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An oncolytic virus for a common childhood brain tumor

In this eighth episode of “This Week in Pediatric Oncology” podcast hosts Dr Tim Cripe, Dr Lars Wagner and Dr Lionel Chow discuss a recent publication by researchers at Baylor/Texas Children’s in Houston that shows remarkable results of Seneca Valley virus SVV-001 on orthotopic mouse models of medulloblastoma.

The TWiPO hosts raise many interesting points about this research and highlight the strengths as well as limitations of this work. This exciting research provides new evidence of promise for oncolytic virus therapy for childhood tumors.

For more information about oncolytic virus trials for pediatric cancers, see a recent webinar “Oncolytic Virotherapy for Pediatric Solid Tumors” presented by the principal investigators of five clinical trials in children and sponsored by Solving Kids’ Cancer.

The article discussed in this episode can be found here:

A single intravenous injection of oncolytic picornavirus SVV-001 eliminates medulloblastomas in primary tumor-based orthotopic xenograft mouse models. Yu L, Baxter PA, et al. Neuro Oncol. 2011 Jan;13(1):14-27. Epub 2010 Nov 12.

Another related article by the same group:

Treatment of invasive retinoblastoma in a murine model using an oncolytic picornavirus. Wadhwa L, Hurwitz MY, et al. Cancer Res. 2007 Nov 15;67(22):10653-6. [fulltext]

Please send questions or comments to twipo@solvingkidscancer.org

Four oncolytic virus trials open at Cincinnati Children’s for pediatric solid tumors

Dr Tim Cripe provided a very helpful comparison chart for the oncolytic virus trials currently open at Cincinnati Children’s, and permission to post it. To open a PDF of the chart, click on this link:

Viral study comparison (PDF document)

The chart lists the similarities and differences of the four oncolytic virus trials:  SVV-001 (NTX-010 or seneca Valley virus), HSV1716 (Herpes simplex), JX-594 (Jennerex vaccina), and Reolysin (reovirus).

Regarding age, the HSV1716 is open for ages 13 to 30, whereas the others are for 2 or 3 years up to 21. Both SVV-001 and Reolysin are given intravenously, whereas HSV1716 and JX-594 are given intratumoral (injected into the tumor).

HSV1716 and JX-594 require short inpatient stays, but Reolysin and SVV-001 are give outpatient. The SVV-001 is given in a single dose (one-hour infusion), whereas the JX-594 and HSV1716 can be administered to tumor sites every 28 days up to four times, and Reolysin is given in a one-hour infusion for five days, and this is repeated every 28 days for up to 12 months.

The chart also lists the current dose levels for each trial (all are phase I studies).

The SVV-001 and Reolysin are open in several COG Phase I centers, and the HSV1716 and JX-594 are only open at Cincinnati Children’s, and that is the only location that has all four trials open. Only the Reolysin trial restricts eligibility to those who have not had prior oncolytic viruses, so it is possible to enroll on these trials in sequence.

For more background on oncolytic virus trials for children, see the following links.

Review article: http://www.nbglobe.com/2010/11/19/status-on-oncolytic-virus-therapies-for-pediatric-solid-tumors/

Webinar: http://www.nbglobe.com/2011/01/26/webinar-on-oncolytic-viruses-for-children/

Big antibody news

The “third generation” humanized anti-GD2 antibody with protein fusion of IL2 to the antibody has completed Phase I and II clinical trials for melanoma and neuroblastoma, and is now ready for use in Phase III clinical trials. The license for hu14.18-IL2 was just acquired by a small biotech in Vienna called Apeiron. The license was acquired from Merck.

Apeiron’s press release:

Apeiron Licenses Phase II/III Anticancer Ab-IL2 Fusion Protein from Merck KGaA

Long-term follow up of children with and without ch14.18/CHO in German trials NB90 and NB97

It has been a very long wait to finally see this graph. The Germans reported on this at ANR 2008 in Japan, and again at ANR 2010 in Stockholm.  See Graph A in Figure 2. “Follow-up analysis of the patient cohort indicated that immunotherapy with ch14.18 [no cytokines] may prevent late relapses.” Remember this group reported in 2004 “analysis failed to demonstrate an advantage of antibody treatment” –

http://jco.ascopubs.org/content/22/17/3549.long

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The statement about late relapses is a little puzzling to me. Graph A shows that “events” (which are usually relapses) occurred up until 10 years in both the ch14.18 and maintenance groups. Only the “no consolidation” group had later events.

