Cavatak (gebasaxturev)

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.

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.

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.

P1/2, N=75, Terminated, Merck Sharp & Dohme LLC | Phase classification: P1b/2 --> P1/2 | Completed --> Terminated; Business Reasons

P2, N=85, Terminated, Merck Sharp & Dohme LLC | Completed --> Terminated; Business Reasons

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.

P1/2, N=90, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

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.

P1b/2, N=75, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed | N=185 --> 75

P2, N=85, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed | N=135 --> 85

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.

P1b/2, N=185, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jun 2024 --> Jul 2023 | Trial primary completion date: Jun 2024 --> Jul 2023

P2, N=135, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: May 2024 --> Jun 2023 | Trial primary completion date: May 2024 --> Jun 2023

These findings suggest responses to this combination may be seen even in patients without a typical "immune-active" microenvironment.

P1b/2, N=185, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Jun 2024 | Trial primary completion date: Jun 2025 --> Jun 2024

P2, N=135, Active, not recruiting, Merck Sharp & Dohme LLC | Recruiting --> Active, not recruiting

Interestingly, the in vivo efficacy of ONCR-021 and ONCR-788 is maintained even in the presence of neutralizing antibodies against CVA21 and SVV, suggesting that administration of LNP-formulated RNA immunotherapy enables the repeated and systemic exposure of disseminated tumors to potently oncolytic viruses. These data highlight an innovative RNA therapeutic modality for the IV treatment of tumors which overcomes the limitations of other RNA-based therapeutics and supports ONCR-021 and ONCR-788 into IND-enabling studies.

P1b/2, N=185, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Sep 2026 --> Jun 2025 | Trial primary completion date: Sep 2026 --> Jun 2025

P1b/2, N=185, Recruiting, Merck Sharp & Dohme Corp. | Trial completion date: Oct 2025 --> Sep 2026 | Trial primary completion date: Oct 2025 --> Sep 2026

This review focuses on the current status of IT agents currently under clinical trials in melanoma. Reviewed therapies include T-VEC, T-VEC with immune checkpoint inhibitors including ipilimumab and pembrolizumab or other agents, RP1, OrienX010, Canerpaturev (C-REV, HF10), CAVATAK (coxsackievirus A21, CVA21) alone or in combination with checkpoint inhibitors, oncolytic polio/rhinovirus recombinant (PVSRIPO), MAGE-A3-expressing MG1 Maraba virus, VSV-IFNbetaTYRP1, suicide gene therapy, ONCOS-102, OBP-301 (Telomelysin), Stimulation of Interferon Genes Pathway (STING agonists) including DMXAA, MIW815 (ADU-S100) and MK-1454, PV-10, toll-like receptors (TLRs) agonists including TLR-9 agonists (SD-101, CMP-001, IMO-2125 or tilsotolimod, AST-008 or cavrotolimod, MGN1703 or lefitolimod), CV8102, NKTR-262 plus NKTR-214, LHC165, G100, intralesional interleukin-2, Daromun (L19IL2 plus L19TNF), Hiltonol (poly-ICLC), electroporation including calcium electroporation and plasmid interleukin-12 electroporation (pIL-12 EP), IT ipilimumab, INT230-6 (cisplatin and vinblastine with an amphiphilic penetration enhancer), TTI-621 (SIRPαFc), CD-40 agonistic antibodies (ABBV-927 and APX005M), antimicrobial peptide LL37 and other miscellaneous agents.

P1/2, N=11, Active, not recruiting, Olivia Newton-John Cancer Research Institute | Trial completion date: Jun 2021 --> Oct 2021

P2, N=135, Recruiting, Merck Sharp & Dohme Corp. | Trial completion date: Feb 2024 --> Jul 2024 | Trial primary completion date: Feb 2024 --> Jul 2024

P1/2, N=11, Active, not recruiting, Olivia Newton-John Cancer Research Institute | Trial completion date: Dec 2020 --> Jun 2021 | Trial primary completion date: Dec 2020 --> Jun 2021

P1b/2, N=185, Recruiting, Merck Sharp & Dohme Corp. | Not yet recruiting --> Recruiting

This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.

In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types...This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.

P1/2, N=11, Active, not recruiting, Olivia Newton-John Cancer Research Institute | Trial primary completion date: Dec 2019 --> Dec 2020

In 2019, a multitude of intratumoral immunotherapies with varied mechanisms of action, including nononcolytic viral therapies such as PV-10 and toll-like receptor 9 agonists and oncolytic viral therapies such as CAVATAK, Pexa-Vec, and HF10, have been extensively evaluated in clinical trials and demonstrated promising antitumor activity with tolerable toxicities in melanoma and other solid tumor types...This review summarizes current knowledge on intratumoral therapies, a novel modality with increased utility in cancer treatment, and T-VEC, the only U.S. FDA-approved oncolytic viral therapy, for medical oncologists. This review evaluates approaches to incorporate T-VEC into daily practice to offer the possibility of response in selected melanoma patients with manageable adverse events as compared with other available immunotherapies.