Clinical Trials of Oncolytic Viruses in Breast Cancer

Breast cancer is the second most common kind of cancer worldwide and oncolytic viruses may offer a new treatment approach. There are three different types of oncolytic viruses used in clinical trials; (i) oncolytic viruses with natural anti-neoplastic properties; (ii) oncolytic viruses designed for tumor-selective replication; (iii) oncolytic viruses modified to activate the immune system. Currently, fourteen different oncolytic viruses have been investigated in eighteen published clinical trials. These trials demonstrate that oncolytic viruses are well tolerated and safe for use in patients and display clinical activity. However, these trials mainly studied a small number of patients with different advanced tumors including some with breast cancer. Future trials should focus on breast cancer and investigate optimal routes of administration, occurrence of neutralizing antibodies, viral gene expression, combinations with other antineoplastic therapies, and identify subtypes that are particularly suitable for oncolytic virotherapy.

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Identification of Cancer Care and Protocol Characteristics Associated With Recruitment in Breast Cancer Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2007.15.3726 ◽

2008 ◽

Vol 26 (27) ◽

pp. 4458-4465 ◽

Cited By ~ 26

Author(s):

Julie Lemieux ◽

Pamela J. Goodwin ◽

Kathleen I. Pritchard ◽

Karen A. Gelmon ◽

Louise J. Bordeleau ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Clinical Trials ◽

Cancer Care ◽

Primary Objective ◽

Cancer Clinical Trials ◽

Cooperative Groups ◽

Number Of Patients ◽

Trial Protocols ◽

Few Data

Purpose It is estimated that only 5% of patients with cancer participate in a clinical trial. Barriers to participation may relate to available protocols, physicians, and patients, but few data exist on barriers related to cancer care environments and protocol characteristics. Methods The primary objective was to identify characteristics of cancer care environments and clinical trial protocols associated with a low recruitment into breast cancer clinical trials. Secondary objectives were to determine yearly recruitment fraction onto clinical trials from 1997 to 2002 in Ontario, Canada, and to compare recruitment fraction among years. Questionnaires were sent to hospitals requesting characteristics of cancer care environments and to cooperative groups/pharmaceutical companies for information on protocols and the number of patients recruited per hospital/year. Poisson regression was used to estimate the recruitment fraction. Results Questionnaire completion rate varied between 69% and 100%. Recruitment fraction varied between 5.4% and 8.5% according to year. More than 30% of patients were diagnosed in hospitals with no available trials. In multivariate analysis, the following characteristics were associated with recruitment: use of placebo versus not (relative risk [RR] = 0.80; P = .05), nonmetastatic versus metastatic trial (RR = 2.80; P < .01), and for nonmetastatic trials, protocol allowing an interval of 12 weeks or longer versus less than 12 weeks (from diagnosis, surgery, or end of therapy) before enrollment (RR = 1.36; P < .01). Conclusion Allowable interval of 12 weeks or longer to randomly assign patients in clinical trials could help recruitment. In our study, absence of an available clinical trial represented the largest barrier to recruitment.

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Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.6.1858 ◽

1996 ◽

Vol 14 (6) ◽

pp. 1858-1867 ◽

Cited By ~ 262

Author(s):

J M Nabholtz ◽

K Gelmon ◽

M Bontenbal ◽

M Spielmann ◽

G Catimel ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Low Frequency ◽

Metastatic Breast ◽

Therapeutic Index ◽

Complete Response ◽

Dose Effect ◽

Clinical Activity ◽

High Dose ◽

Number Of Patients

PURPOSE AND METHODS The objective of this multicenter study was to compare the therapeutic index of two different doses of paclitaxel given as a 3-hour infusion in patients with metastatic breast cancer (MBC), who had failed to respond to previous chemotherapy. A total of 471 patients with MBC were randomized to receive intravenous paclitaxel at a dose of 175 or 135 mg/m2 every 3 weeks. RESULTS Better treatment results were achieved with high-dose (HD) versus low-dose (LD) paclitaxel: overall response rate, 29% versus 22% (P = .108); complete response (CR) rate, 5% versus 2% (P = .088); median time to disease progression, 4.2 versus 3.0 months (P = .027); and median survival time, 11.7 versus 10.5 months (P = .321). Patients previously exposed or resistant to anthracyclines were as likely to respond as those without such prior exposure. Treatment was well tolerated, as documented by the number of administered treatment courses (median, six v five; range, one 17 v one to 18), the low frequency of dose reductions (14% v 7%, P = .024), and the small number of patients (n = 9 or 4% vn = 5 or 2%) who required treatment discontinuation for adverse reactions. The incidence and severity of neutropenia and peripheral neuropathy were dose-related. After quality-of-life-adjusted time-to-progression analysis, the HD arm (175 mg/m2) retained its advantage over the LD arm (135 mg/m2). CONCLUSION The results of this trial substantiate the activity of paclitaxel in the treatment of MBC. The observed superior efficacy with a dose of 175 mg/m2 over 135 mg/m2 suggests a dose-effect relationship. The clinical activity in anthracycline-resistant patients is particularly noteworthy. Paclitaxel in breast cancer needs further evaluation in large trials that use combination chemotherapy and involve earlier disease stages.

