The Story of the Band of Parents and humanized 3F8

by Caryn Franca and Shirley Staples

It was summer of 2007.  A group of parents had asked Dr. Nai-Kong Cheung to meet and update them on new treatments for neuroblastoma at Memorial Sloan-Kettering Cancer Center.  Most had children with relapsed neuroblastoma; all knew the terrible odds.  Dr. Cheung, head of the neuroblastoma program at MSKCC, and a long-time proponent of antibody therapy, met with the group at Ronald McDonald House.  After the presentation, one dad posed a question.  “What,” he asked, “do you need, to give our children more treatment options?”   “Money” was the simple, yet daunting answer.

Dr. Cheung then described an important research goal—the development of a new, humanized form of the 3F8 antibody that had been used since 1986 to treat neuroblastoma at MSKCC.  Researchers believed the new version, “Hu3F8,” had the potential to be many times more effective in fighting neuroblastoma, but Dr. Cheung estimated that $2-3 million dollars would be needed to fund the development of the drug.  After the meeting, parents excitedly discussed this revelation. The consensus was that they could and would do whatever was necessary to make hu3F8 treatment a reality.  A crusade was born.

Within a matter of days, an online group had been created and parents had begun brainstorming.  The name of the new parent group came from a California dad:  the “Band of Parents.”  One group of parents began the discussions and eventually the legal steps to form a tax-exempt foundation. Seven dads began planning to bike across the United States to raise funds and awareness–a ride they called “The Loneliest Road” to reflect the daily challenges facing neuroblastoma families. Ultimately they raised over $200,000 for hu3F8. Soon there were 60 families in the “BOP,” and the energy was palpable, from garage and jewelry sales, to writing fundraising letters to friends, to telling individual stories to local newspaper reporters.

Donations began to pour in, some from as far away as the Middle East.  As December approached, a New York City mom conceived the idea of a massive bake sale of holiday cookies.  Over several weeks, parents, friends, and volunteers from the culinary world baked, packaged and shipped 96,000 cookies from a small rented kitchen, raising several hundred thousand dollars. A few months later, families in Virginia banded together to organize the “Rock’n for a Cure.”  Band of Parent funds were mounting.

The efforts that followed were too many and varied to detail, but the key phrase is “banded together” – parents of children with neuroblastoma, along with family, friends and perfect strangers, came together to raise the funds needed to create a new treatment option for children with neuroblastoma.  Great personal determination was required.  As the months passed, many Band of Parents members lost their child to neuroblastoma – including the parent who coined the name “Band of Parents,” the mother who conceived the cookie bake-off, three of the bikers on The Loneliest Road, and the first three presidents of the BOP.  However, parents pushed forward despite the grief and loss felt by all in the group.  Golf tournaments, yard sales, and concerts were organized, sometimes from hospital bedsides; holiday decorations, tee-shirts, and greeting cards were designed and sold.  Last but not least, the dedicated neuroblastoma team at MSKCC cleared the regulatory and many other hurdles to taking a new drug from the laboratory to the clinic.

In August 2011 the day finally arrived that so many had worked for and dreamed of.  A new phase 1 trial of hu3F8, a drug specifically designed for the treatment of neuroblastoma, opened at Memorial Sloan-Kettering, and the very first child received the promising new treatment. Ordinary people had accomplished an extraordinary labor of love. For all those involved, this will be remembered as a time when it was shown that, by banding together, a group of parents could give new hope in the battle against an aggressive childhood cancer.  Today, the members of the Band of Parents are still working to raise awareness and funding for research, so that someday no child will suffer from the terrible disease of neuroblastoma.

Editors note: the trial opened in August 2011 and is listed here: http://clinicaltrials.gov/ct2/show/NCT01419834

The trial allows for relapsed or refractory NB with evidence of disease, and is given without cytokines IL2 or GM-CSF.

New phase I trial opening soon at University of Alabama, Birmingham

This trial will enroll 6 patients at 2 dose levels for IL2 given with fixed dose of zoledronic acid. Zoledronic acid will be given IV once every 3 weeks, and daily subcutaneous IL2 given weekdays for 2 weeks.

Patients must have evidence of disease and have not received prior antibody therapy with IL2.

