Cavatak (gebasaxturev) / Merck (MSD) - LARVOL DELTA

Neoadjuvant anti-PD-1 alone or in combination with anti-TIGIT or an oncolytic virus in resectable stage IIIB-D melanoma: a phase 1/2 trial. (PubMed, Nat Med) - P1/2 | "Here we report results from the first three arms: pembrolizumab plus vibostolimab (anti-TIGIT), pembrolizumab plus gebasaxturev (coxsackievirus A21) and pembrolizumab monotherapy. Longer follow-up will provide insight into the incremental benefit of combining neoadjuvant pembrolizumab with other therapies in stage IIIB-D melanoma. ClinicalTrials.gov registration: NCT04303169 ."

IO biomarker • Journal • P1/2 data • Tumor mutational burden • Melanoma • Oncology • Solid Tumor • TIGIT • TMB

Combination of oncolytic viruses, radiation therapy, and immune checkpoint inhibitor treatment in a breast cancer model (ESMO-IO 2024) - "We demonstrated that a combination of Echovirus 7, Enterovirus B75, Coxsackievirus A21, and Poliovirus Type 3 with radiation therapy and immune checkpoint inhibitors (ICIs) shows efficacy in in vivo breast cancer models.Methods Breast cancer cell line 4T1-PVR (expressing human poliovirus receptor PVR/CD155), were obtained through lentiviral transduction...Treatment with the PD-L1 inhibitor alone had no effect on tumor growth, indicating that the tumor was resistant to ICI. Therapeutic responses were associated with increased infiltration of CD45+ immune cells into the tumor, including an increase in CD8+ T cells and a decrease in regulatory T cells.Conclusions In a preclinical surrogate model, the triple combination of oncolytic viruses, radiation, and immune checkpoint inhibition resulted in increased tumor infiltration by CD8+ T cells, correlating with reduced tumor volumes and improved animal survival."

Checkpoint inhibition • Oncolytic virus • Preclinical • Breast Cancer • Oncology • Solid Tumor • CD8 • ITGAM • PTPRC • PVR

Oncolytic Coxsackievirus B3 Strain PD-H Is Effective Against a Broad Spectrum of Pancreatic Cancer Cell Lines and Induces a Growth Delay in Pancreatic KPC Cell Tumors In Vivo. (PubMed, Int J Mol Sci) - "In vitro, PD-H exhibited robust replication, as measured by plaque assays, and potent lytic activity, as assessed by XTT assays, in most pancreatic tumor cell lines, outperforming two other coxsackievirus strains tested, H3N-375/1TS and CVA21...Although pancreatic tumors respond to PD-H treatment, its therapeutic efficacy is limited. Combining PD-H with other treatments, such as those aiming at reducing the desmoplastic stroma which impedes viral infection and spread within the tumor, may enhance its efficacy."

IO biomarker • Journal • Oncolytic virus • Preclinical • Gastrointestinal Cancer • Hepatology • Infectious Disease • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CASP3 • CASP7

Clinical and Genomic Epidemiology of Coxsackievirus A21 and Enterovirus D68 in Homeless Shelters, King County, Washington, USA, 2019-2021. (PubMed, Emerg Infect Dis) - "Phylogenetically clustered CVA21 and EV-D68 cases occurred in some shelters. Some shelters also hosted multiple CVA21 lineages."

Journal • Review • Infectious Disease • Respiratory Diseases

KEYMAKER-U02 substudy 02C: Neoadjuvant pembrolizumab (pembro) and investigational agents followed by adjuvant pembro for stage IIIB-D melanoma (ESMO 2024) - P1/2 | "We present initial results from arm 4 (pembro + MK-4830 [anti-ILT4]) and arm 5 (favezelimab [anti-LAG-3] coformulated with pembro [fave/pembro]) and updated results from arm 1 (pembro + vibostolimab [vibo; anti-TIGIT]), arm 2 (pembro + gebasaxturev [geba; coxsackievirus A21]), and arm 3 (pembro alone). Adults with resectable stage IIIB-D melanoma were randomly assigned to open arms. All arms had manageable safety in stage IIIB-D melanoma. With the promising antitumor activity observed in this study, further investigation of pembro + vibo and fave/pembro in this setting is warranted. RFS by major pathologic response will be presented."

Clinical • Melanoma • Oncology • Solid Tumor • TIGIT

Treatment of malignant melanoma with coxsackievirus A21 (V937): An emerging oncolytic virotherapy. (PubMed, Exp Dermatol) - "In addition to reporting manageable safety profiles, clinical trial data examining intratumoral V937 combination therapy with pembrolizumab and ipilimumab also endorsed favourable objective response rates compared to immune checkpoint inhibitor monotherapy (47% vs. 38% and 21% vs. 10%, respectively). Although small subsets of patients experienced severe adverse effects and study design limitations imposed constraints on collected data, evidence for the efficacy of V937 remains encouraging. With few clinical trials evaluating V937 in melanoma, additional data is required before routine usage in standard treatment for metastatic lesions."