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The authors concluded:”Today, the most effective way of antibody based maintenance therapy seems to be a combination immunotherapy with MAB ch14.18, cytokines, and retinoic acid. But these results need confirmation by at least another randomized trial. Further, metronomic low dose oral chemotherapy consolidation was found as effective as MAB ch14.18 consolidation in this retrospective analysis and, therefore, also warrants further evaluation. Prospective clinical trials must demonstrate if the concept of low dose metronomic chemotherapy is feasible and effective after ASCT and in combination with immunotherapy.”

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Since the early results did not show a benefit of ch14.18 without cytokines, and yet the COG trial showed 20% advantage in early results, it could be argued that there might be a big difference in survival between oral metronomic chemotherapy and ch14.18 with cytokines.

http://www.biomedcentral.com/content/pdf/1471-2407-11-21.pdf

Germans report on outcomes of relapsed NB patients who received three different regimens

Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials.

Simon, T., Berthold, F., Borkhardt, A., Kremens, B., De Carolis, B. and Hero, B. (2011), Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials. Pediatric Blood & Cancer, 56: 578–583. doi: 10.1002/pbc.22693

This is an important publication and was presented at ANR 2010. Few groups have tackled relapsed NB in any systematic way. Wendy London’s abstract presented at ASCO 2010 and ANR 2010 on survival after relapse suggests that some relapsed NB children are salvageable, and the Germans and Swedes are advancing understanding in treating relapse. This same approach looking at more aggressive measures for relapsed leukemia kids is how relapse protocols were developed to treat relapsed leukemias.

Drs John Maris and Yael Mosse awarded patent for ALK mutation link to diagnosis, prognosis, and treatment of neuroblastoma

Summary of patent:

CHK1 suspected to be a promising target in NB — inhibitors are being tested in adults

‎”CHK1 mRNA expression was higher in MYC–Neuroblastoma-related (MYCN)–amplified (P < 0.0001) and high-risk (P = 0.03) tumors.”

RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in n

www.pnas.org

Edited by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved December 17, 2010 (received for review August 23, 2010)

Protein May Be Key to New Treatment in a Childhood Cancer — PHILADELPHIA, Feb. 7, 2011 /PRNewswire-

New clinical trials using oncolytic viruses for pediatric solid tumors

Solving Kids’ Cancer hosted a fantastic webinar on oncolytic viruses for children with solid tumors January 25, 2011.

All four principal investigators of five trials for children presented–starting with an overview given by Dr Tim Cripe:

• Dr Michael Burke on Seneca Valley virus (NTX-101/SVV-001)
• Dr Timothy Cripe on herpes simplex (HSV1716) and vaccinia (JX-594)
• Dr Corey Raffel on modified measles (MV-CEA)
• Dr E. Anders Kolb on reovirus (Reolysin)

The meeting was recorded and the video is 1 hour and 40 minutes long.

Nearly 100 parents and researchers participated in this live event.

These novel, low-toxicity therapies are advancing quickly and present great promise– perhaps one day children with cancer will be cured without chemotherapy!

Oncolytic Virotherapy for Pediatric Solid Tumors from D Ludwinski on Vimeo.

Neuroblastoma bits from November 2010

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NCI featured article on ALK inhibitor Crizotinib

While encouraging responses are being seen in lung cancer patients with ALK mutation, drug resistance is expected to be a problem.

Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance

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FDA discusses Crizotinib pediatric trial design

Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC) Nov 30, 2010

“If the current COG Phase I/II studies evaluating crizotinib in refractory pediatric solid tumors or ALCL shows promising activity in neuroblastoma, should crizotinib be evaluated in the post-transplant relapsed/refractory setting or should a randomized trial in a less heavily treated population be considered? If the former population (i.e., post-transplant relapsed or refractory) is a more appropriate setting, please discuss whether Progression Free Survival (PFS) is an adequate endpoint.”