See NIH listing for rationale:

To further explore means of harnessing the immune system to attack NB, the investigators are studying the combination of zoledronic acid (ZOL) and interleukin-2 (IL-2). ZOL has been demonstrated to have direct anti-neuroblastoma effects in laboratory studies. ZOL also augments the production of tumor killing white blood cells called gamma-delta T cells. When used in combination with IL-2, ZOL is capable of eliciting potent anti-cancer effects in patients, in part, via the expansion of gamma-delta T cells. In this present trial the investigators aim to study the tolerability of the combination of ZOL and IL-2 in pediatric NB patients. Patients will also be monitored radiologically for tumor response to therapy. Correlative biological studies will study the ability of this drug combination to elicit the production of NB killing gamma-delta T cells in children.

Joseph Pressey, MD
Assistant Professor of Pediatrics at University of Alabama at Birmingham, and Director, Experimental Therapeutics Program

Dr. Pressey is a graduate of the University of Georgia and the Medical College of Georgia. After completing his pediatric residency at the Children’s Hospital Medical Center in Cincinnati, he trained in pediatric hematology-oncology at the Children’s Hospital of Philadelphia.  Dr. Pressey’s primary clinical interest is in the treatment of pediatric solid tumors, with a particular focus on pediatric sarcomas.  He serves as UAB’s principal investigator for the Children’s Oncology Group Phase I developmental therapeutics program and the Sarcoma Alliance for Research Through Collaboration (SARC) consortium.  Through these organizations, Dr. Pressey is interested in providing patients with access to cutting edge therapies for all types of relapsed and refractory cancers.  Dr. Pressey’s primary research interest is the biology and treatment of sarcomas. Working with others at UAB, he is studying pediatric tumors with the intent of finding more effective and tolerable therapies.  

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/

Antibodies for relapsed neuroblastoma

Given that recent studies such as COG-3973 [1] and others reveal that half or more of all children with high-risk neuroblastoma are refractory to induction or relapse, and that the majority worldwide never received antibodies as part of frontline treatment, there is currently a significant demand for access to antibody treatment after relapse.

Currently, the only offerings of antibodies for relapse are:

• 3F8 (murine) at Memorial-Sloan Kettering Cancer Center,
• ch14.18/CHO (chimeric) at Griefswald in Germany, and
• hu14.18K322A (humanized) at St Jude’s, Memphis TN

Memorial-Sloan Kettering Cancer Center (MSKCC) in New York has been using 3F8 antibodies in the relapse setting for 20 years or more [2]. Ideally the relapsed disease must first be reduced to minimal or undetectable levels. Dr Kushner presented at ASCO in 2007 showing that 20% of children with bone marrow refractory disease became long term survivors [3]. Bone disease and soft tissue relapses are less responsive to 3F8. Since MSKCC uses a 100% mouse antibody, the child can make antibodies against the 3F8, called HAMA, for human anti-mouse antibodies. These antibodies prevent further treatment with 3F8, unless HAMA can be reduced using Rituxan (rituximab) and waiting for HAMA to subside. Rituxan, also an antibody, targets CD20 that is highly expressed on B-cells which are responsible for making antibodies. Prior to beginning treatment with 3F8, high doses of cyclophosphamide are given (4200 mg/m2) in order to reduce the immune system’s capacity to produce HAMA.

MSKCC has opened various 3F8 trials in the past decade, including heat-modified [4], with beta-glucan, high-dose, and use after donor (parent) NK cells, with the latter two open currently for relapse. The Band of Parents funds neuroblastoma projects at MSKCC and anticipates a humanized version of 3F8 and a “turbo” version of 3F8 to be available in 2011 for children with relapsed or refractory disease. In short, antibodies have been available for relapse at MSKCC for the past 20 years.

Meanwhile, the chimeric (25% mouse/75% humanized) antibody ch14.18 given with IL2 and GM-CSF that improved the two-year event-free survival by 20% over the no-antibody arm is now available to all children as part of frontline treatment in the COG (North America and Australia). Randomization was stopped after early review in March 2009, and the study continues to accrue for more safety and efficacy data (COG-ANBL0032), as well as an additional study open for the registration data to gain FDA approval (COG-ANBL0931). This antibody is not currently available to relapsed children in the COG. A NANT trial for relapsed children will open in late 2011 with ch14.18 in combination with lenalidomide (stimulates production of natural cytokines in the tumor environment), and NED (remission) after relapse will be eligible.

