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.  

Randomization to ch14.18 alone challenged, UK court rules in favor of child

The SIOPEN trial now accruing in 20 countries in Europe randomizes children to the antibody ch14.18 alone or ch14.18 with subcutaneous IL2. Part of this trial was amended after the March 2009 release of the Children’s Oncology Group early results showing 2-year event free survival of 66% with ch14.18, IL2, and GM-CSF versus 46% in children who received no antibody treatment. Both groups received cis-retinoic acid (isotretinoin). SIOPEN began accruing in the fall of 2009.

GM-CSF (Leukine or Sargramostim, a cytokine acquired by Genzyme) is not available in Europe. Ch14.18 was used without cytokines in a German trial and not reported to improve survival in a 2004 study (non-randomized) “Compared with oral maintenance chemotherapy and no consolidation treatment, ch14.18 had no clear impact on the outcome of patients.” In a 2011 publication, the German’s reported on long-term follow-up and  concluded that ch14.18 antibody therapy “may prevent late relapses.” In an April 2010 interview with Dr John Maris discussing the results of the COG trial, Dr Maris said: “for the cancer community in general, this is the first study to show that adding in the cytokines, the chemicals to rev up the immune system, are an important piece of the picture. Now, we didn’t study whether or not antibody alone, or if you need the GMCSF or the IL2 or both. We may never know that, but what we do know is that the whole package is effective, so now our obligation is to build on that, and our future clinical trials will take this result and try to improve upon that.”

The family of a child randomized to ch14.18 alone challenged the NHS trust and the court ruled that “it would be in her best interests to receive immunotherapy treatment that includes isotretinoin, anti-GD2 and IL2.”

The press release is below:

children’s cancer charity neuroblastoma alliance uk celebrates high court order against nhs trust

3 August 2011: The Neuroblastoma Children’s Cancer Alliance UK is today celebrating a High Court order that it is in the best interests of a child with neuroblastoma to receive a combination of immunotherapy drugs, if she withdraws from a clinical trial in which she had been randomly allocated to receive a single drug.

The Neuroblastoma Alliance UK, which was until recently known as the 2Simple Trust, helps families affected by neuroblastoma, an aggressive childhood cancer of the nervous system. The charity has supported the family during the legal case and has funded treatment for the child in the USA, as – despite the order – the NHS Trust, in the South of England, said it was unable to confirm it could provide the drugs in the UK to the mother.

“We are over the moon about this judgement. While we welcome further research, the interests of today’s children must come first. This mother was not prepared to accept the status quo and fought for her child to receive the drugs in the UK. We’re delighted she won this order and her hard work in taking this matter to court is likely to help many more parents in the future,” said Alison Moy, Chief Executive of the Neuroblastoma Alliance UK.

Anne-Marie Irwin, a solicitor at Irwin Mitchell, who helped the mother bring her case to the High Court said: “It was a hard fought battle to achieve this significant legal step for our client. Even though this order is too late for many, including the family of the claimant who have been forced to move to the USA so that their daughter has the best chance of survival, it is a step in the right direction for families who want their children to receive the best available treatment in the UK.”

The four-year-old child – known as CB* – suffers from high risk neuroblastoma, an advanced form of the cancer that has a very poor prognosis. The child is in the final stage of neuroblastoma treatment, known as immunotherapy. In the UK, immunotherapy treatment is only available to children that enrol onto a randomised trial, where they are randomly allocated either one or two drugs by a computer based in Austria*².

Last year, a study published in the New England Medical Journal in America, reported that giving children three drugs*³ – including two of the drugs being tested in the UK trial – during immunotherapy resulted in a 20 percent lower relapse rate and an 11 percent higher survival rate over a two year period.

When the mother heard in June that her child had been allocated to receive only one of the two drugs available in the UK, she decided to take her NHS Trust to court.

“When I heard that a computer had randomly selected my child to receive one of the three drugs that American scientists have shown can save a child’s life, I decided to take action,” said the mother. “Given that American scientists have already proven the effects of the three drugs in a clinical trial, why do UK doctors need to continue experimenting on children? I didn’t want my little girl to be part of this experiment.”

On 23 July, High Court judge Mr Justice Ryder ordered*⁴ that if the child withdrew from the clinical trial, it would be in her best interests to receive both drugs. This interim order opens the way for other neuroblastoma sufferers, who have only been allocated one drug in the trial, to challenge the decision.