Journal • Oncolytic virus • Review • Melanoma • Oncology • Solid Tumor

Disentangling Anti-Tumor Response of Immunotherapy Combinations: A Physiologically Based Framework for V937 Oncolytic Virus and Pembrolizumab. (PubMed, Clin Pharmacol Ther) - "Additionally, this platform allows us to investigate not only the contribution of processes related to the viral kinetics and dynamics on tumor response, but also the influence of its interaction with an ICI. Additionally, the model can be used to explore different scenarios aiming to optimize treatment combinations and support clinical development."

Journal • Oncolytic virus • Oncology • CD8 • PD-1 • PD-L1

Oncolytic virus V937 in combination with PD-1 blockade therapy to target immunologically quiescent liver and colorectal cancer. (PubMed, Mol Ther Oncol) - "In addition, both recombinant interferon-gamma and pembrolizumab increased ICAM-1 on tumor cell lines or organoids and, in turn, amplified V937-mediated oncolysis and immunogenicity. These findings provide critical mechanistic insights on the cross-talk between V937-mediated oncolysis and immune responses, demonstrating the therapeutic potential of V937 in combination with PD-1 blockade to treat immunologically quiescent cancers."

Combination therapy • Journal • Oncolytic virus • Colorectal Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • Melanoma • Oncology • Solid Tumor • ICAM1 • IFNG • TERC

Development of a robust cell-based potency assay for a coxsackievirus A21 oncolytic virotherapy. (PubMed, Heliyon) - "Furthermore, the plaque assay quantifies OV infectivity with better precision (32% vs 58%), with higher sample throughput (22 samples/week vs 3 samples/week) and shorter assay turnaround time (4 days vs 7 days) than the TCID50 method. This assay development strategy can provide guidance for the development of robust cell-based potency methods for OVs and other infectious viral products."

Journal • Oncolytic virus • Infectious Disease • Oncology

A Study of Gebasaxturev (V937) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors (V937-013) (clinicaltrials.gov) - P1/2 | N=75 | Terminated | Sponsor: Merck Sharp & Dohme LLC | Phase classification: P1b/2 ➔ P1/2 | Completed ➔ Terminated; Business Reasons

Combination therapy • Metastases • Phase classification • Trial termination • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Squamous Cell Skin Cancer • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

The Preclinical Profile of Maturation Inhibitor VH3739937 (CROI 2024) - "Background: VH3739937 (VH937) is a next generation maturation inhibitor (MI) currently in clinical trials. The pre-clinical virology profile of VH937 supported the progression of this MI into clinical development."

Preclinical • Human Immunodeficiency Virus • Infectious Disease

Efficacy, Safety, and Tolerability of Gebasaxturev (V937) Administered Intravenously or Intratumorally With Pembrolizumab (MK-3475) Versus Pembrolizumab Alone in Participants With Advanced/Metastatic Melanoma (V937-011) (clinicaltrials.gov) - P2 | N=85 | Terminated | Sponsor: Merck Sharp & Dohme LLC | Completed ➔ Terminated; Business Reasons

Combination therapy • Metastases • Trial termination • Melanoma • Oncology • Solid Tumor • CD4

The Effects of Mesenchymal Stem Cells Loaded with Oncolytic Coxsackievirus A21 on Mouse Models of Colorectal Cancer. (PubMed, Curr Cancer Drug Targets) - "The results of the current study suggest that MSCs loaded with oncolytic CVA21 therapy for the CRC mouse model may have some potential advantages. On the other hand, the results of the study showed that, in addition to activating the acquired immune system, the use of MSCs loaded with oncolytic CVA21 also stimulates the innate immune system by increasing levels of nitric oxide."

Journal • Oncolytic virus • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • IFNG • IL10 • IL4 • TGFB1

KEYMAKER-U02 Substudy 02C: Substudy 02C: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With Stage III Melanoma Who Are Candidates for Neoadjuvant Therapy (MK-3475-02C/KEYMAKER-U02) (clinicaltrials.gov) - P1/2 | N=90 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Melanoma • Oncology • Solid Tumor

The efficacy and safety assessment of oncolytic virotherapies in the treatment of advanced melanoma: a systematic review and meta-analysis. (PubMed, Virol J) - "Given the relative safety and tolerability of oncolytic viruses, and the lack of reports of dose-limiting-dependent toxicities, more patients treated with T-VEC with or without ICIs should be added to future assessment analyses. There is still a long way to go before it can be used as a first-line therapy for patients with advanced or unresectable melanoma."

Journal • Metastases • Oncolytic virus • Retrospective data • Review • Dermatology • Herpes Simplex • Melanoma • Oncology • Pain • Pruritus • Solid Tumor • CSF2

A physiologically based pharmacokinetic model for V937 oncolytic virus in mice. (PubMed, Front Pharmacol) - " To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the in vivo behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate."