In Europe, the availability of ch14.18/CHO (produced from hamster rather than mouse cells) for frontline treatment is limited to those treated on the current SIOP high-risk protocol. The study has been modified several times since it opened in 2002. These randomization arms have closed:

• G-CSF or no G-CSF –all get G-CSF after showing less neutropenia, fever, hospitalization days, chemo delays [5]
• busulfan + melphalan (BuMel) or carboplatin + etoposide + melphalan --all now receive BuMel for survival advantage [not published as of 3/2011]
• ch14.18 or no ch14.18 –all get ch14.18 with or without subcutaneous IL2 [trial listing not updated as of 3/2011]

Dr Holger Lode has a trial open to treat relapsed and refractory neuroblastoma with ch14.18 and IL2 at Griefswald in Germany. In the past year families have traveled from the UK, Australia, and other countries to access this treatment.

A COG trial using hu14.18-IL2 with GM-CSF and cis-retinoic acid is opening very soon, and will be open to relapsed and refractory neuroblastoma with measurable or detectable disease (second response will not be eligible). This is a humanized antibody with IL2 fused directly to the antibody. It has completed phase I and phase II studies in neuroblastoma and melanoma, and a pilot is ongoing for melanoma at University of Wisconsin-Madison.

Now that hu14.18-IL2 and ch14.18 are licensed to Apeiron and United Therapeutics respectively, availability for trials will be governed by these companies.

Extrapolating the annual incidence of high-risk neuroblastoma and relapse, a minimum of 800 children in SIOP and COG countries will require ch14.18 for frontline treatment every year, and potentially another 400 for relapse treatment. Hopefully, this demand will be satisfied soon. Since melanoma expresses GD2 also, these anti-GD2 antibodies may be in demand to treat melanoma also.

References

1. Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG A3973) study. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9505

2. GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. Blood. 1989 May 15;73(7):1936-41.

3. Anti-GD2 monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) for primary refractory neuroblastoma (NB) in bone marrow (BM). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9502

4. Successful Multifold Dose Escalation of Anti-G_D2 Monoclonal Antibody 3F8 in Patients With Neuroblastoma: A Phase I Study; J Clin Oncol. 2011 Feb 22.

5. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul 20;28(21):3516-24. Epub 2010 Jun 21.

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-

Many therapies, robust rationale needed

For years I have (obsessively) tracked clinical trials and therapies available to children with relapsed and refractory neuroblastoma, driven by hope that curing relapsed NB is possible. Since there are many therapies for “unspecified solid tumors” as well as specifically for neuroblastoma, the resulting variety of trials is quite astounding.

I started tracking these trials for possibilities for my son, discussing with other astute parents, and watching and praying for responses in their children to new treatments. I searched for meeting abstracts for unpublished results, and scrutinized the published results of trials. Between the heterogeneity of the disease and the varied treatment paths of each child the comprehensive study of effective relapse therapies is nearly impossible.

A parent naturally wants to know what options are available when their child is fighting for survival–but far more critical is knowing which option to choose at a given point in time. Finding all the options is conceivable, but determining the best possible option is a completely different problem. The question “What is available?” is easy to answer. The question “What should we do?” is not easy to answer.

In part, this activity led to a bigger project. Several volunteers (about 30 in all) worked on a “NB Parent Handbook” during the period 2006 – 2008 for Children’s Neuroblastoma Cancer Foundation. The entire book (220 pages) can be found on the CNCF site at cncfhope.org. The project is ongoing–new chapters are being added and material is being updated. I am currently updating the relapse chapter.

My purpose in posting this update on relapse treatment is two-fold:

1 – draw attention to the Handbook project and attract more help

2 – generate some dialogue concerning the question of relapse therapy — is a “rational” approach even possible?

Approach to relapse therapy differs widely from one study group to another, and one institution to another. There are no firm rules or universal recommendations, although one study group has recently recommended a very general plan for NB relapse treatment using salvage chemotherapy and MIBG only.  Much depends on the experience of the treating oncologist, careful consideration of the child’s history and status, and trials that may be open and accruing at the local institution.

What makes this landscape so incredibly complex is that there are many options, but the options are spread far and wide. Once a parent begins to consider options at a distant facility, the close oversight of the oncologist most familiar with the child is often jeopardized, and the parents have to make choices based on limited information.