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Evolution and landscape of clinical trials for breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1601 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1601-1601

Author(s):

Semih Dogan ◽

Aicha Goubar ◽

Monica Arnedos ◽

Suzette Delaloge ◽

Fabrice Andre

Keyword(s):

Social Sciences ◽

Breast Cancer ◽

Cancer Research ◽

Clinical Trials ◽

Clinical Research ◽

Breast Cancer Research ◽

Targeted Agents ◽

First Semester ◽

Therapeutic Trials ◽

Number Of Patients

1601 Background: Recent advances in cancer research are expected to have dramatically changed the way clinical trials are being done. In an effort to outline new trends of clinical research in the breast cancer area, we have evaluated the evolution of clinical trials started between 2006 and 2011. Methods: 622 clinical trials, started during the first semester 2006, the second semester 2008 and the first semester 2011, were analyzed. The data source was Clinicaltrials.gov. 30 items were included in the database. Results: The overall number of patients included in prospective clinical trials increased over these periods (n=67,820, n=91,429, n=98,417). However, when large epidemiological cohorts are excluded, a significant fall in the number of patients is seen (n=67,820, n=44,554, n=37,417). The absolute number of therapeutic trials also decreased during this time (n=93, n=99, n=78), mainly related to the dramatic fall in the number of trials testing conventional treatments (n=40, n=24, n=20). In the meantime, the number of trials testing targeted agents remained similar (n=46, n=67, n=50). Interestingly, in the same time, the number of trials testing a targeted agent in a population defined by a biomarker increased (n=1, n=6, n=14). At the opposite, prospective studies aimed at validating biomarkers did not increase, and remained only driven by large consortiums. As illustration, when we exclude RxPONDER trial, the biomarker-validation studies opened in 2011 planned to include only 2 493 patients, representing 2% of the breast cancer research field. Prospective trials testing social sciences and supportive care (n= 70, n=72, n=70) tend to become as important as therapeutic trials. Finally, large epidemiological cohorts opened in 2011 will represent more than 60% of the patients included in clinical trials. Conclusions: The part of cohorts and social sciences in breast cancer research is increasing and represents now the majority of the clinical research activity. When the analysis focuses on therapeutic trials, the breast cancer field recently shifted to targeted agents and early data suggest that therapeutic research is increasingly incorporating companion biomarker. Analysis on all 2,762 clinical trials done between 2006 and 2011 will be presented.

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Treatment of mild to moderate Graves' ophthalmopathy with sodium diclofenac: a pilot study

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302011000900004 ◽

2011 ◽

Vol 55 (9) ◽

pp. 692-695 ◽

Cited By ~ 6

Author(s):

Walter Bloise ◽

Lidia Yuri Mimura ◽

Janete Moura ◽

Wilian Nicolau

Keyword(s):

Therapeutic Option ◽

Ppar Gamma ◽

Controlled Study ◽

Clinical Activity ◽

Ocular Pain ◽

Sodium Diclofenac ◽

Graves Ophthalmopathy ◽

Number Of Patients ◽

New Treatment ◽

Oral Sodium

OBJECTIVE: To report the use of sodium diclofenac, an antagonist of PPAR-gamma and cyclooxigenase-2 (COX-2) inhibitor in the treatment of mild to moderate Graves' ophthalmopathy. SUBJECTS AND METHODS: Thirteen patients with clinical activity score (CAS) 2 to 7 were treated during a period ranging from 3 to 12 months (mean 7.8 ± 3.4) with oral sodium diclofenac, 50 mg every 12 hours. RESULTS: Extra-ocular muscle restriction and CAS improved significantly, p = 0.003 and = 0.004, respectively. Ocular pain and diplopia disappeared, except for one patient who reported improvement of these symptoms. No recurrence was found after interruption of treatment. CONCLUSIONS: Treatment of moderate Graves' ophthalmopathy with oral sodium diclofenac is a good, safe and less expensive therapeutic option. Like others new treatment trials, findings must be confirmed in a greater number of patients in a controlled study.