The NHS Trust resisted CB’s application and has not yet confirmed that it would provide the drugs to the mother outside the trial. On the 22 July, the family travelled to the US, where CB started immunotherapy treatment on 25 July. The Neuroblastoma Alliance has funded the child’s treatment from the charity’s reserves. The treatment is expected to cost between $300,000-$400,000 (approximately £185,000-£245,000).

The mother plans to continue her legal battle against the NHS Trust, and hopes that all three immunotherapy drugs will be made available to UK neuroblastoma patients in the future.

“We were left with no choice but to take her to the USA, and I am just extremely grateful to the Neuroblastoma Alliance UK for helping us to fund the treatment,” she said. “I only hope that this court action paves the way for other families to receive the best possible cancer drug treatment for their children without having to travel abroad.”

The order was also welcomed by many of the other families that the Neuroblastoma Alliance UK supports, including John Rogers and Allison Hyde, whose three-year-old daughter Stella received treatment for neuroblastoma in the US last year.

“Until this legal action, parents were forced to accept the treatment they were offered in the randomised trial – even if the alternative treatment might offer better prospects for their child,” said John. “This court order is putting the interests of children before research – the lives of children shouldn’t come secondary to research.”

There are a number of other families in a similar situation and it may also be in their best interests to receive both drugs.

Notes 

* The child, the mother and the Trust are anonymous in this release on order of the court, which said the child should be known as “CB”, the mother as “SB” and the Trust as “S Trust”.

*² Neuroblastoma sufferers taking part in the SIOPEN trial (a neuroblastoma immunotherapy trial taking place in the UK and Europe) are offered either anti-GD2 (an antibody) or anti-GD2 and IL2 (a cytokine).

*³ The study carried out by the Child Oncology Group (COG) in US, Canada and Australia gave one set of patients standard neuroblastoma therapy of isotretinoin, and the other set of patients a combination of three drugs: anti-GD2, IL2 and GM-CSF (another type of cytokine).

The trial found that children receiving the immunotherapy treatment (anti-GD2, IL2 and GM-CSF) had an increased event-free survival rate (66% vs. 46% for standard therapy) and an increased overall survival rate (86% vs. 75% for standard therapy) over two years.

The study was published in the New England Medical Journal in September 2010. http://www.nejm.org/doi/full/10.1056/NEJMoa0911123

*⁴ The exact court order is as follows:

“IT IS DECLARED ON AN INTERIM BASIS THAT

1.         In the event that the Claimant withdraws from the current clinical trial at the <hospital name>, it would be in her best interests to receive immunotherapy treatment that includes isotretinoin, anti-GD2 and IL2″

The hospital name has been removed, in accordance with the judge’s order that the family and Trust are to remain anonymous.

http://www.childrenscancer.org.uk/latest-news/children-s-cancer-charity-neuroblastoma-alliance-uk-celebrates-high-court-order-against-nhs-trust.php

Anti-ALK antibody explored at Children’s Hospital of Philadelphia

An increasingly important research topic in neuroblastoma focuses on anaplastic lymphoma kinase (ALK) mutation or expression. At AACR there were 8 presentations on ALK and NB. While efforts are ongoing to better target the ~7% of NB cases that have an ALK mutation, now there is also compelling research on the ALK protein expression which is found in 90% of NB cases. ALK expression is found in some cancers (primary lymphoma) and is detected using monoclonal antibodies. In normal tissues, ALK protein is expressed in only a few cells within the developing and mature nervous system (glial cells, neurons, endothelial cells and pericytes).[1]

Dr Max van Noesel from Erasmus MC-Sophia Children’s Hospital, Rotterdam, Netherlands presented interesting data showing that the percent of NB cells in a tumor sample that are positive for ALK protein expression correlate with outcome and risk stratification. His team examined 71 NB cases (all risk categories) for ALK expression, and found that tumor samples that showed 75-100% positive cells for ALK expression had the worst outcome,  and that response to the ALK inhibitor TAE684 was dependent on higher ALK expression. Tumors with ALK mutation had higher ALK protein expression and responded better to in vitro testing of the ALK inhibitor.[2]

Meanwhile, Dr Erica Carpenter, a researcher in Dr Yael Mosse’s lab at CHOP, examined targeting NB cells with anti-ALK antibody. Given that the worst NBs express the ALK protein, this is a compelling idea for several reasons. Although this work is still in early preclinical stage, researchers will be seeking to answer many questions including– could this antibody strategy be more effective than anti-GD2 antibodies? Could this therapy present less toxicity?

