VIO-01 for Recurrent Cancer
Recruiting in Palo Alto (17 mi)
+2 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Waitlist Available
Sponsor: Valerio Therapeutics
Disqualifiers: Neurologic disorders, HER2 positive, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called VIO-01 to see if it can help treat certain types of advanced cancers with specific genetic mutations. The study will check how safe the drug is, how well the body absorbs it, and its effects on the tumors.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on endocrine therapy for hormone receptor-positive breast cancer, it must be completed at least 7 days before starting the trial treatment.
What data supports the effectiveness of the treatment VIO-01, OX425 for recurrent cancer?
Oncolytic viruses (OVs), like those potentially related to VIO-01, have shown promise in cancer treatment by selectively targeting and killing cancer cells while also boosting the body's immune response against tumors. Studies have demonstrated that OVs can improve outcomes in various cancer models, suggesting potential effectiveness for recurrent cancer.
12345Is VIO-01 (also known as OX425) safe for humans?
Oncolytic viruses, like the one used in VIO-01, generally have a tolerable safety profile with minimal human toxicity, as they selectively target and replicate in cancer cells.
678910How is the treatment VIO-01 (OX425) different from other treatments for recurrent cancer?
VIO-01 (OX425) is unique because it is an oncolytic virus therapy, which means it uses viruses to specifically target and destroy cancer cells while also stimulating the body's immune system to fight the cancer. This approach is different from traditional treatments like chemotherapy, as it acts like a vaccine by releasing tumor-specific antigens and can be combined with other therapies to enhance its effectiveness.
35111213Eligibility Criteria
This trial is for people with recurrent solid tumors, including specific types like prostate, ovarian, and breast cancers. Participants should have previously tried standard treatments without success. The study will also focus on individuals with advanced HRRm or HRD+ solid tumors and those with the same conditions in recurrent ovarian cancer.Inclusion Criteria
Participants must have measurable disease per RECIST 1.1
My cancer has worsened despite treatment, or I can't tolerate standard treatments.
My breast cancer has returned or spread, and I know my cancer's hormone and HER2 status.
Exclusion Criteria
I have had more than one treatment for my cancer after it spread.
I have a chronic neurological condition like MS or Parkinson's.
Participant Groups
The trial is testing VIO-01's safety when used alone or alongside other anti-cancer therapies. It consists of two parts: determining the maximum safe dose and how well patients tolerate it (Part 1), followed by assessing its effectiveness in advanced HRRm/HRD+ solid tumors (Part 2).
3Treatment groups
Experimental Treatment
Group I: Dose Expansion HRRm or HRD+ Solid TumorsExperimental Treatment1 Intervention
Participants with advanced HRRm or HRD+ solid tumors will be administered recommended Phase 2 dose of VIO-01 via intravenous infusion over a 60-minute period once weekly.
Group II: Dose Expansion HRRm or HRD+ Ovarian CancerExperimental Treatment1 Intervention
Participants with advanced HRRm or HRD+ ovarian cancer will be administered recommended Phase 2 dose of VIO-01via intravenous infusion over a 60-minute period once weekly.
Group III: Dose EscalationExperimental Treatment1 Intervention
Dose escalation: Multiple dose levels of VIO-01 will be administered via intravenous infusion over a 60-minute period once weekly.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Stephenson Cancer Center - University of OklahomaOklahoma City, OK
Florida Cancer Specialists & Research InstituteLake Mary, FL
Next OncologySan Antonio, TX
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Who Is Running the Clinical Trial?
Valerio TherapeuticsLead Sponsor
References
Optimizing oncolytic virotherapy in cancer treatment. [2020]In the wake of the success of modern immunotherapy, oncolytic viruses (OVs) are currently seen as a potential therapeutic option for patients with cancer who do not respond or fail to achieve durable responses following treatment with immune checkpoint inhibitors. OVs offer a multifaceted therapeutic platform because they preferentially replicate in tumour cells, can be engineered to express transgenes that augment their cytotoxic and immunostimulatory activities, and modulate the tumour microenvironment to optimize immune-mediated tumour eradication, both at locoregional and systemic sites of disease. Lysis of tumour cells releases tumour-specific antigens that trigger both the innate and adaptive immune systems. OVs also represent attractive combination partners with other systemically delivered agents by virtue of their highly favourable safety profiles. Rational combinations of OVs with different immune modifiers and/or antitumour agents, based on mechanisms of tumour resistance to immune-mediated attack, may benefit the large, currently underserved, population of patients who respond poorly to immune checkpoint inhibition.