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Immunotherapy using PD‑1/PDL-1 inhibitors in triple‑negative breast cancer: a systematic review

Oncology Reviews ◽

10.4081/oncol.2021.497 ◽

2021 ◽

Vol 15 (2) ◽

Author(s):

Dione Tavares ◽

Victoria Chaves Ribeiro ◽

Laércio Moreira Cardoso-Júnior ◽

Thiago Rhangel Gomes Teixeira ◽

Gabriela Ramos Varrone ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Metastatic Breast ◽

Cochrane Central Register ◽

Combination Strategies ◽

Central Register ◽

Metastatic Setting ◽

New Treatment

Breast cancer is the most commonly diagnosed cancer in women and is one of the leading causes of death from cancer in women worldwide. Despite the significant benefits of using conventional chemotherapy in the treatment of breast cancer, one of its subtypes, the triple negative breast cancer, is still a challenge in clinical practice. Recent studies have been investigating the role of the immune system in breast cancer and the development of immunotherapy. Although recently the use of atezolizumab, an anti-PD-L1 monoclonal antibody, combined with chemotherapy was approved, an important step in the treatment of patients with triple negative metastatic breast cancer, the use of immunotherapy to treat breast tumors remains a major challenge. In this systematic literature review, following PRISMA guidelines, we searched for clinical trials using immunotherapy in the treatment of triple negative breast cancer published until June 2019 in the databases EMBASE, PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), with no language restrictions. We did not contact the authors of the clinical trials to obtain additional information.Two researchers independently collected the data and assessed the quality of this study. The literature shows that immunotherapy with anti-PD-1/PD-L1 agents is emerging as a new treatment option in breast cancer. On the other hand, when compared to other types of cancer in which several agents have already been approved, the research is still in its infancy. The use of anti-PD-1/PD-L1 agents monotherapy revealed encouraging results in the metastatic setting, especially when administered in the early course of the disease, although combination strategies with chemotherapy appear to increase its efficacy.

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Viral therapies for glioblastoma and high-grade gliomas in adults: a systematic review

Neurosurgical FOCUS ◽

10.3171/2020.11.focus20854 ◽

2021 ◽

Vol 50 (2) ◽

pp. E2

Author(s):

Joshua L. Wang ◽

Kristen M. Scheitler ◽

Nicole M. Wenger ◽

J. Bradley Elder

Keyword(s):

Gene Therapy ◽

Clinical Trials ◽

Viral Vectors ◽

Cytosine Deaminase ◽

Treatment Strategies ◽

Oncolytic Viruses ◽

Phase Iii ◽

Viral Gene ◽

High Grade ◽

High Grade Gliomas

OBJECTIVEHigh-grade gliomas (HGGs) inevitably recur and progress despite resection and standard chemotherapies and radiation. Viral therapies have emerged as a theoretically favorable adjuvant modality that might overcome intrinsic factors of HGGs that confer treatment resistance.METHODSThe authors present the results of systematic searches of the MEDLINE and ClinicalTrials.gov databases that were performed for clinical trials published or registered up to July 15, 2020.RESULTSFifty-one completed clinical trials were identified that made use of a virus-based therapeutic strategy to treat HGG. The two main types of viral therapies were oncolytic viruses and viral vectors for gene therapy. Among clinical trials that met inclusion criteria, 20 related to oncolytic viruses and 31 to gene therapy trials. No oncolytic viruses have progressed to phase III clinical trial testing, although there have been many promising early-phase results and no reported cases of encephalitis or death due to viral therapy. Three phase III trials in which viral gene therapy was used have been completed but have not resulted in any FDA-approved therapy. Recent efforts in this area have been focused on the delivery of suicide genes such as herpes simplex virus thymidine kinase and cytosine deaminase.CONCLUSIONSDecades of research efforts and an improving understanding of the immunomodulatory effects of viral therapies for gliomas are informing ongoing clinical efforts aimed at improving outcomes in patients with HGG. The available clinical data reveal varied efficacy among different virus-based treatment strategies.