Journal • Oncolytic virus • PK/PD data • Preclinical • Oncology

KEYMAKER-U02 substudy 02C: Neoadjuvant pembrolizumab (pembro) + vibostolimab (vibo) or gebasaxturev (geba) or pembro alone followed by adjuvant pembro for stage IIIB-D melanoma (AACR 2023) - P1/2 | "Neoadjuvant pembro + vibo, pembro + geba, and pembro alone followed by adjuvant pembro had manageable safety and promising antitumor activity in patients with stage IIIB-D melanoma. Of the combination treatments, pembro + vibo showed the most promise."

Clinical • Melanoma • Oncology • Solid Tumor • TIGIT

A Study of Gebasaxturev (V937) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors (V937-013) (clinicaltrials.gov) - P1b/2 | N=75 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed | N=185 ➔ 75

Combination therapy • Enrollment change • Metastases • Trial completion • Breast Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Head and Neck Cancer • Hepatocellular Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Squamous Cell Skin Cancer • Triple Negative Breast Cancer • ER • HER-2 • PD-L1 • PGR

Efficacy, Safety, and Tolerability of Gebasaxturev (V937) Administered Intravenously or Intratumorally With Pembrolizumab (MK-3475) Versus Pembrolizumab Alone in Participants With Advanced/Metastatic Melanoma (V937-011) (clinicaltrials.gov) - P2 | N=85 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed | N=135 ➔ 85

Combination therapy • Enrollment change • Metastases • Trial completion • Melanoma • Oncology • Solid Tumor • CD4

Analysis of ICAM-1 Expression on Bladder Carcinoma Cell Lines and Infectivity and Oncolysis by Coxsackie Virus A21. (PubMed, Methods Mol Biol) - "To date, a number of viruses have been delivered intravesically in patients and in murine models with bladder cancer and antitumour effects demonstrated. Here, we describe in vitro methods to evaluate Coxsackie virus, CVA21, as an oncolytic virus for the treatment of human bladder cancer by determining the susceptibility of bladder cancer cell lines expressing differing levels of ICAM-1 surface receptor to CVA21."

IO biomarker • Journal • Preclinical • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • ICAM1

Glutathione affinity chromatography for the scalable purification of an oncolytic virus immunotherapy from microcarrier cell culture. (PubMed, Front Bioeng Biotechnol) - "In this work, scalable methods were investigated for the manufacture of an oncolytic virus immunotherapy application consisting of a prototype strain of coxsackievirus A21 (CVA21) produced in adherent MRC-5 cells...The large-scale bioreactors controlled at 34°C during infection maintained a three-fold increase in productivity in the GSH elution, and excellent clearance of host cell and media impurities was observed across all batches. This study presents a robust method for the manufacture of an oncolytic virus immunotherapy application that may be implemented for the scalable production of other viruses and viral vectors which interact with glutathione."

Journal • Oncolytic virus • Preclinical • Gene Therapies • Infectious Disease

Continuous in-line diafiltration using a novel multi-channel prototype cassette for viral vector buffer exchange (ACS-Fall 2023) - "This work details the evaluation of single-stage 30 kDa and 300 kDa PES membrane cassette prototypes using an oncolytic strain of Coxsackievirus A21 (CVA21), a non-enveloped, 30 nm picornavirus...Scanning electron microscopy analysis of the retentate film layer indicated increased surface roughness of the 300 kDa PES filter that may trap large virus particles with the low crossflow of SP-TFF. These results demonstrated a high-yield BX of a viral vector with the 30 kDa IL-DF prototype, but further development with larger MWCO cassettes is necessary to minimize potential losses to the membrane surface."

Viral vector

COVID-19 induced remission of biliary and renal cell carcinomas. (ASCO 2023) - "After 5 years he progressed on Sunitinib and began Nivolumab...Case 3: 75 year old male with unresectable cholangiocarcinoma on second line Atezolizumab... Effects of SARS-CoV-2 (COVID-19) on cancers remain unknown. Few case reports of cancer remissions after infections are emerging. These are two cases of renal cell cancers in complete remission after COVID-19 vaccination while on immunotherapy."

Clinical • Biliary Cancer • Cholangiocarcinoma • Fatigue • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Multiple Myeloma • Musculoskeletal Pain • Novel Coronavirus Disease • Oncology • Pain • Renal Cell Carcinoma • Respiratory Diseases • Solid Tumor • SDC1

Assessment of clinical response to V937 oncolytic virus after intravenous or intratumoral administration using physiologically-based modelling. (PubMed, Clin Pharmacol Ther) - "Unfortunately, the latter process could not be identified at the current clinical setting. This work provides insights on selecting optimal OV considering replication rate and infectivity."

Journal • Oncolytic virus • Oncology

Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study. (PubMed, J Immunother Cancer) - P1b | "Responses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies."

Journal • Metastases • Oncolytic virus • P1 data • Dermatology • Fatigue • Hepatology • Melanoma • Oncology • Pruritus • Solid Tumor