Committee discussion questions

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Insight Genetics Awarded Qualifying Therapeutic Discovery Program Grant

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http://www.eurojournals.com/ejsr_40_1_15.pdf

www.eurojournals.com

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Scientific American describes the recent advances in viruses that kill cancer — now available to children this year for the first time –

Cancer Therapy Goes Viral: Progress Is Made Tackling Tumors with Viruses: Scientific American

“A new generation of oncolytic viruses are entering late-stage clinical trials, repurposing smallpox and herpesvirus to take on tough tumors.”

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Search goes on for toxins to kill neuroblastoma

“Luesch is experimenting with toxins—drawn from several species of cyanobacteria—on several types of cancer, including neuroblastoma, a childhood disease that attacks nerve cells. In July 2009, he launched a four-year, $1.2 million NCI-funded study, part of which entails… largazole testing on mice.”

Why Scientists Are Searching for Cures Underwater – Newsweek

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Childhood cancer survival in Australia

“Survival outcomes using the period method for 11903 children diagnosed with cancer between 1983 and 2006 and prevalent at any time between 1997 and 2006. The overall relative survival was 90.4% after 1 year,  79.5% after 5 years and 74.7% after 20 years.”

Population-based survival estimates for childhood cancer in Australia during the period 1997–2006

www.nature.com

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Accutane (cis-retinoic acid or isotretinoin) and depression?

A child with neuroblastoma is far more more often a preschooler than a teen. So the risk of suicide and depression is unlikely with such small children. It is a concern with the few teens and young adults with neuroblastoma on this drug, especially since the dosing is 2 to 10 times higher than what is prescribed for acne, and the lower dose is the basis for all the previous studies looking at incidence of depression and suicide. This small study gives important evidence that the drug may not contribute entirely to increased risk:

Severe Acne Linked to Suicide Risk Even Before Treatment Is Started

cme.medscape.com

In a retrospective Swedish cohort, suicide attempts were associated with severe acne even before treatment with isotretinoin was started.

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A review of a new therapy for neuroblastoma

Significant and accelerating progress is underway in the oncolytic virus arena. In the past decade numerous clinical trials using several different oncolytic viruses against adult cancers have been completed and more are underway. Many trials have shown anti-tumor activity in various adult tumors. A major milestone was reached this year with three oncolytic virus trials open to children for the first time in the US using vaccinia, Seneca Valley virus, and herpes simplex virus, and two more to open next year using reovirus and modified measles. In addition, a Newcastle disease virus trial will enroll children in Jerusalem.[1] Researchers from Spain published a recent report describing a few cases of oncolytic adenovirus given to children with neuroblastoma, with encouraging responses observed in two children.[2] One more oncolytic virus is in early development, Maraba, so at least eight oncolytic viruses are currently of interest for treating children with cancer.

This exciting field holds great promise for many reasons. After decades of exploring combination therapies that primarily utilize highly toxic treatments, 80% of all children diagnosed with a malignancy (in the most developed countries) can expect to still be alive after five years. While this denotes a significant degree of success, there are still 20% who do not survive five years. Added to this, the serious issue of late effects, late relapses, secondary malignancies, and increased morbidity continue to darken the future for childhood cancer survivors. Clearly more work is needed to find non-toxic and more effective therapies for all of these children. There is great potential for oncolytic viruses to dramatically solve these challenges – the increasing possibility of tumor-specific viruses that replicate in tumor tissue and kill tumor cells only while completely sparing normal tissue presents an extremely attractive scenario.

This report outlines the “state-of-the-art” of oncolytic virus therapy for children.

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A spotted history

An excellent review, “Oncolytic Virotherapy Reaches Adolescence” published August 2010 in Pediatric Blood & Cancer by Drs Adrienne Hammill and Timothy Cripe (Cincinnati Children’s), reads more like an intriguing historical account than a dry scientific treatise.[3] Beginning with anecdotal observations of infections followed by spontaneous remissions of various cancers documented since the mid-1800s, the authors trace the efforts of researchers to advance the understanding and use of oncolytic viruses. Numerous studies in the 1960s and 1970s were performed and remissions documented. However, some investigators planned and carried out unethical experiments, such as extracting viruses from infected patients and directly infecting other patients with body fluids, and even injecting human tumor cells into prisoners and patients without consent.[4] The resulting public outrage led to the modern era of robust regulatory oversight for all phases of clinical research. Meanwhile, interest in oncolytic virotherapy research diminished during the next few decades.