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Oncolytic viruses for triple negative breast cancer and beyond

Biomarker Research ◽

10.1186/s40364-021-00318-4 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Shengye Jin ◽

Qin Wang ◽

Hao Wu ◽

Da Pang ◽

Shouping Xu

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Biological Therapy ◽

Therapeutic Potential ◽

Growth Factor Receptor ◽

Oncolytic Viruses ◽

Therapeutic Effects ◽

Major Player

AbstractBiological therapy is considered an alternative treatment capable of eliciting the same effects on tumors as surgery, radiotherapy, and chemotherapy. As a major player in biological therapy, oncolytic viruses (OVs) have attracted great attention and achieved good results. Specifically, the successful application of OVs in head and neck cancer, as well as melanoma, promoted its research in triple negative breast cancer (TNBC). TNBC is a high-risk molecular type of breast cancer, characterized by strong invasion, easy recurrence, and metastasis. Due to the absence of estrogen and progesterone receptors, as well as the absence of overexpression or gene amplification of human epidermal growth factor receptor 2 (HER2), endocrine therapy and anti HER-2 targeted therapy have proven ineffective. Although chemotherapy has shown substantial efficacy in some TNBC patients, the occurrence of drug resistance and poor prognosis have prompted the exploration of new and effective treatment methods. The emerging concept of OVs provides a new platform to treat TNBC. Indeed, several studies have confirmed the therapeutic effects of OVs in TNBC. Numerous studies have also investigated the efficacy of OVs in other malignances, including solid tumor clinical trials, thus further demonstrating the promising application of oncolytic virotherapy for TNBC. The primary focus of the current review is the examination of OV mechanisms underlying their antitumor properties, while also summarizing the ongoing progress in OV research regarding TNBC treatment, as well as the various combinatorial strategies comprising OVs and other therapies. We also briefly introduce specific relevant clinical trials and discuss some of the progress in the research of novel OVs for the treatment of other malignancies, thereby affirming the significant therapeutic potential of OVs for the treatment of TNBC, as well as other cancers.

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Noncanonical Cell Death Induction by Reassortant Reovirus

Journal of Virology ◽

10.1128/jvi.01613-20 ◽

2020 ◽

Vol 94 (22) ◽

Author(s):

Roxana M. Rodríguez Stewart ◽

Vishnu Raghuram ◽

Jameson T. L. Berry ◽

Gaurav N. Joshi ◽

Bernardo A. Mainou

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Host Cell ◽

Caspase 3 ◽

Gene Segment ◽

Oncolytic Viruses ◽

Viral Gene ◽

Genetic Composition ◽

Type 3

ABSTRACT Triple-negative breast cancer (TNBC) constitutes 10 to 15% of all breast cancer and is associated with worse prognosis than other subtypes of breast cancer. Current therapies are limited to cytotoxic chemotherapy, radiation, and surgery, leaving a need for targeted therapeutics to improve outcomes for TNBC patients. Mammalian orthoreovirus (reovirus) is a nonenveloped, segmented, double-stranded RNA virus in the Reoviridae family. Reovirus preferentially kills transformed cells and is in clinical trials to assess its efficacy against several types of cancer. We previously engineered a reassortant reovirus, r2Reovirus, that infects TNBC cells more efficiently and induces cell death with faster kinetics than parental reoviruses. In this study, we sought to understand the mechanisms by which r2Reovirus induces cell death in TNBC cells. We show that r2Reovirus infection of TNBC cells of a mesenchymal stem-like (MSL) lineage downregulates the mitogen-activated protein kinase/extracellular signal-related kinase pathway and induces nonconventional cell death that is caspase-dependent but caspase 3-independent. Infection of different MSL lineage TNBC cells with r2Reovirus results in caspase 3-dependent cell death. We map the enhanced oncolytic properties of r2Reovirus in TNBC to epistatic interactions between the type 3 Dearing M2 gene segment and type 1 Lang genes. These findings suggest that the genetic composition of the host cell impacts the mechanism of reovirus-induced cell death in TNBC. Together, our data show that understanding host and virus determinants of cell death can identify novel properties and interactions between host and viral gene products that can be exploited for the development of improved viral oncolytics. IMPORTANCE TNBC is unresponsive to hormone therapies, leaving patients afflicted with this disease with limited treatment options. We previously engineered an oncolytic reovirus (r2Reovirus) with enhanced infective and cytotoxic properties in TNBC cells. However, how r2Reovirus promotes TNBC cell death is not known. In this study, we show that reassortant r2Reovirus can promote nonconventional caspase-dependent but caspase 3-independent cell death and that the mechanism of cell death depends on the genetic composition of the host cell. We also map the enhanced oncolytic properties of r2Reovirus in TNBC to interactions between a type 3 M2 gene segment and type 1 genes. Our data show that understanding the interplay between the host cell environment and the genetic composition of oncolytic viruses is crucial for the development of efficacious viral oncolytics.

