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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Trial open at Penn State Hershey Medical Center

A Phase I Trial Combining Decitabine, IFN-gamma, and Vaccine Therapy for Patients With Neuroblastoma

The phase I trial will enroll 15 children ages 2 months to 17 years who have relapsed neuroblastoma.

The stated purpose:

This treatment study for relapsed high-risk neuroblastoma involves an autologous cancer testis (CT) antigen specific dendritic cell (DC) vaccine preceded by decitabine as a demethylating chemotherapy and IFN-gamma to stimulate an immune response.

The vaccine is given in the following schedule:

The neuroblastoma oral papers (OP2) presented on Friday October 22, 2010 at SIOP in Boston covered a range of topics including prognostic factors, targets, and stem cell contamination. This report will focus on the presentation on prognostic significance of segmental alterations in neuroblastoma tumors.

Accumulation of segmental alterations determines progression in neuroblastoma (O024)

Neuroblastoma tumor biology has long been an intense subject of study because of the heterogeneous nature of this disease. Looking at macro, micro, and genetic features reveals the differences in tumors, and why some children with neuroblastoma survive without treatment and others do poorly with the most intense treatments conceived. Now that technology is accessible to analyze genetic profiles, more precise risk can be assigned, and appropriate treatment given. Further, this analysis allows for understanding the evolution of tumor genetics as relapse and progression occurs.

Gudrun Schleiermacher from France presented on a study of numerical and segmental chromosome alterations in neuroblastoma tumors. This subject was a matter of interest at ANR in Stockholm as well, and this abstract was also presented at ASCO in June.[1]  This topic has been the subject of many abstracts at recent meetings, and several recent publications confirm the importance of this work [2-6].

Prior publication in 2009 from this French group included  a comprehensive overview of the genetic alterations of neuroblastoma and clinical significance. A series of 493 neuroblastoma samples was investigated by array-based comparative genomic hybridization and the analysis identified several types of profiles:

Tumors presenting exclusively whole-chromosome copy number variations were associated with excellent survival. No disease-related death was observed in this group. In contrast, tumors with any type of segmental chromosome alterations characterized patients with a high risk of relapse. The analysis of the overall genomic pattern, which probably unravels particular genomic instability mechanisms rather than the analysis of individual markers, is essential to predict relapse in NB patients. It adds critical prognostic information to conventional markers and should be included in future treatment stratification.[2]

Caren and collegues (Sweden) also concurred that these studies have:

implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment. [5]

Schleiermacher and colleagues analyzed 394 neuroblastoma tumors with array-based comparative genomic hybridization and linked the results to clinical data for outcomes. The tumor samples included all risk groups, and analysis was performed again in the event of relapse to discover changes in the tumor profile. The study confirmed that neuroblastoma tumors are characterized by two distinct genetic profiles — either numerical or segmental chromosome alterations.

Tumors were first divided into five groups based on genomic aberrations: numerical only, segmental only, MYCN amplified, numerical and segmental, MYCN and numerical. The tumors with only numerical alterations had the best prognosis. No breakpoint pattern was observed in the segmental-only group which contained up to 1000 breakpoints. Seven or more breakpoints portended a worse prognosis, and was an independent factor in multivariate analysis. More breakpoints were correlated with higher age at diagnosis, higher stage of disease, and higher risk of relapse.

Tumors with only numerical alterations at diagnosis frequently acquired segmental alterations upon relapse. This could not be strictly attributed to chemotherapy since tumors treated with surgery only had acquired segmental aberrations. The authors concluded that tumor progression is directly linked to an accumulation of segmental alterations.

References

1. J Clin Oncol. 2010 Jul 1;28(19):3122-30. Epub 2010 Jun 1. Accumulation of Segmental Alterations Determines Progression in Neuroblastoma. PMID: 20516441

2. J Clin Oncol. 2009 Mar 1;27(7):1026-33. Epub 2009 Jan 26.  Overall genomic pattern is a predictor of outcome in neuroblastoma. PMID: 19171713

3. British Journal of Cancer (2007) 97, 238–246.  Chromosomal CGH identifies patients with a higher risk of relapse in neuroblastoma without MYCN amplification. [free fulltext]

4. Am J Pathol. 2010 Jun;176(6):2616-25. Epub 2010 Apr 15. 2p24 Gain region harboring MYCN gene compared with MYCN amplified and nonamplified neuroblastoma: biological and clinical characteristics. PMID: 20395439

5. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4323-8. Epub 2010 Feb 9.  High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset. [free fulltext]

6. N Engl J Med 2005; 353:2243-2253.  Chromosome 1p and 11q Deletions and Outcome in Neuroblastoma. [free fulltext]

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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Swedish researchers share the prize at SIOP for winning posters on neuroblastoma

Drs Fredrik Hedborg (Uppsala University) and Catarina Trägar (Karolinska Institute) shared the top prize for neuroblastoma research poster at SIOP 2010.

PH036 Age dependent genotypes in high-risk neuroblastoma: MYCN amplification is a fast track to aggressive disease whereas segmental deletion of 11q implies a more complex, multi-step tumor evolution (p. 896)

Dr Hedborg and colleagues explored the age-dependence of the genetics of aggressive disease in 30 high-risk and 4 intermediate-risk children. MYCN amplification was present in all but one of the 12 youngest children (mean age 29.6 months, range 4 – 30 months) and MYCN amplification was absent in all but one of the 11 oldest (mean age 65.6 months, range 57 – 169 months), and 12/18 of these had 11q loss. This age differential was confirmed by the Swedish Childhood Cancer Registry where mean ages at diagnosis were 29.4 months for MYCN amplified (n=65)  and 54.8 months for MYCN-non-amplified (n=46). Significantly more segmental chromosome aberrations were noted in older children with 11q loss, and this data suggest that two major pathways exist in the development of aggressive neuroblastoma. MYCN-amplification tumors in younger children result from fewer but rapid genetic events, whereas tumors in older children with 11q loss are the result of a slower, multi-step process.

PH038 Differences in biological features and survival improvement between genetic subsets of high-risk neuroblastoma indicate the need of adapted treatment (p. 897)

Dr Trägar and colleagues also looked at Swedish registry data and noted older age for 34 children with 11q deletion (median age 41 months) and longer median survival of 40 months compared to children with MYCN-amplified tumors (median age 22.5 months, median survival 16 months), but both groups had similar 8 year overall survival rate of ~35%.

Survival data were reported as follows:
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The researchers concluded that 11q-deletion tumors present later than MYCN-amplified tumors, but noted that prognosis is similar, and suggest further consideration is needed for therapeutic approaches for 11q-deleted tumors since prognosis has not improved for this group since the 1980s.

Both research teams have contributed to increased understanding concerning the relationship between age and biology of neuroblastoma high-risk tumors.

Travel to this meeting was supported by:

• Lighthouse Laboratories
• Max’s Ring of Fire
• Magic Water
• Friends of Will
• Solving Kids’ Cancer
• Children’s Neuroblastoma Cancer Foundation

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