Oncolytic Viruses for Cancer Therapy: Barriers and Recent Advances. [2020]Oncolytic viruses (OVs) are powerful new therapeutic agents in cancer therapy. With the first OV (talimogene laherparepvec [T-vec]) obtaining US Food and Drug Administration approval, interest in OVs has been boosted greatly. Nevertheless, despite extensive research, oncolytic virotherapy has shown limited efficacy against solid tumors. Recent advances in viral retargeting, genetic editing, viral delivery platforms, tracking strategies, OV-based gene therapy, and combination strategies have the potential to broaden the applications of oncolytic virotherapy in oncology. In this review, we present several insights into the limitations and challenges of oncolytic virotherapy, describe the strategies mentioned above, provide a summary of recent preclinical and clinical trials in the field of oncolytic virotherapy, and highlight the need to optimize current strategies to improve clinical outcomes.
Clinical landscape of oncolytic virus research in 2020. [2021]Oncolytic viruses (OVs) are a new class of cancer therapeutics. This review was undertaken to provide insight into the current landscape of OV clinical trials. A PubMed search identified 119 papers from 2000 to 2020 with 97 studies reporting data on 3233 patients. The viruses used, presence of genetic modifications and/or transgene expression, cancer types targeted, inclusion of combination strategies and safety profile were reported. In addition, information on viral bioshedding across the studies, including which tissues or body fluids were evaluated and how virus was detected (eg, PCR, plaque assay or both), is also reported. Finally, the number of studies evaluating antiviral and antitumor humoral and cellular immune responses were noted. We found that adenovirus (n=30) is the most common OV in clinical trials with approximately two-thirds (n=63) using modified or recombinant viral backbones and granulocyte-macrophage colony-stimulating factor (n=24) was the most common transgene. The most common tumors targeted were melanoma (n=1000) and gastrointestinal (GI; n=577) cancers with most using monotherapy OVs given by intratumoral (n=1482) or intravenous (n=1347) delivery. The most common combination included chemotherapy (n=36). Overall, OV treatment-related adverse events were low-grade constitutional and local injection site reactions. Viral shedding was frequently measured although many studies restricted this to blood and tumor tissue and used PCR only. While most studies did report antiviral antibody titers (n=63), only a minority of studies reported viral-specific T cell responses (n=10). Tumor immunity was reported in 48 studies and largely relied on general measures of immune activation (eg, tumor biopsy immunohistochemistry (n=25) and serum cytokine measurement (n=19)) with few evaluating tumor-specific immune responses (n=7). Objective responses were reported in 292 (9%) patients and disease control was achieved in 681 (21.1%) patients, although standard reporting criteria were only used in 53% of the trials. Completed clinical trials not reported in the peer-reviewed literature were not included in this review potentially underestimating the impact of OV treatment. These data provide insight into the current profile of OV clinical trials reporting and identifies potential gaps where further studies are needed to better define the role of OVs, alone and in combination, for patients with cancer.
Oncolytic viruses as therapeutic cancer vaccines. [2021]Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity. With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF (such as T-VEC and Pexa-Vec) or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy. Coadministration with a HDAC inhibitor inhibits innate immunity transiently to promote infection and spread of OVs, and significantly enhances anti-tumor immunity and improves the therapeutic index. Local administration or OV mediated-expression of ligands for Toll-like receptors can rescue the function of tumor-infiltrating CD8+ T cells inhibited by the immunosuppressive tumor microenvironment and thus enhances the antitumor effect. Combination with cyclophosphamide further induces ICD, depletes Treg, and thus potentiates antitumor immunity. In summary, OVs properly armed or in rational combinations are potent therapeutic cancer vaccines.
Pre-surgical neoadjuvant oncolytic virotherapy confers protection against rechallenge in a murine model of breast cancer. [2020]The use of oncolytic viruses (OVs) for cancer treatment is emerging as a successful strategy that combines the direct, targeted killing of the cancer with the induction of a long-lasting anti-tumor immune response. Using multiple aggressive murine models of triple-negative breast cancer, we have recently demonstrated that the early administration of oncolytic Maraba virus (MRB) prior to surgical resection of the primary tumor is sufficient to minimize the metastatic burden, protect against tumor rechallenge, cure a fraction of the mice and sensitize refractory tumors to immune checkpoint blockade without the need for further treatment. Here, we apply our surgical model to other OVs: Vesicular stomatitis virus (VSV), Adenovirus (Ad), Reovirus (Reo) and Herpes simplex virus (HSV) and show that all of the tested OVs could positively change the outcome of the treated animals. The growth of the primary and secondary tumors was differently affected by the various OVs and most of the viruses conferred survival benefits in this neoadjuvant setting despite the absence of direct treatment following rechallenge. This study establishes that OV-therapy confers long-term protection when administered in the pre-operative window of opportunity.