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A virus revival

Why then has there been a sudden resurgence of research in this field now? Renewed interest has soared the past decade because of dramatic progress in understanding cell processes, tumor biology and microenvironment, immunology, and the advent of recombinant DNA technology among many other advances. In the past, wild-type viruses carried the risk of uncontrolled infectious complications. Newly created attenuated viruses are harmless to normal tissue and engineered to be far more tumor-specific. Techniques have been developed and regulations defined to safely produce, purify, and administer the oncolytic viruses to patients. Many new viruses have been identified, modified, and tested on cancer cell lines and in animal models. Publications have exponentially increased, and hundreds of researchers in both academic and industry-sponsored laboratories are actively involved in cancer virotherapy research. The 2009 NCI funded research portfolio returns 532 results totaling over $200 million in a search with the keyword “oncolytic virus.”[5]

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Oncolytic virus trials for childhood tumors

These are indeed exciting times for advances in treating pediatric cancer, and rapid progress in opening these trials for children is the direct result of significant funding and support from pediatric cancer research non-profit charities such as Solving Kids’ Cancer in addition to public funding. In the Hamill review, four oncolytic virus trials for pediatric tumors are described including the background of preclinical studies and adult trials. Currently five oncolytic virus trials are open (or soon to open) for children in the US:

• Herpes simplex virus-1 (HSV1716) – intratumoral injection: CURRENTLY OPEN for enrollment for patients aged 13-30 years with solid tumors (non-CNS)
• Vaccinia (JX-594) – intratumoral injection: CURRENTLY OPEN for enrollment for patients for patients aged 2-21 years with solid tumors (non-CNS)
• Seneca Valley virus (SVV-001/NTX-010) – intravenous route: CURRENTLY OPEN for enrollment for patients for patients aged 3-21 years with solid tumors (non-CNS)
• Modified Measles virus (MV-CEA) – local injection into resected recurrent tumor bed: NOT OPEN/estimated to open first quarter 2011 for patients aged 2-21 years with recurrent medulloblastoma
• Reovirus (Reolysin) – intravenous route: NOT OPEN/estimated to open fourth quarter 2011, for patients aged 3-21 with solid tumors.

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Prior experience in adult tumors

HSV1716

The safety of intratumoral injection of HSV1716 virus has been studied in five phase I clinical trials in glioma, melanoma, and squamous cell carcinoma. No toxicities were observed, and evidence of tumor necrosis and viral replication in tumor were seen. Tumor response was seen in a glioma and melanoma patient.[3]

JX-594

The vaccinia virus is a poxvirus, and has been tested in five clinical trials using intratumoral injection from 1964 to 2001. In metastatic melanoma, 25/44 showed an objective response, with complete response in injected tumor site in 11/25  patients. In bladder cancer, 3 of 4 patients were in complete response four years later. Modifications to increase tumor specificity in vaccinia resulted in the JX-594 virus. Four trials have been launched in adults using both intratumoral and intravenous administration in several adult cancers with responses and stable disease observed. The recently completed phase II in hepatocellular carcinoma will have results released in 2011. Mild flu-like symptoms only were observed.[3]

SVV-001/NTX-010

A phase I of intravenous Seneca Valley virus (SVV-001) in 30 adults with advanced solid tumors (with neuroendocrine features) showed objective response in a carcinoid tumor and stable disease longer than 16 months in a lung cancer patient. A phase II is currently ongoing for lung cancer to determine if efficacy is improved in combination with chemotherapy.[3]

MV-CEA

The modified measles (MV-CEA) was tested in a phase I trial for ovarian carcinoma in 21 women with recurrent ovarian carcinoma by intraperitoneal injection. No dose limiting toxicity observed with fever, fatigue, and abdominal pain. A phase I Intra-tumoral MV-CEA for recurrent glioblastoma is ongoing at Mayo Clinic.[8]

Reovirus/Reolysin

Numerous studies have been completed in adults with the reovirus in various tumors with both intravenous and intratumoral injection. Indications of efficacy have been observed, with no toxicities beyond flu-like symptoms. More studies using combination therapies have been completed and are underway, including plans for a phase III with chemotherapy for head and neck cancers.[3]

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Delivering the virus to the tumor

Oncolytic viruses can be safely administered via intratumoral injection or intravenous route. The virus self-replicates in the tumor and can then spread throughout the body. Tumor kill in distant metastases has been observed, as well as vaccine-like effects with anti-tumor immune responses. The intravenous route delivers the virus systemically, but some viruses stimulate an immune response and the antibodies produced can interfere with the desired effect.  Ongoing research seeks to solve this challenge.

