027

Monotherapy • Trial primary completion date • Oncology • Solid Tumor

1456-0001 study: A Study to Test Different Doses of BI 1831169 Alone and in Combination With an Anti-PD-1 Antibody in People With Different Types of Advanced Cancer (Solid Tumors) (clinicaltrials.gov) - P1 | N=190 | Recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: May 2028 ➔ Oct 2028

Trial completion date • Oncology • Solid Tumor

Characterization of VSV-GP morphology by cryo-EM imaging and SEC-MALS. (PubMed, Mol Ther Methods Clin Dev) - "In developing an orthogonal method with higher throughput, we showed that the morphological profile of the VSV-GP particles can be characterized by size exclusion chromatography coupled with a multi-angle light scattering detector (SEC-MALS) based on a novel shape-based separation mechanism. Together, the two complementary techniques enable the analysis of morphological profile for VSV-GP and potentially other non-spherical viruses or nanoparticles."

Journal • CNS Disorders • Infectious Disease • Oncology

Molecular Pathology Methods to Characterize Biodistribution and Pharmacodynamics of the Oncolytic Virus VSV-GP in a Nonclinical Tumor Model. (PubMed, Toxicol Pathol) - "We identified distinct patterns of viral biodistribution and replication across tumor and nontumor sites but no major differences in biodistribution, off-tumor cell tropism, or immune cell responses between tumor-free and tumor-bearing mouse models. Our findings characterize key cellular changes following systemic exposure to VSV-GP, provide a better understanding of a nonclinical permissive tumor model for OV assessment, and demonstrate how current molecular pathology methods can provide a bridge between traditional biodistribution and pathology readouts."

Journal • PK/PD data • Preclinical • CNS Disorders • Infectious Disease • Oncology • IFNAR1

Repeated harvest enables efficient production of VSV-GP. (PubMed, Front Bioeng Biotechnol) - "While no effect on cell density was observed, the cumulated infectious titer following repeated harvest was over 400 times higher than the evaluated batch process yield. This shows that repeated harvests or perfusion have the potential to boost viral yields and should be considered when deciding on a process format for production."

Journal

DEVELOPMENT OF A THERAPEUTIC HPV16 VACCINE BASED ON THE VIRAL VECTOR VSV-GP (IPVC 2024) - "Our results show that at least one local application seemed to be beneficial for induction of HPV-specific TRMS in the genital tract, which are associated with the efficacy of therapeutic HPV vaccines. To overcome the vector immunity we will further analyze heterologous prime/boost vaccination regimens. For now, taken together, VSV-GP is a promising candidate as therapeutic HPV vaccine as the vector combines a favorable safety profile with a robust induction of HPV-specific T cell responses at an entry side of HPV."

Viral vector • Human Papillomavirus Infection • Infectious Disease • Oncology

First results for intravenous (IV) VSV-GP (BI 1831169) in patients (pts) with advanced solid tumors from the 1456-0001 study (ESMO 2024) - P1 | "Here we present the first results for the IV administration of the VSV-GP in pts with advanced solid tumors. The 1456-0001 study (NCT05155332) is a Phase I, open-label, dose-escalation study evaluating intratumoral (IT), IV, or IT+IV VSV-GP as monotherapy (Part 1) or in combination with the anti-PD-1 antibody ezabenlimab (Part 2). The study is ongoing to determine the MTD of IV VSV-GP monotherapy."

Clinical • Metastases • Oncology • Solid Tumor

Updated results from the phase I 1456-0001 study for intratumoral (IT) VSV-GP (BI 1831169) in patients with advanced solid tumors (ESMO 2024) - P1 | "Here we report updated results for IT VSV-GP monotherapy. In this Phase I, open-label, dose-escalation study, VSV-GP is administered IT, intravenously (IV), or IT+IV as monotherapy (Part 1) or with the anti-PD-1 antibody ezabenlimab (Part 2). The study is ongoing to evaluate safety and determine the MTD of IT VSV-GP monotherapy."

