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]:

adult oncolytic virus trials in phase II and III

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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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