It is impossible to describe just how terrifying and overwhelming it is for a parent to walk away from a child’s trusted primary oncologist and the loyalty developed for the home hospital, into the unknown. An unintended but serious consequence is the risk of the parent assuming full responsibility for the outcome–especially when things do not go well.

“Of all the treatments available, what is best for my child at this point in time?”

Think about how difficult this is to answer. The primary oncologist has a limited set of treatments to offer, and limited experience with treatments that are not offered at the home hospital. This creates a difficulty for the parents when they look beyond the confines of the home hospital, and strive to understand the potential for treatments available elsewhere. What we need is an oncologist who is familiar with every treatment and intimately knows the patient, and can recommend the best course of action in a thoroughly objective manner. But the reality is — that is asking too much — no oncologist has the time to scrutinize 50 or 100 open trials in addition to many off-the-shelf therapies to determine the best fit for a particular child. There is no incentive to send patients away, either.

So what is the solution? Is there a solution? I don’t know. That is why I am asking for feedback.

The medical community recognizes that there is a role in this arena for patient advocates. However, the patient advocate role presents a grave quandary — the advocate may be trusted for lack of any agenda other than concern for a child’s life, but the patient advocate is not a doctor and not qualified to recommend any treatment decisions.

Your feedback, thoughts, ideas, concerns, and brainstorms are greatly appreciated. What if you had a comprehensive list of every treatment possible, right now. How would you chose the best treatment for a given situation? What would help you the most? What do you think?

An outline of the of the draft follows — see the CNCF website for the full chapter (pages 113- 123).

Dealing with Relapse — draft outline

(treatments discussed are being updated now)

Beginning Relapse Treatment.

Relapse Treatment Rationale

Your doctor will take into consideration many factors when recommending treatment for relapse:

• Age of child
• How long the child was in remission after treatment
• Where disease is located
• How much disease (tumor burden)
• Rate of tumor growth
• Prior treatment history
• Organ function
• Available stem cells
• Changing characteristics of the child’s NB, or new information
• Goals of treatment

Treatments for relapse vary in approach and intensity.

Can we know what will actually work against my child’s NB?

• High-dose chemo/radiation.
• Medium-dose chemo.
• Low-dose chemo.
• Targeted drugs (“small molecules”) and biologics.
• Immunological treatments – antibodies.
• Immunological treatments – vaccines and viruses.

Second remission treatment issues.

Special issues with late relapse.

Maximizing your child’s treatment options is an important part of the relapse decision process.

Weighing quality of life and other considerations.

Investigating doctors and clinical trials.

It is common for children to see one or more of the following treatment categories during the battle against relapse:

• Enrollment on phase I or II clinical trials. These may be specific to NB or for unspecified solid tumors. Phase III studies are rare for relapsed pediatric tumors including NB.
• Treatment “per” a clinical trial protocol although not enrolled, if not eligible and drugs are already FDA approved.
• Treatment with “off the shelf” agents that are FDA approved.
• Treatment on a “compassionate use” basis with drugs not yet FDA approved.

Phase I and Phase II distinctions.

Timing of entry.

Interpreting “response” from study reports.

Risks and benefits of treatment.

SUMMARY

The rigors of relapse treatment cannot be minimized. You may be consulting with new and different doctors, traveling far from home for your child’s treatment on various clinical trials, weighing difficult quality of life issues for your family, and at times making treatment decisions based on a leap of faith. An oncologist with experience in treating relapsed NB, and equally importantly, someone you feel comfortable with and can communicate with effectively, is the key resource in making your treatment decisions. However, the more informed you are, the more comfortable you will feel that you have made the best possible choices for your child.

There are successes in relapse situations.  Unfortunately, because the relapse population involves such variation in relapse sites, in amount of disease, types of treatments tried, multiple treatment centers, and many other variables, it is virtually impossible to report long-term survival statistics. Even so, the reports of long-term survivors in some studies, the increasing numbers and approaches of available treatments, and the anecdotal evidence — all suggest that the prospect for long survivorship after relapse is improving.  There is increasing hope for relapsed children, and having an NB team who expresses and shares your hope is also essential to this stage of the battle.