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Current status of pediatric trials

Investigators have provided updates on the oncolytic virus trials November 2010 for various pediatric solid tumors. The first child to receive an oncolytic virus in the US was treated with Seneca Valley (SVV-001/NTX-010) virus at the University of Minnesota in March 2010. As of November 2010 eight children (four with neuroblastoma, four with other solid tumors including carcinoid tumors) have been treated with SVV-001/NTX-010 at six different COG (Children’s Oncology Group) phase I consortium sites (MN, AL, PA, IN, TN, TX) with six children receiving the first dose level and two receiving the second dose level. Three young patients have been treated with HSV1716 (at lung, pelvic, and neck sites) at Cincinnati Children’s and the second dose level cohort will be open to enrollment December 2010 after routine safety review. The first child enrolled November 2010 in the JX-594 trial at Cincinnati Children’s with hepatocellular carcinoma. The reovirus trial has just been approved CTEP (Cancer Therapy Evaluation Program), and will be open at COG phase I consortium sites in 2011. This trial includes low-dose oral cyclophosphamide and children will be eligible to receive up to 12 cycles of the reovirus (given days 1-5 of each 28 day cycle). Plans to open the measles virus trial for recurrent medulloblastoma are also underway.

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Toxicities

Some children have had mild flu-like symptoms and some have had pain at tumor sites from tumor swell. No other serious toxicities have been observed, and virus clearance has occurred as expected. Many adult trials have established the safety of virus administration, as well as demonstrating responses and disease stabilization. A significant point to consider is the low “opportunity cost” for a child enrolling in an oncolytic virus trial—the risk of eliminating the child from further therapy options is very unlikely. Most of these trials require a month or less of observation for virus clearance, and no other toxicities are expected to affect eligibility for other trials, such as bone marrow suppression or organ toxicities. This provides a promising option for children with resistant disease because many current therapies contribute to cumulative organ toxicities.

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Future directions

New viruses have been recently identified and modified that demonstrate potent tumor specificity such as double-mutated Maraba virus in neuroblastoma.[6] These promising viruses deserve the attention of funding mechanisms and accelerated introduction to clinical trials. With encouraging results from adult trials being reported,[7] growing enthusiasm is appropriate for the use of oncolytic virus therapy in children.

More information on oncolytic virus trials in adults can be found in recent Molecular Therapy editorial [9], European Journal of Scientific Research [10], NCI Journal [11], and  companies involved in developing oncolytic viruses in a market analysis on BioMedReports.[12]. A 2009 review discusses preclinical work testing herpes simplex viruses in pediatric cell lines, including neuroblastoma.[13]

The chart below shows adult phase II and III oncolytic virus trials (click on the image below to go to the April 2010 JNCI article) [11]:

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References

1. Clinical Application of Intravenous New Castle Disease Virus – HUJ Oncolytic Virus in the Treatment of Advanced Glioblastoma Multiforme, Soft and Bone Sarcomas and Neuroblastoma Patients, Resistant to Conventional Anti- Cancer Modalities. NCT01174537
2. Discovery Medicine. Oct 2010; 53.  Oncolytic Virotherapy for Neuroblastoma.
3. Pediatric Blood Cancer. 2010 Dec 15;55(7):1253-63. Oncolytic Virotherapy Reaches Adolescence.
4. New England Journal of Medicine 2004; 351:628-630. Sins of Omission — Cancer Research without Informed Consent.
5. NCI Funded Research Portfolio 2009 (keyword: oncolytic virus)
6. Molecular Therapy. 2010 Aug;18(8):1440-9. Epub 2010 Jun 15. Identification of genetically modified Maraba virus as an oncolytic rhabdovirus.
7. Pediatr Blood Cancer. 2010 Dec 15;55(7):1253-63. Oncolytic Virotherapy Reaches Adolescence.
8. Personal communication, Dr Corey Raffel, Nationwide Children’s Hospital, Columbus, OH
9. Molecular Therapy 2010 18 (2), 233–234. doi:10.1038/mt.2009.314  Oncolytic Viruses: An Approved Product on the Horizon?
10. European Journal of Scientific Research, ISSN 1450-216X Vol.40 No.1 (2010), pp.156 -171. Oncolytic Viruses in Cancer Therapy
11. J Natl Cancer Inst. 2010 May 5;102(9):590-5. Epub 2010 Apr 26. Oncolytic viruses move forward in clinical trials.
12. BioMedReports, Nov 22, 2010. Oncolytic Viruses: Are They The Future of Cancer Therapy?
13. Molecular Therapy 2009  July; 17(7): 1125–1135. Herpes Simplex Virus Oncolytic Therapy for Pediatric Malignancies [full text]