Dr Carpenter also explored the combination of anti-ALK antibody with the ALK inhibitor PF-02341066 in NB cell lines, and found that the combination is more effective than either agent alone because the ALK inhibitor drives up ALK protein expression on the NB cell surface:

Therefore, we hypothesized that antibody targeting of ALK in neuroblastoma was a therapeutically appropriate strategy. To first confirm the potential of anti-ALK antibody-mediated immunotherapy, we used in vitro assays to demonstrate enhanced immune-cell induced cytotoxicity of antibody-treated human neuroblastoma-derived cell lines. We next showed that in vitro antibody treatment of neuroblastoma cell lines expressing activated ALK led to growth inhibition and cell death. These effects were enhanced by treatment with PF-02341066, an orally available small-molecule inhibitor of the ALK tyrosine kinase. To identify the mechanism behind this enhanced combined effect, we used flow cytometry to show that PF-02341066 sensitizes cells to antibody treatment by inducing accumulation of cell-surface ALK, thus increasing the accessibility of antigen for antibody binding. Finally, to further predict in vivo cytotoxic mechanisms of dual ALK targeting, we used flow cytometry to demonstrate enhanced apoptosis and proliferation inhibition resulting from combined antibody and inhibitor treatment as compared to either drug alone.[3]

The next step in this exciting project is developing a clinical grade antibody, which is underway, and after further preclinical testing, the agent will be ready for clinical trials.

References

1. http://www.nordiqc.org/Epitopes/ALK1/ALK1.htm
2. Anaplastic lymphoma kinase (ALK) expression is an independent prognostic factor in neuroblastoma patients and correlates well with ALK inhibitor response in vitro
3. Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma

The American Association for Cancer Research (AACR) is the oldest and largest scientific organization in the world focused on every facet of cancer research. AACR was founded in 1907 by 11 physicians and scientists interested in research with the goal to “to further the investigation and spread the knowledge of cancer.” Since then, the AACR has grown to 33,000 members and publishes seven peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research, and launched a new journal in 2010, Cancer Discovery.

AACR’s mission is to accelerates progress toward the prevention and cure of cancer by promoting research, education, communication, and collaboration.

The 102nd Annual Meeting 2011 begins April 2 in Orlando FL and will feature over 6000 abstracts presented by basic science, translational, and clinical researchers. Over 17,000 attendees and presenters will learn in a variety of settings: plenary lectures, symposia, minisymposia, workshops, poster sessions, and other formats.

A selection of neuroblastoma-related presentations

Several presentations and posters on neuroblastoma are of interest. Click on the title to see the abstract on AACR site.

4336/4 – Oncolytic reovirus as a novel therapy for neuroblastoma Amelia Kellar, Nicole Redding, Karen Blote, Qiao Shi, Jason Spurrell, Paul Beaudry, Don Morris. University of Calgary, Calgary, AB, Canada Poster Session

4340/8 – Sorafenib induces growth arrest and apoptosis in neuroblastoma cells via inhibition of JAK2/STAT3 and MEK1/2/MAPK (p44/42) signaling pathways Fan Yang¹, Veronica Jove¹, Ralf Buettner¹, Hong Xin¹, Sangkil Nam¹, Tasnim Ara², Yves A. DeClerck², Robert C. Seeger², Hua Yu¹, Richard Jove¹. ¹City of Hope, Duarte, CA; ²The Saban Research Institute of Children’s Hospital Los Angeles, Los Angeles, CA Poster Session

4346/14 – Differential response of a novel protein kinase C-iota inhibitor (ICA-1) on neuroblastoma cells Prajit P. Pillai, Mildred Acevedo-Duncan. Univ. of South Florida, Tampa, FL Poster Session