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:

New trial for neuroblastoma opens at University of North Carolina – Chapel Hill

Temsirolimus and Valproic Acid in Treating Young Patients With Relapsed Neuroblastoma, Bone Sarcoma, or Soft Tissue Sarcoma

This phase I study will enroll 20 patients age 2 to 18 to determine the maximum tolerated dose of temsirolimus in combination with valproic acid, as well as safety, pharmacokinetics, and progression-free survival. Principal investigator is Dr Julie Blatt.

Valproic acid (VPA) has been used to treat epilepsy for decades. Recent research has show VPA to be a histone deacetylase inhibitor (HDACi), cell cycle modulator, and an antiangiogenetic agent. VPA also induces tumor cell death. Czech researchers published in March 2010 :

Preclinical data suggest that the anticancer effect of chemotherapy is augmented when VPA is used in combination with cytostatics. Besides the effects of pretreatment with HDAC inhibitors, which increases the efficiency of 5-aza-2′-deoxycytidine, VP-16, ellipticine, doxorubicin and cisplatin, pre-exposure to VPA increases the cytotoxicity of topoisomerase II inhibitors. There are two suggested cell death mechanisms caused by potentiation of anticancer drugs by HDAC inhibitors that are neither exclusive nor synergistic. The first involves apoptosis and can be both p53 dependent or independent; the second involves mechanisms other than apoptosis. In resistant chronic myeloid leukemia (CML), VPA restores sensitivity to imatinib. We have demonstrated the synergistic effects of VPA and cisplatin in neuroblastoma cells. VPA can be taken orally, crosses the blood brain barrier and can be used for extended periods.[1]

There are 229 valproic acid clinical trials listed in the NIH database; 68 are recruiting and 26 are for cancer conditions. There are 88 temsirolimus trials currently open to treat cancer.

In 2008 Italian researchers reported on the mechanism of cell death from valproic acid on 2 NB cell lines:

To our knowledge, this is the first demonstration of an HDAC inhibitor-dependent activation of the p53 pathway in neuroblastoma cells known for an abnormal p53 function that is responsible for their resistance to chemotherapy. As a consequence of this ability to restore p53 function, we consider HDAC inhibitors to be a promising class of drugs for the treatment of chemoresistant neuroblastoma tumours.[2]

Temsirolimus is a specific inhibitor of mTOR (mammalian target of rapamycin) and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells. FDA approval was granted in 2007 for the treatment of advanced renal cell carcinoma. It was used previously in a frontline NB study at St Jude’s. The NIH clinical trials site currently lists 15 open trials for children with solid tumors using temsirolimus in combination with a wide range of other agents.

There is apparently no published data (or submitted meeting abstracts) in the medical literature for the preclinical work using the combination of temsirolimus and valproic acid on cancer cell lines.

References

1. Curr Drug Targets. 2010 Mar;11(3):361-79. Valproic Acid in the complex therapy of malignant tumors. PMID: 20214599

2. Br J Pharmacol. 2008 Feb;153(4):657-68. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. PMID: 18059320 [free fulltext]

New Approaches to Neuroblastoma Therapy (NANT) consortium offers trials for relapsed and refractory neuroblastoma

Dr Kate Matthay spoke at the Children’s Neuroblastoma Cancer Foundation CNCF parent conference in Chicago July 10, 2010, detailing the status of several NANT trials. She mentioned that these trials open and close periodically, so contacting the principal investigator is the best way for an interested parent to get the most current information about the trial.

NANT is a consortium of researchers and investigators that now includes 15 institutions in North America, lead by Dr Kate Matthay (UCSF) and Dr Judith Villablanca (CHLA). NANT was formed in 2000 as a result of National Cancer Institute (NCI) award for a proposal submitted by Dr Robert Seeger.

Current member institutions are:

• C.S. Mott Children’s Hospital, University of Michigan – Ann Arbor, MI
• Children’s Healthcare of Atlanta (CHOA) – Atlanta, Georgia
• Childrens Hospital and Regional Medical Center – Seattle, WA
• Children’s Hospital Boston, Dana-Farber Cancer Institute – Boston, MA
• Childrens Hospital Los Angeles – Los Angeles, CA
• Children’s Hospital Medical Center – Cincinnati, OH
• Childrens Hospital of Philadelphia – Philadelphia, PA
• Cook Children’s Health Care System – Fort Worth, TX
• Hospital for Sick Children – Toronto, Ontario Canada
• Lucile Packard Children’s Hospital – Palo Alto, CA
• Morgan Stanley Children’s Hospital of New York-Presbyterian (Columbia) – New York, NY
• Texas Childrens Cancer Center, Baylor College of Medicine – Houston, TX
• University of California, San Francisco – San Francisco, CA
• University of Chicago Comer Children’s Hospital – Chicago, IL
• University of Wisconsin Comprehensive Cancer Center – Madison, WI