Therapy with oncolytic viruses: progress and challenges. [2023]Oncolytic viruses (OVs) are an emerging class of cancer therapeutics that offer the benefits of selective replication in tumour cells, delivery of multiple eukaryotic transgene payloads, induction of immunogenic cell death and promotion of antitumour immunity, and a tolerable safety profile that largely does not overlap with that of other cancer therapeutics. To date, four OVs and one non-oncolytic virus have been approved for the treatment of cancer globally although talimogene laherparepvec (T-VEC) remains the only widely approved therapy. T-VEC is indicated for the treatment of patients with recurrent melanoma after initial surgery and was initially approved in 2015. An expanding body of data on the clinical experience of patients receiving T-VEC is now becoming available as are data from clinical trials of various other OVs in a range of other cancers. Despite increasing research interest, a better understanding of the underlying biology and pharmacology of OVs is needed to enable the full therapeutic potential of these agents in patients with cancer. In this Review, we summarize the available data and provide guidance on optimizing the use of OVs in clinical practice, with a focus on the clinical experience with T-VEC. We describe data on selected novel OVs that are currently in clinical development, either as monotherapies or as part of combination regimens. We also discuss some of the preclinical, clinical and regulatory hurdles that have thus far limited the development of OVs.
Improving the cytotoxic response of tumor-infiltrating lymphocytes towards advanced stage ovarian cancer with an oncolytic adenovirus expressing a human vIL-2 cytokine. [2023]While the presence of tumor-infiltrating lymphocytes (TILs) associates with improved survival prognosis in ovarian cancer (OvCa) patients, TIL therapy benefit is limited. Here, we evaluated an oncolytic adenovirus coding for a human variant IL-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, as an immunotherapeutic strategy to enhance TIL responsiveness towards advanced stage OvCa tumors. Fragments of resected human OvCa tumors were processed into single-cell suspensions, and autologous TILs were expanded from said samples. OvCa tumor specimens were co-cultured with TILs plus vIL-2 virus, and cell killing was assessed in real time through cell impedance measurement. Combination therapy was further evaluated in vivo through a patient-derived xenograft (PDX) ovarian cancer murine model. The combination of vIL-2 virus plus TILs had best cancer cell killing ex vivo compared to TILs monotherapy. These results were supported by an in vivo experiment, where the best OvCa tumor control was obtained when vIL-2 virus was added to TIL therapy. Furthermore, the proposed therapy induced a highly cytotoxic phenotype demonstrated by increased granzyme B intensity in NK cells, CD4+ T, and CD8+ T cells in treated tumors. Our results demonstrate that Ad5/3-E2F-d24-vIL2 therapy consistently improved TILs therapy cytotoxicity in treated human OvCa tumors.
Oncolytic viral therapy using reovirus. [2009]Current mainstays in cancer treatment such as chemotherapy, radiation therapy, hormonal manipulation, and even targeted therapies such as trastuzumab (Herceptin) for breast cancer or erlotinib (Tarceva) for non-small cell lung cancer are limited by lack of efficacy, cellular resistance, and toxicity. Dose escalation and combination therapies designed to overcome resistance and increase efficacy are limited by a narrow therapeutic index. Oncolytic viruses are one such group of new biological therapeutics that appears to have a wide spectrum of anticancer activity with minimal human toxicity. Because the malignant phenotype of tumours is the culmination of multiple mutations that occur in several genes eventually leading to aberrant signalling pathways, oncolytic viruses, either natural or engineered, specifically target tumour cells, taking advantage of this cellular deviant signalling for their replication. Reovirus is one such naturally occurring double-stranded RNA (dsRNA) virus that exploits altered Ras signalling pathways in a myriad of cancers. The ability of reovirus to infect and lyse tumours both solid and haematological, under in vitro, in vivo, and ex vivo conditions, is discussed in this chapter. The major mechanism of reovirus oncolysis of cancer cells has been shown to occur through apoptosis. In addition, the synergistic anti-tumour effects of reovirus in combination with radiation or chemotherapy has also been demonstrated for reovirus-resistant and moderately sensitive tumours. In most of the clinical trials undertaken to date, an anti-reovirus immune response has been seen likely circumventing efficacy. Investigation into the use of reovirus as an immune adjuvant is currently underway to try and re-direct this immune response to tumour. Reovirus phase I clinical trials have shown indications of efficacy and several phase I/II trials are ongoing at present. The extensive pre-clinical efficacy, replication competency, and low toxicity profile in humans has placed the reovirus as an attractive anti-cancer therapeutic for ongoing clinical testing.