954 – ABCC/MRP multidrug transporters contribute to neuroblastoma biology, pathogenesis and clinical outcome, independently of any role in cytotoxic drug efflux Murray D. Norris¹, Michelle J. Henderson¹, Antonio Porro², Marcia Munoz¹, Nunzio Iraci², Chengyuan Xue¹, Jayne Murray¹, Claudia Flemming¹, Jamie Fletcher¹, Samuele Gherardi², Alan Kwek¹, Amanda Russell¹, Wendy B. London³, Allen B. Buxton³, Lesley Ashton¹, Alan C. Sartorelli⁴, Susan L. Cohn⁵, Manfred Schwab⁶, Glenn M. Marshall¹, Giovanni Perini², Michelle Haber¹. ¹Children’s Cancer Institute Australia, Sydney, Australia; ²University of Bologna, Bologna, Italy; ³University of Florida and Children’s Oncology Group Statistics and Data Center, Gainesville, FL; ⁴Yale University School of Medicine, New Haven, CT; ⁵University of Chicago, Chicago, IL; ⁶German Cancer Research Center, Heidelberg, Germany Minisymposium

4758 – Inhibition of checkpoint kinase 1 (Chk1) as a potential therapeutic for pediatric neuroblastoma Mike R. Russell, Kristina A. Cole, John M. Maris. Children’s Hospital of Philadelphia, Philadelphia, PA Minisymposium

LB-312/3 – Methylated RASSF1a is the first specific DNA marker for minimal residual disease testing in neuroblastoma Janine Stutterheim, Fatima Ait Ichou, Emmy Den Ouden, Rogier Versteeg, Huib N. Caron, Godelieve A.M. Tytgat, C. Ellen Van der Schoot. Sanquin, Amsterdam, Netherlands, Academic Medical Center, Amsterdam, Netherlands

4563/5 – Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma Erica L. Carpenter¹, Elizabeth A. Haglund¹, Adrian K. Chow¹, Andrew C. Wood¹, Lili T. Belcastro¹, James G. Christensen², Marc Vigny³, John M. Maris¹, Mark A. Lemmon⁴, Yael P. Mosse¹. ¹Children’s Hospital of Philadelphia, Philadelphia, PA; ²Pfizer Global Research and Development, La Jolla, CA; ³INSERM, Paris, France; ⁴University of Pennsylvania, Philadelphia, PA Poster Session

LB-366/11 – Patient-derived EBV-immortalized B-lymphocytes are a dominant contaminant of in vitro cultured human neuroblastoma tumor-initiating cells isolated from bone marrow. Sven Påhlman, Sofie A. Johnsson, Alexander Pietras, Caroline Wigerup, Ingrid Øra, Michael Andäng, Kenneth Nilsson, Tor Olofsson, David Gisselsson. Lund Univ., Malmö, Sweden, Lund Univ., Lund, Sweden, Karolinska Institute, Stockholm, Sweden, Uppsala Univ., Uppsala, Sweden Late-Breaking Poster Session

742/26 – Mechanisms of resistance to small molecule inhibition of anaplastic lymphoma kinase in human neuroblastoma Erica L. Carpenter¹, Elizabeth A. Haglund¹, Adrian K. Chow¹, James G. Christensen², John M. Maris¹, Yael P. Mosse¹. ¹Children’s Hospital of Philadelphia, Philadelphia, PA; ²Pfizer Global Research and Development, La Jolla, CA Poster Session

3942/29 – A pilot trial testing the feasibility of using molecular-guided therapy in patients with refractory or recurrent neuroblastoma Giselle L. Saulnier Sholler¹, Javed Kahn², William Ferguson³, Genvieve Bergendahl¹, Erika Currier¹, Shannon Lenox¹, Jeffrey Bond¹, William Roberts⁴, Deanna Mitchell⁵, Don Eslin⁶, Jacqueline Kraveka⁷, Joel Kaplan⁸, Nehal Parikh⁹, Suman Malempati¹⁰, Gina Hanna¹¹, Barton Kamen¹², Craig Webb¹³. ¹University of Vermont, Burlington, VT; ²National Institute of Health, Bethesda, MD; ³St. Louis University School of Medicine, St. Louis, MO; ⁴University of California San Diego School of Medicine, San Diego, CA; ⁵Michigan State University, Grand Rapids, MI; ⁶MD Anderson Cancer Center Orlando, Orlando, FL; ⁷Medical University of South Carolina, Charleston, SC; ⁸Levine Children’s Hospital, Charlotte, NC; ⁹Connecticut Children’s Medical Center, Hartford, CT; ¹⁰Oregon Health & Science University, Portland, OR; ¹¹Inova Fairfax Hospital for Children and Women, Falls Church, VA; ¹²Cancer Institute of New Jersey, New Brunswick, NJ; ¹³Van Andel Research Institute, Grand Rapids, MI Poster Session