Clinical • Metastases • P1 data • Oncology • Solid Tumor

Characterization of the Anti-Viral and Vaccine-Specific CD8+ T Cell Composition upon Treatment with the Cancer Vaccine VSV-GP. (PubMed, Vaccines (Basel)) - "Finally, the heterologous combination of peptide and viral vaccine elicits the highest proportion of antigen-specific CD8+ T cells in the tumor and tumor-draining lymph nodes. In summary, we provide a basic immune characterization of various factors that affect anti-viral and vaccine target-specific CD8+ T cell proportions and phenotypes, thereby enhancing our vaccinology knowledge for future vaccine regimen designs."

Journal • Oncology • CD8

High-Throughput Determination of Infectious Virus Titers by Kinetic Measurement of Infection-Induced Changes in Cell Morphology. (PubMed, Int J Mol Sci) - "We demonstrate the applicability of the KIT assay for the genetically engineered oncolytic VSV-GP, Newcastle disease virus (NDV), and parapoxvirus ovis (ORFV), but it can potentially be extended to a wide range of viruses that induce morphological changes upon infection. The versatility of this assay, combined with its independence from specific instruments or software, makes it a promising solution to overcome the analytical bottleneck in infectivity assays within the pharmaceutical industry and as a routine method in academic research."

Journal • Infectious Disease

Induction of Autologous Tier 2 HIV-neutralizing Antibodies in Rabbits by Heterologous Combinations of the Viral Vector VSV-GP and Next-generation Native-like Trimers (AIDS 2024) - "In conclusion, VSV-GP is well suited to display native-like Env trimers on virus and cell membranes. Thus, recombinant VSV-GP-Env vectors qualify as promising vaccine candidates in prime-boost vaccination schedules against HIV."

Preclinical • Viral vector • Human Immunodeficiency Virus • Infectious Disease

Boosting of VSV-vector-induced HIV Env responses by delivery of recombinant Env protein via an Osmotic Pump elicits immune responses superior to conventional intramuscular protein administration in non-human primates (AIDS 2024) - "BACKGROUND: Vector-mediated antigen delivery and/or the modality of protein delivery is believed to impact follicular helper T cell (Tfh) recruitment to draining lymph nodes, germinal center formation and eventually the quality and sustainability of binding and neutralizing antibody responses. Four groups of 10 cynomolgus monkeys were primed (W0, W4) with a VSV-GP vector (i.m.) expressing a first generation membrane-tethered clade C 96ZM651 gp140 (VSV-gp140) and boosted at W12 and W24 with a state-of-the-art prefusion stabilized ConC Env trimer (ConCv5KIKO) either via the i.m. route (group 1, G1) or via an osmotic pump (OP) that was transplanted into the deltoid to release the ConCv5KIKO trimer protein subcutaneously over a period of 2 weeks (G2)... Co-administration of VSV-gp140 as part of the booster immunizations had no impact on the immunological outcome. ConCv5-KIKO Env trimer booster immunizations via the osmotic pump were clearly superior to i.m. protein delivery..."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CXCR5 • PD-1

A membrane-anchored consensus-C-Env-protein delivered via combinations of a DNA vaccine with viral vectors elicits potent and long-lasting adaptive immune responses (AIDS 2024) - "Here, we aimed to modify next-generation soluble, prefusion-stabilized, close-to-native, glycan-engineered clade C gp140 envelope (Env) trimers (sC23v4 KIKO and ConCv5 KIKO) for optimal display on the cell surface following homologous or heterologous vector delivery. A combination of the following modifications scored best regarding the preservation of closed, native-like Env trimer conformation and antigenicity when using a panel of selected broadly neutralizing (bnAb) and non-neutralizing (nnAb) monoclonal antibodies for flow cytometry: i) replacing the natural cleavage site with a native flexible linker and introducing a single amino acid substitution to prevent CD4 binding (*), ii) fusing a heterologous VSV-G-derived transmembrane moiety to the gp140 C-terminus, and iii) deleting six residues proximal to the membrane. When delivering membrane-tethered sC23v4 KIKO* and ConCv5 KIKO* via DNA, VSV-GP, and NYVAC vectors, the two native-like Env trimers provide..."