Boosting cytotoxicity of adoptive allogeneic NK cell therapy with an oncolytic adenovirus encoding a human vIL-2 cytokine for the treatment of human ovarian cancer. [2023]Despite good results in the treatment of hematological malignancies, Natural killer (NK) cells have shown limited effectiveness in solid tumors, such as ovarian cancer (OvCa). Here, we assessed the potential of an oncolytic adenovirus expressing a variant interleukin-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, to enhance NK cell therapy efficacy in human OvCa ex vivo. Human OvCa surgical specimens were processed into single-cell suspensions and NK cells were expanded from healthy blood donors. OvCa sample digests were co-cultured ex vivo with NK cells and vIL-2 virus and cancer cell killing potential assessed in real time through cell impedance measurement. Proposed therapeutic combination was evaluated in vivo with an OvCa patient-derived xenograft (PDX) in mice. Addition of vIL-2 virus significantly enhanced NK cell therapy killing potential in treated OvCa co-cultures. Similarly, vIL-2 virus in combination with NK cell therapy promoted the best in vivo OvCa tumor control. Mechanistically, vIL-2 virus induced higher percentages of granzyme B in NK cells, and CD8+ T cells, while T regulatory cell proportions remained comparable to NK cell monotherapy in vivo. Ad5/3-E2F-d24-vIL2 virus treatment represents a promising strategy to boost adoptive NK cell therapeutic effect in human OvCa.
From Benchtop to Bedside: A Review of Oncolytic Virotherapy. [2020]Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not fully understood, major advances have been made in our understanding of how OVs function and interact with the host immune system, resulting in the recent FDA approval of the first OV for cancer therapy in the USA. This review provides an overview of the history of OVs, their selectivity for cancer cells, and their multifaceted mechanism of antitumor action, as well as strategies employed to augment selectivity and efficacy of OVs. OVs in combination with standard cancer therapies are also discussed, as well as a review of ongoing human clinical trials.
The emergence of combinatorial strategies in the development of RNA oncolytic virus therapies. [2009]Oncolytic viruses (OVs) represent an exciting new biological approach to cancer therapy. In particular, RNA viruses have emerged as potent agents for oncolytic virotherapy because of their capacity to specifically target and destroy tumour cells while sparing normal cells and tissues. Several barriers remain in the development of OV therapy, including poor penetration into the tumour mass, inefficient virus replication in primary cancers, and tumour-specific resistance to OV-mediated killing. The combination of OVs with cytotoxic agents, such as small molecule inhibitors of signalling or immunomodulators, as well as stealth delivery of therapeutic viruses have shown promise as novel experimental strategies to overcome resistance to viral oncolysis. These agents complement OV therapy by unblocking host pathways, delivering viruses with greater efficiency and/or increasing virus proliferation at the tumour site. In this review, we summarize recent development of these concepts, the potential obstacles, and future prospects for the clinical utilization of RNA OVs in cancer therapy.
Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory. [2021]Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV) is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.
Combination Immunotherapy Using Oncolytic Virus for the Treatment of Advanced Solid Tumors. [2021]Oncolytic virus (OV) is a new therapeutic strategy for cancer treatment. OVs can selectively infect and destroy cancer cells, and therefore act as an in situ cancer vaccine by releasing tumor-specific antigens. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype by stimulating widespread host immune responses against the tumor. Recent evidence suggests several possible applications of OVs against cancer, especially in combination with immune checkpoint inhibitors. In this review, we describe the molecular mechanisms of oncolytic virotherapy and OV-induced immune responses, provide a brief summary of recent preclinical and clinical updates on this rapidly evolving field, and discuss a combinational strategy that is able to overcome the limitations of OV-based monotherapy.