It is significant to note that the core NANT investigators are the ones who conducted the research in the 1990s that established the current global standard of care for neuroblastoma, including the use of stem cell transplant and cis-retinoic acid. The NANT trials that are planned and conducted now for relapsed and refractory neuroblastoma provide the rationale for better future frontline therapies.

Open trials are:

• N99-02: Modulation of Intensive Melphalan (L-PAM) by Buthionine Sulfoximine (BSO) (NSC-326321) and Autologous Stem Cell Support For Recurrent High-Risk Neuroblastoma (NCI 68).
• N2004-03: A Phase I study of intravenous fenretinide in pediatric neuroblastoma.
• N2004-04: A Phase I Study of Fenretinide Lym-X-Sorb^TM (LXS) Oral Powder in Patients with Recurrent or Resistant Neuroblastoma (IND # 68,254)
• N2004-06: Irinotecan and Vincristine with ¹³¹I-MIBG Therapy for Resistant/Relapsed High-Risk Neuroblastoma
• N2007-01: A Phase 2a Study of Ultratrace^TM Iobenguane I 131 in Patients with Relapsed/Refractory High-Risk Neuroblastoma
• N2007-02: A Phase I Study Of Bevacizumab With Bolus And Metronomic Cyclophosphamide And Zoledronic Acid In Children With Recurrent Or Refractory Neuroblastoma
• N2007-03: Vorinostat and MIBG in Recurrent or Resistant Neuroblastoma Patients

Dr Matthay presented an update on NANT drug trials, and Dr Greg Yanik spoke about trials using MIBG radiotherapy.

CEP-701

In her presentation Dr Matthay noted that new NANT trials will focus on the use of approved agents to avoid the unfortunate circumstance when a company decides to drop a new drug because of lack of efficacy in other cancers. This is what happened to CEP-701, a Trk inhibitor, even though it was granted orphan drug status in 2006. In 10 dose levels given to 47 patients no MTD (maximum tolerated dose) was reached. There were 2 partial responses and 9 stable disease in the neuroblastoma relapse/refractory children.

Oral fenretinide, IV fenretinide

A new phase I trial using the oral powder formulation of fenretinide is open for relapsed or refractory children, and those in a second remission are also be eligible. An arm will include the use of the antifungal drug ketoconazole to help raise the plasma levels of fenretinide. A phase I trial using IV fenretinide has also opened, and a video consent explains the trial. The results of the first phase I oral powder was presented at ASCO in 2009, showing 4 complete responses and 6 stable disease in 30 patients.[1]

BSO/Melphalan

As of July this phase I trial accrued 18 patients with dose levels 20-64 mg/m2. The next dose level is 80 mg/m2. Total to be accrued is 30. A video consent explains this study in more detail.

Zometa + Cytoxan

The phase I has been completed and responses are being evaluated. A new phase I has opened that uses intravenous and oral Cytoxan in combination with zometa and Avastin (a humanized antibody that targets VEGF-A or vascular endothelial growth factor A). Since December 2009 6 patients have enrolled.

Vorinostat (SAHA) and cis-retinoic acid

SAHA, approved for lymphoma, is a histone deacetylase inhibitor (HDACi) and slows neuroblastoma growth. It has shown preclinical synergy with cis-retinoic acid.

Aurora A kinase inhibitor

Aurora A kinase inhibitor has shown increased effectiveness against MYCN-amplified cell lines, and NANT is planning to combine this inhibitor with irinotecan and temozolomide in a new trial.

Emphasis on older patients

Neuroblastoma normally affects very young children, but the needs of the small population of adolescents and young adults also require special attention. This is becoming a new focus for NANT, first demonstrated by the raised age limits for NANT trials to 30. Some NANT investigators see a large number of teens and young adults with neuroblastoma.

References

1. J Clin Oncol 27:15s, 2009 (suppl; abstr 10009)