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Three new oncolytic virus trials to treat neuroblastoma: vaccinia (JX-594), herpes simplex (HSV1716), and Newcastle Disease virus

Vaccinia JX-594

A Phase I, Open-Label, Dose Escalation Study of JX-594 (Vaccinia GM-CSF/Thymidine Kinase-Deactivated Virus) Administered by Intratumoral Injection in Pediatric Patients With Unresectable Refractory Solid Tumors

A phase I study using intratumoral injection of modified vaccinia virus derived from the smallpox virus is scheduled to begin accruing children 2 to 21 years old with refractory solid tumors, including neuroblastoma. The principal investigator is Dr Timothy Cripe and the trial is sponsored by Jennerex Biotherapeutics and Solving Kids Cancer. Locations are Cincinnati Children’s Hospital Medical Center in Ohio and Texas Children’s Hospital in Houston, and a  total of 15 will be enrolled. The Jennerex site shows a diagram of their oncolytic viruses in the pipeline (click on image):

Recent use of this virus is detailed in a 2009 review from Leeds in the UK:

JX-594 is a replication-competent Wyeth strain vaccinia virus that was genetically modified to inactive the endogenous thymidine kinase gene and to express human GM-CSF and LacZ genes. In development by Jennerex Inc and licensee Green Cross Corp, the modified virus is a novel therapy for treatment-refractive metastatic malignancies from various sites of origin. Targeted oncolytic virotherapy has demonstrated promise in preclinical studies, and more than ten viral species have subsequently entered clinical trials. JX-594 has been modified to augment the intrinsic targeting and oncolytic potential of the vaccinia virus and to enhance antitumor immunity by the expression of the GM-CSF transgene in situ. In vitro and in vivo animal studies have demonstrated the replication specificity of JX-594 for cancer cell lines and tumors, and the restriction of serum human GM-CSF expression to tumor-bearing animals, resulting in significantly reduced tumor burden and an increase in median survival. In phase I trials, JX-594 was well tolerated, with mild systemic toxicity reported. In a phase I trial in seven patients with melanoma, one partial response and one complete response after surgery were observed. In another phase I trial in patients with hepatic carcinoma, three out of ten evaluable patients had a partial response and six had stable disease; the MTD was also established. A phase II trial in patients (expected n = 30) with unresectable primary hepatocellular carcinoma was recruiting at the time of publication, with completion expected in March 2010, and a phase III trial in patients with hepatocellular carcinoma was planned for the second half of 2010. Further clinical investigations are needed to explore the potential of this agent as a single therapy and as part of multimodal treatment regimens.[1]

This oncolytic virus has been used to treat liver and other cancers, as reported in Lancet in this 2008 study from Korea. Details from the abstract:

JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer.

Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10.9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial. Patients received one of four doses of intratumoral JX-594 every 3 weeks at Dong-A University Hospital (Busan, South Korea). The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment.

Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated and had large tumours. Patients received a mean of 3.4 cycles of JX-594. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses. Three patients had partial response, six had stable disease, and one had progressive disease.

Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. [2]

This photo from Jennerex shows the needle developed for intratumoral injection.