1558/6 – Paracrine signaling through Mycn enhances tumor-vascular microenvironment in neuroblastoma Yvan H. Chanthery, W. Clay Gustafson, William A. Weiss. UCSF, San Francisco, CA Poster Session

4350/18 – Translating diagnostic gene expression profiles for pediatric solid tumors Daniel H. Wai¹, Michele R. Wing², Kelley Kneile², Yvonne Moyer², Jonathan D. Buckley³, Robert C. Seeger⁴, Douglas S. Hawkins⁵, Stephen X. Skapek⁶, Timothy J. Triche⁴. ¹Center for Personalized Medicine, Los Angeles, CA; ²The Research Institute at Nationwide Children’s Hospital, Columbus, OH; ³University of Southern California, Los Angeles, CA; ⁴Children’s Hospital Los Angeles, Los Angeles, CA; ⁵Seattle Children’s Hospital, Seattle, WA; ⁶University of Chicago, Chicago, IL Poster Session

5237/25 – Development of organ-selective neuroblastoma cell lines to identify genes mediating bone marrow and liver colonization Zillan Neiron¹, Kacper Jankowski¹, Jayne Murray¹, Sophia Champion², Murray D. Norris¹, Michelle Haber¹, Jamie I. Fletcher¹. ¹Children’s Cancer Institute Australia, Randwick, NSW, Australia; ²University of New South Wales, Kensington, NSW, Australia Poster Session

130/14 – MiR-204 acts as a tumor suppressor in neuroblastoma through down-regulation of the neurotrophic receptor TrkB Jacqueline M. Ryan¹, Amanda Tivnan¹, Isabella Bray¹, Joanna Fay¹, Andrew M. Davidoff², Lorraine Tracey², Raymond Stallings¹. ¹Royal College of Surgeons in Ireland & National Children’s Research Centre, Dublin, Ireland; ²St. Jude Children’s Research Hospital, Memphis, TN Poster Session

4685 – Mechanistic guidance of ALK inhibition for the treatment of neuroblastoma Scott C. Bresler¹, Andrew Wood², Elizabeth Haglund², James Christensen³, John M. Maris², Mark A. Lemmon¹, Yael P. Mosse². ¹University of Pennsylvania School of Medicine, Philadelphia, PA; ²Children’s Hospital of Philadelphia, Philadelphia, PA; ³Pfizer Inc., La Jolla, CA Minisymposium

1808/28 – Neuroblastoma cell lines established from progressive disease that exhibit partial or multi drug resistance are highly sensitive to chimeric receptor scFv(ch14.18)-zeta mediated NK cell killing Diana Seidel¹, Anastasia Shibina², C. Patrick Reynolds², Winfried S. Wels³, Holger N. Lode¹, Nicole Huebener¹. ¹University Medicine Greifswald, Greifswald, Germany; ²Texas Tech University Health Sciences Center, Lubbock, TX; ³Chemotherapeutisches Forschungsinstitut, Georg-Speyer-Haus, Frankfurt, Germany Poster Session

508/4 – Signal transduction and activator of transcription (STAT) 3 is necessary for environment-mediated drug resistance Tasnim Ara¹, Rie Nakata¹, Hiroyuki Shimada¹, Ralf Buettner², Robert C. Seeger¹, Hua Yu², Richard Jove², Yves A. DeClerck¹. ¹USC/Children’s Hospital Los Angeles, Los Angeles, CA; ²Beckman Research Institute/City of Hope, Duarte, CA Poster Session