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Identification of cancer care and protocol characteristics associated with recruitment rate in breast cancer clinical trials in Ontario

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.17042 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 17042-17042

Author(s):

J. Lemieux ◽

P. J. Goodwin ◽

K. Pritchard ◽

K. Gelmon ◽

L. Bordeleau ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Multivariate Analysis ◽

Relative Risk ◽

Cancer Care ◽

Time Frame ◽

Recruitment Rate ◽

Pharmaceutical Companies ◽

Cooperative Groups ◽

Number Of Patients

17042 Background: Recruitment rate (RR) in clinical trials (CT) has been recognized to be low. Poor accrual may lead to premature closing of CT or decrease of the planned power to detect an effect if present. Methods: Objectives were primarily to identify characteristics of cancer care settings and clinical trials protocols associated with low RR and secondarily (1) to determine the RR and (2) to compare the RR between years. A cross-sectional design was used. Poisson regression was used for multivariate analysis. RR was calculated by CT, hospital and year in Ontario between 1997 and 2002. Number of patients recruited in each CT was obtained from cooperative groups and pharmaceutical companies. Number of patients with breast cancer (BC) was obtained from the Ontario Cancer Registry. Prevalence of women with metastatic BC was calculated from the British Columbia Breast Cancer Outcome Unit database. Characteristics of cancer care and protocols were collected. Results: Response rates were 84% (66/79) for hospitals, 69% (9/13) for cooperative groups and 80% (8/10) for pharmaceutical companies. Recruitment rates varied between 1.3% and 5.5% (median, p=0.0003). Characteristics of cancer care were not associated with RR (number of oncologists, breast oncologists, breast surgeons, investigators, clinical research associates and being a cancer centre or an academic centre). Among protocol characteristics, the following were associated with RR in univariate analysis: phase, randomization, type of intervention, placebo, extent of the trials (local vs. national vs. international), number of sites, population (adjuvant vs. metastatic), menopausal status, premature closing of the trial, time frame for enrolment, extra baseline and follow-up testing. In multivariate analysis, type of control arm and time frame for enrolment were significant. CT using placebo compared to an active control arm were less likely to recruit patients (relative risk 0.57, p=0.0144). CT with a time frame for enrolment greater than 9 weeks were more likely to enrol patients (relative risk 1.43, p=0.0020). Conclusions: RR is very low. No easily modifiable factors have been identified. This project was funded by the Canadian Breast Cancer Foundation, Ontario Chapter. [Table: see text]

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Evaluation of cardiovascular status in clinical trials in breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e14038 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e14038-e14038

Author(s):

Ohad Oren ◽

Michal Oren

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Treatment Options ◽

Single Agent ◽

Locally Advanced ◽

Metastatic Breast ◽

P Value ◽

Number Of Patients ◽

Cardiac Status

e14038 Background: With the expansion of treatment options in oncology, patients are now increasingly exposed to potentially cardio-injurious compounds. Nevertheless, many clinical trials do not assess the cardiac status of participants, from time of enrollment to study completion. Methods: We reviewed the landmark clinical trials of each of the single-agent chemotherapies specified by the NCCN for use in locally advanced/metastatic breast cancer. We analysed the cardiovascular exclusion criteria, baseline cardiac evaluation as well as cardiac surveillance of patients in each study. We then investigated the literature in the years following each index publication, scrutinising for evidence of cardiac toxicity. Results: 14 phase 2/3 studies were analysed. The total number of patients was 2,522. 42.8% (6/14) of the studies excluded patients with clinically-determined cardiovascular disease, 66.6% (4) of which specified normal EF as a pre-requisite for enrollment. 42.8% (6/14) of the studies evaluated the baseline cardiovascular function of participants using EKG or TTE. 35.7% (4/14) of the studies included a more rigorous monitoring that included serial EKGs and/or TTEs. New Heart Failure (HF) occurred in 1.63% (20/1226) and 0.87% (9/1024) of patients in the more- and less- rigorous trials, respectively (P value = 0.11). Subsequent follow-up studies (published a mean of 8.5 years later) disclosed significantly higher incidence of symptomatic HF (range 2.3-28.0%) with 3 (of 4) chemotherapies in the more-rigorous study group (doxorubicin, cyclophosphamide, epirubicin) and 1 (of 10) chemotherapies in the less-rigorous group (docetaxel). Conclusions: The majority of clinical studies in breast cancer do not prospectively assess cardiac status beyond a pure clinical assessment. The discrepancy between the toxicity profile shown by original studies and that detected in subsequent investigations implies that the tools currently used to evaluate the cardiovascular status of enrollees may be insufficiently sensitive in predicting the development of HF. Novel tools (circulating markers, imaging) and longer follow-up periods are needed to ascertain the cardiotoxic profile of new chemotherapies.

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