Herpes Simplex Virus-1 Mutant HSV1716

A Phase I Dose Escalation Study of Intratumoral Herpes Simplex Virus-1 Mutant HSV1716 in Patients With Refractory Non-Central Nervous System (Non-CNS) Solid Tumors

This study opened in March 2010 and will accrue 18 young patients aged 13 to 30. This trial is also supported by Solving Kids Cancer lead by Dr Tim Cripe and open at Cincinnati Children’s. This particular oncolytic virus has been tried in squamous cell carcinomas, melanoma, and brain tumors.  A mouse study published by researchers from Mass General in 2008 revealed neuroblastoma tumor reduction with a related oncolytic virus. [4]

Newcastle Disease Virus (NDV)

Clinical Application of Intravenous New Castle Disease Virus – HUJ Oncolytic Virus in the Treatment of Advanced Glioblastoma Multiforme, Soft and Bone Sarcomas and Neuroblastoma Patients, Resistant to Conventional Anti- Cancer Modalities

This phase I/II study for recurrent or refractory solid tumors will begin accruing September 2010 at Hadassah Medical Organization in Jerusalem, Israel.  This trial uses the Newcastle Disease Virus systemically rather than intratumorally, and a total of 30 patients will receive daily doses of the oncolytic virus at least 5 days a week for a minimum of a year or until disease progression. For more information on Newcastle Disease Virus the University of Minnesota provides a helpful brief review of the use of NDV as an oncolytic virus.

References

1.  Curr Opin Investig Drugs. 2009 Dec;10(12):1372-82. JX-594, a targeted oncolytic poxvirus for the treatment of cancer. PMID: 19943208

2.  Lancet Oncol. 2008 Jun;9(6):533-42. Epub 2008 May 19. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. PMID 18495536

3. Recent Pat CNS Drug Discov. 2009 Jan;4(1):1-13.  Advances in oncolytic virus therapy for glioma. [full text]

4.  Clin Cancer Res. 2008 Dec 1;14(23):7711-6. Combination Immunotherapy for Tumors via Sequential Intratumoral Injections of Oncolytic Herpes Simplex Virus 1 and Immature Dendritic Cells. [full text]

Dr Michael Burke from the University of Minnesota is the Principal Investigator of the Seneca Valley Virus trial COG-ADVL0911:

“Seneca Valley Virus-001 in Treating Young Patients With Relapsed or Refractory Neuroblastoma, Rhabdomyosarcoma, or Rare Tumors With Neuroendocrine Features”

Dr Burke gave a presentation on this trial at the CNCF parent conference July 10, 2010.

By early July, this Phase I trial had enrolled three children (two with NB) since March 2010, with a planned accrual of 34 children, and is currently open at:

• Alabama ~ UAB Comprehensive Cancer Center
• California ~ Children’s Hospital of Orange County
• Illinois ~ Children’s Memorial Hospital – Chicago
• Indiana ~ Indiana University Melvin and Bren Simon Cancer Center
• Michigan ~ C.S. Mott Children’s Hospital at University of Michigan Medical Center
• Minnesota ~ Masonic Cancer Center at University of Minnesota
• Missouri ~ Siteman Cancer Center at Barnes-Jewish Hospital – Saint Louis
• Ohio ~ Cincinnati Children’s Hospital Medical Center
• Pennsylvania ~ Children’s Hospital of Pittsburgh
• Texas ~ Baylor University Medical Center – Houston
• Washington ~ Children’s Hospital and Regional Medical Center – Seattle

Seneca Valley Virus, or NTX-010, is the first picornavirus (small RNA virus) to be evaluated as an anticancer agent. This virus is very small–about one-fourth the size of adenovirus so can penetrate tumor cells and replicate rapidly. It is highly selective for cancer cells with neuroendocrine features and does not harm normal cells, humans lack pre-existing neutralizing antibodies (ie prior exposure in humans is very rare), does not cause disease in humans or animals, and not transmitted among people or animals. It was accidentally discovered in a laboratory growth medium, and thought to be naturally occurring in pigs. [1]

NTX-010 was tested first in adults, with a trial that opened in 10 locations in 2006 and enrolled 42 adults with tumors with neuroendocrine features. This trial was sponsored by Neotropix and the results of this phase I study were presented at the 2009 ASCO meeting:

NTX-010 is the first picornavirus to be evaluated as an anticancer therapeutic. A single IV dose of 10¹¹ vp/kg of NTX-010 is safe, has predictable viral kinetics, and shows promising activity against neuroendocrine tumors. [2]

A Phase II randomized study for small cell lung cancer has recently opened and will enroll 99 adults.[3]

Neotropix scientists published a summary of the preclinical work with Seneca Valley Virus on cell lines and mice in 2007, and the image below shows the response of SCLC small-cell lung cancer tumors in mice to a single infusion of the virus.