926 – Whole genome and transcriptome sequencing defines the spectrum of somatic changes in high-risk neuroblastoma Olena Morozova¹, Inanc Birol¹, Richard Corbett¹, Karen Mungall¹, Edward F. Attiyeh², Shahab Asgharzadeh³, Yongjun Zhao¹, Richard A. Moore¹, Martin Hirst¹, Steven Jones¹, Michael D. Hogarty², Sharon Diskin², Yael P. Mosse², Maura Diamond², Richard Sposto³, Lingyun Ji³, Daniela S. Gerhard⁴, Malcolm A. Smith⁴, Javed Khan⁴, Robert C. Seeger³, Marco A. Marra⁵, John M. Maris², the NCI TARGET Initiative. ¹Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; ²Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA; ³Children’s Hospital of Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA; ⁴National Cancer Institute, Bethesda, MD; ⁵Genome Sciences Centre, BC Cancer Agency and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada Minisymposium

1800/20 – 4-HPR (fenretinide) sensitizes human neuroblastoma cells for antibody-independent and ch14.18-mediated NK cell killing Anastasia Shibina¹, Diana Seidel², Srinivas Somanchi³, Holger N. Lode², Dean A. Lee³, C.Patrick Reynolds¹, Nicole Huebener². ¹Texas Tech Univ. Health Sciences Ctr., Lubbock, TX; ²University Medicine Greifswald, Pediatric Hematology/Oncology, Greifswald, Germany; ³The University of Texas MD Anderson Cancer Center, Houston, TX Poster Session

1423/15 – Effects of DFMO-based combination therapy in advanced stage neuroblastoma Dana-Lynn T. Koomoa, Ingo Lange, Andre S. Bachmann. University of Hawaii, College of Pharmacy, Hilo, HI Poster Session

TARGET Project Team Highlights: Neuroblastoma Javed Khan. National Insts. of Health, Bethesda, MD NCI/NIH-Sponsored Session

NIH15. The NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative: Using Large-Scale Genomics to Identify Novel Therapeutic Targets for Childhood Cancers

Towards a personalized approach to pediatric cancer management: Neuroblastoma as an example John M. Maris. Children’s Hospital of Philadelphia, Philadelphia, PA Major Symposium
Recent Findings from Genomic Analyses of Tumors

5359/30 – Cytotoxicity of MLN8237 and SAHA in pediatric cancer cell lines Jodi Muscal¹, Kathy Scorsone¹, Jeffrey Ecsedy², Stacey Berg¹. ¹Baylor College of Medicine, Houston, TX; ²Millenium Pharmaceuticals, Inc., Cambridge, MA Poster Session

4756 – Exome sequencing of 81 neuroblastomas identifies a wide diversity of somatic mutation Trevor J. Pugh¹, Michael Lawrence¹, Carrie Sougnez¹, Gad Getz¹, Edward Attiyeh², Michael Hogarty², Sharon Diskin², Mosse Yael², Maura Diamond², Shahab Asgharzadeh³, Richard Sposto³, Jun S. Wei⁴, Thomas Badgett⁴, Wendy B. London⁵, Julie Gastier-Foster⁶, Malcolm A. Smith⁴, Daniela S. Gerhard⁴, Robert Seeger³, Javed Khan⁴, Matthew L. Meyerson¹, John M. Maris², NCI Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative. ¹The Broad Institute of MIT and Harvard, Cambridge, MA; ²Children’s Hospital of Philadelphia, Philadelphia, PA; ³Children’s Hospital of Los Angeles, Los Angeles, CA; ⁴National Cancer Institute, Bethesda, MD; ⁵Dana-Farber Cancer Institute and Children’s Oncology Group Statistic and Data Center, Boston, MA; ⁶Nationwide Children’s Hospital, Columbus, OH Minisymposium

Overview of environment: Mediated drug resistance Yves A. DeClerck. USC/Children’s Hospital Los Angeles, Los Angeles, CA Educational Session

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

.

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.

.

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-

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:

Rare news

A disease that afflicts only 350 children per year in the US (in the high-risk form) does not make headlines very often. But after the September 30, 2010 publication of the New England Journal of Medicine article revealing the results of the phase III chimeric antibody trial (ch14.18 given with two cytokines GM-CSF and IL2), neuroblastoma was all over the news including prime time national news. Over 200 news stories appeared within the next 2 days and over 3000 blogs reported on the story. Click on image below for a nice example of one of the medical blogs:

From Science Life blog at University of Chicago

The news was actually first released March 19, 2009 after an early review of the study. The study was amended so that the randomization was stopped and all eligible children could  receive the antibody.

This is quite a dramatic story on many levels.