Viral vector • Human Immunodeficiency Virus • Infectious Disease • CD4

Absolute quantification of viral proteins from pseudotyped VSV-GP using UPLC-MRM. (PubMed, Microbiol Spectr) - "The assay extends the potential for quantifying full-length GPC, which provides an understanding of the processing of GPC (along with the quantification of GP1 and GP2 separately). We used this assay in tracking GPC processing in HEK-293-F production cell lines infected with VSV-GP."

Journal • Infectious Disease

Bimodal Effect of NKG2A Blockade on Intratumoral and Systemic CD8 T Cell Response Induced by Cancer Vaccine. (PubMed, Cancers (Basel)) - "Here, we report the impact of NKG2A blockade on antitumoral CD8 T cell immune response elicited by KISIMA-VSV-GP-TAg vaccination in tumor mouse models. Combination therapy significantly reduced the amount of vaccine-induced exhausted CD8 T cells infiltrating the tumor, resulting in short-term improved tumor growth control and prolonged mouse survival, while it also influenced the establishment of systemic effector memory CD8 T cell response. Taken together, these data show a compartment-dependent effect of NKG2A blockade on cancer vaccine-induced T cell immunity, increasing intratumoral T cell efficacy and attenuating the development of peripheral effector memory CD8 T cell response."

Journal • Oncology • CD8 • KLRC1

Phase I, open-label, dose-escalation trial investigating the safety and efficacy of oncolytic virus BI 1821736 in patients with advanced solid tumors. (ASCO 2024) - P1 | "BI 1821736 is a genetically engineered pseudotype variant of VSV-GP encoding an immune-stimulatory cargo. A total of six patients have received BI 1821736 as of January 29, 2024. Patients are currently being enrolled to dose level 2."

Clinical • IO biomarker • Metastases • Oncolytic virus • CNS Disorders • Infectious Disease • Oncology • Solid Tumor

Development of a replication-competent Vesicular Stomatitis Virus (VSV) vector for therapeutic hepatitis B vaccination (EASL-ILC 2024) - "Background and Aims: Eliciting robust immune responses against hepatitis B virus (HBV) through therapeutic vaccination holds significant promise to cure chronic hepatitis B. We have developed a heterologous prime-boost clinical vaccine candidate, TherVacB, employing a protein-prime with recombinant HBV surface and core antigens (HBsAg, HBcAg), and a vector-boost with recombinant Modified Vaccinia virus Ankara vector (MVA) expressing HBV antigens. The protein-prime/vector-boost strategy stands as a promising and optimal therapeutic vaccine approach to cure chronic hepatitis B, in which VSV-GP-HBs/c could efficiently serve as a boost viral vector."

Hepatitis B • Hepatology • Infectious Disease • Inflammation

Development of a replication-competent Vesicular Stomatitis Virus (VSV) vector for therapeutic hepatitis B vaccination (EASL-ILC 2024) - "Background and Aims: Eliciting robust immune responses against hepatitis B virus (HBV) through therapeutic vaccination holds significant promise to cure chronic hepatitis B. We have developed a heterologous prime-boost clinical vaccine candidate, TherVacB, employing a protein-prime with recombinant HBV surface and core antigens (HBsAg, HBcAg), and a vector-boost with recombinant Modified Vaccinia virus Ankara vector (MVA) expressing HBV antigens. The protein-prime/vector-boost strategy stands as a promising and optimal therapeutic vaccine approach to cure chronic hepatitis B, in which VSV-GP-HBs/c could efficiently serve as a boost viral vector."

Hepatitis B • Hepatology • Infectious Disease • Inflammation