The authors concluded on p. 1632:

The life cycle of SVV-001 is very rapid and is completed within 12 hours, thus allowing for rapid spread to neighboring tumor cells and several rounds of virus replication before the development of an immune response. SVV-001 is a simple single-stranded RNA virus and therefore does not require an intermediate DNA step during replication, so there is no possibility for insertion mutagenesis of viral RNA into the host genome. Moreover, the genomes of picornaviruses carry no oncogenes that may induce tumors in animals. Finally, SVV-001 replicates in the mouse, which is a widely accepted relevant model in which to study toxicity and efficacy.

Nonpathogenicity in humans and animal species and stability of the viral genome in vitro and in vivo are two other desirable properties of oncolytic viruses. SVV-001 is not linked to any disease condition in pigs, the natural host of the virus (Hales LM, Jones BJ, Knowles NJ, Landgraf JG, Swenson SL, Skele KL, et al.: unpublished data). We found that systemic administration of the virus into immune-competent and immune-deficient mice was well tolerated and caused no toxicity. Moreover, to evaluate the ability of SVV-001 to adapt to replicate in nonpermissive cells, the virus was passaged intentionally three times in nonpermissive cell lines A549, H460, and Hep3B, and no virus was produced, suggesting that the virus did not change its tropism (data not shown). In addition, no antibody escape mutants of SVV-001 were produced in PER.C6 cells when SVV-001 was grown with media containing anti-SVV mouse hyper immune serum (data not shown). These data suggest that the genome of SVV-001 is stable.

Our study has several potential limitations. Although the in vivo efficacy data reported here were generated using immune-deficient athymic mice, it is unknown whether immune responses in cancer patients would limit the effectiveness of SVV-001 in patients and prevent repeat administration, if it was necessary. In addition, studies were done using subcutaneous tumor models using well-defined cell lines and, as such, may not simulate patients with metastases. Immune-competent and metastasis models are currently being explored to address these limitations.[4]

The virus is toxic to embryonic cell lines, so the first adult study required surgical sterilization of females who were of childbearing age.[5]

The preclinical pediatric testing was just published (Aug 2010) “Initial testing of the replication competent Seneca Valley virus (NTX-010) by the pediatric preclinical testing program” (p. 299):

NTX-010 shows high-level activity against selected cell lines and xenografts from the PPTP’s in vitro and in vivo panels. A single dose of NTX-010 induced complete responses in 8 of 10 of the rhabdomyosarcoma and neuroblastoma xenografts evaluated, including all 4 alveolar rhabdomyosarcoma xenografts studied. Of note is the similar sensitivity to NTX-010 in Rh30 xenografts (established at diagnosis) and Rh30R xenografts (established at patient relapse), suggesting NTX-010 has therapeutic utility in both chemosensitive and chemorefractory disease.[6]

Considering this trial for a child with relapsed or refractory neuroblastoma

Phase I studies are safety studies, so evidence of efficacy has not been established. Since phase I agents are usually tried in adults first, it is encouraging if responses are seen, but of course adults have different tumors (in the phase I adults with carcinoid tumors showed responses[2]). All of this information indicate some agents hold more promise than others. The attractive thing about this study is the lack of toxicity, and the short time commitment to the study (infusion of virus, then test blood and stool for 28 days or until virus clears).  A child with a small tumor burden, or a child with stable disease may be a good candidate for this trial since the risk of progression while on study may be minimal. As always, discussing treatment options with a trusted pediatric oncologist is essential.

References

1.  NTX-010 A Novel Mechanism Anti-Cancer Agent in Phase I/II Clinical Development (2007 Neotropix summary)

2. Rudin CM, Senzer N, Stephenson J, et al. Phase I study of intravenous Seneca Valley virus (NTX-010), a replication competent oncolytic virus, in patients with neuroendocrine (NE) cancers. J Clin Oncol 2009;27: abstract 4629.

3. Seneca Valley Virus-001 After Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Cancer; NCT01017601

4. J Natl Cancer Inst. 2007 Nov 7;99(21):1623-33. Epub 2007 Oct 30. [fulltext]

5. Safety Study of Seneca Valley Virus in Patients With Solid Tumors With Neuroendocrine Features;  NCT00314925

6. Pediatr Blood Cancer. 2010 Aug;55(2):295-303. PMID 20582972