An absolute must read is an excellent article giving more background on the story in the NCI Cancer Bulletin. The article details the incredible perseverance required of Dr Alice Yu, Dr Paul Sondel, Dr Malcolm Smith, and the entire COG team to bring this antibody to children with neuroblastoma. The research on this antibody began in 1985, and yet it took 25 years to get solid proof that the antibody improves survival. Why did it take so long?

Antibody and drug development are not the same

Antibodies are first isolated from mice that are “challenged” with a tumor and produce antibodies against that tumor. The production is shown in the illustration below from a wikipedia article which describes the process:

This particular antibody targets GD2 which is a glycolipid (sugar-fat) antigen on the surface of NB cells. This antigen is also present on other cancers, including melanoma. GD2 is also expressed on some normal nerve cells, which is why the treatment causes pain. “First generation” antibodies are entirely mouse products (termed “murine”) and is why a normal immune system reacts quickly to produce anti-mouse human antibodies (HAMA) which effectively neutralize the action of the mouse antibody. Examples of first generation anti-GD2 antibodies are Memorial Sloan-Kettering’s 3F8 antibody (research also began in 1985[1]) and 14G1,14G2b, and 14G2a antibodies.[2]  The ch14.18 chimeric antibody is a “second generation” anti-GD2 antibody, since it has been engineered to be 75% human and 25% mouse in makeup, and why it is labeled chimeric (a “mix” of human and mouse). This greatly reduced the incidence of forming antibodies against the ch14.18. Two “third generation” antibodies that are fully humanized have been developed to date  and have been tested in clinical trials:

• St Jude’s hu14.18K322A, in a phase 1 study now for neuroblastoma and melanoma, and given without cytokines
• hu14.18-IL2, a fusion protein where the cytokine IL2 is attached to the antibody (in phase 2 study now for melanoma)

The hu14.18-IL2 antibody has already shown significant efficacy in a phase II study for relapsed and refractory neuroblastoma with results just published in October 4, 2010 issue of the Journal of Clinical Oncology.[3]

Plans are underway now for both ch14.18 and hu14.18-IL2 to be used in further clinical trials in combination with other promising agents for relapsed/refractory neuroblastoma and these trials will begin accruing at COG institutions in 2011.

More to the story

Ironically, this pivotal phase III ch14.18 trial that showed such a dramatic improvement to survival had some difficulty accruing. It is interesting to note that the other recent phase III studies all accrued patients at a relatively even pace (~90-100 patients per year) with the exception of this ch14.18 antibody study:

• CCG-3891 (1991 – 1996) double randomization of transplant and cis-retinoic acid accrued 539 over 6 years or ~ 90 per year [4]
• COG-A3973 (2001 – 2006) randomization for purge vs no purge of stem cells for stem cell transplant accrued 489 over 5 years or ~ 98 per year [5]
• COG-ANBL0032 (2001 – 2009) randomization of ch14.18 vs no ch14.18 accrued 226 over 7.5 years or ~ 30 per year [6]
• COG-ANBL0532 (2007 – 2012) randomization of single vs tandem transplant is accruing on schedule (should be complete by fall 2012) at 495 over 5 years or ~ 99 per year [7]

The striking fact is that if the early analysis had not revealed a significant difference in outcome, accruing at this rate this trial might have been ongoing until 2014.

Medical ethics, trial design, and real children

With success also comes inevitable heart ache. Hindsight can be a bitter pill to swallow. It is impossible to forget the children who did not receive the antibody and had increased chance of relapse as a result. By the time 2 years elapsed from randomization, 38/113 children had relapsed after receiving the antibody,  but 61 children had relapsed after receiving no antibody, an excess incidence of relapse in 23 children. Was it really necessary to randomize the antibody? If it was a promising treatment why was it not just given to everyone?

There are no easy answers to this fair and difficult question. While there were high hopes the ch14.18 antibody given with two cytokines would help, no one really knew if it would make a difference in survival. After all, in 2004 the German study group (GPOH) had published their retrospective findings that the ch14.18/CHO antibody (made with hamsters instead of mice, and given without cytokines) made no difference in survival when groups were compared from GPOH NB90 and NB97 protocols.[8]

A perfect example of this very quandary was played out with neuroblastoma not long ago. A method was devised in the early 1990s to purge stem cells of neuroblastoma with monoclonal antibodies (of all things) and magnetic beads. The purged stem cells could then be frozen and returned to children after high-dose (myeloablative) chemotherapy. This idea made so much sense: why not clean up the stem cells first and remove the risk of re-infusing the child with NB cells?

Fast forward to the negative results of a very costly and lengthy phase III study — purging had made no difference at all in the survival of high-risk NB children. These results were presented at the 2007 ASCO meeting, but are still not published to date. [9]

So what are the implications? The purging costs upwards of $30,000 per child. It also wastes 50% or more of the stem cells in the process. Knowing that this expensive, wasteful  process is not needed is a very important finding. A similar finding could have been in store for ch14.18 with cytokines. Randomizing is not necessary when a dramatic and consistent response results from a treatment. Not every child responded to ch14.18 treatment in earlier studies, so efficacy had to be proven before it could become a standard treatment. After all, 5 months of ch14.18 treatment with cytokines is a very expensive and complex ordeal, and children are required to spend up to 7 additional weeks in the hospital for this intensive treatment.

In the midst of the celebration over this genuine breakthrough, it is nevertheless heartbreaking to realize that a total of 99 children out of the 226 (both groups) had relapsed by two years — or 44%. It is poignant to note that each of the researchers interviewed about this remarkable study also made the comment “We must do better.” There is an impressive array of researchers and clinicians who have dedicated their entire careers to pushing that sad high-risk neuroblastoma survival curve upward. They see the faces of the children who have been lost along the way in those curves too.

Costly development and production

Developing an antibody (a biopharmaceutical) is far more complex that developing a drug. Cost of production and additional regulatory requirements make this an expensive endeavor. For example, $8 million of 2009 stimulus funds were awarded December 2009 to SAIC-Frederick (NCI research partner) to produce a two year supply of ch14.18:

NCI, through the BDP [Biopharmaceutical Development Program], is to deliver sufficient number of vials of finished product to treat all neuroblastoma patients for whom antibody Ch14.18 has become the clinical standard of care. This 2-year interval for NCI production can be used as a transition to licensing and commercial production. In addition, for the Cancer Immunotherapy Network, the NCI, through the BDP, will develop and supply vials of agents of great interest of the extramural community for further clinical investigation.

Transitioning is currently underway for United Therapeutics to begin producing ch14.18, and complete the FDA registration process. Keeping an eye on further use in melanoma is of interest since that will potentially make ch14.18 a more profitable product for United Therapeutics.[10]

Implications for Europe

At ANR (Advances in Neuroblastoma Research) in 2008 and 2010 and at SIOP 2009 the German group (GPOH) reported that after longer follow-up, the ch14.18/CHO treatment might prevent late relapses. The GPOH is planning to reintroduce ch14.18/CHO treatment. The large SIOP trial SIOP-EUROPE-HR-NBL-1 opened in 2002 and had planned to randomize ch14.18 but since the results of the COG study, the SIOP study was amended to give all eligible children ch14.18 with or without subcutaneous IL2. There is such a great body of evidence showing that GM-CSF is an essential part of this treatment, hopefully the regulatory hurdles will be quickly resolved and children in Europe will soon have the opportunity to get this better treatment regimen. See John Roger’s ANR report for more on this very important subject.

References

1. Biochem Biophys Res Commun. 1985 Feb 28;127(1):1-7. Ganglioside GD2 specificity of monoclonal antibodies to human neuroblastoma cell.

2. Cancer Research 49, 2857-2861, June 1, 1989. Functional Properties and Effect on Growth Suppression of Human Neuroblastoma Tumors by Isotype Switch Variants of Monoclonal Antiganglioside GD2 Antibody 14.18

3. J Clin Oncol. 2010 Oct 4. Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children’s Oncology Group (COG) Phase II Study

4. J Clin Oncol. 2009 Mar 1;27(7):1007-13. Long-Term Results for Children With High-Risk Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy Followed by 13-cis-Retinoic Acid: A Children’s Oncology Group Study

5.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9505 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

6. N Engl J Med. 2010 Sep 30;363(14):1324-34. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.

7. Correspondence with investigators

8. J Clin Oncol. 2004 Sep 1;22(17):3549-57. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma.

9.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9505 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

10.  Clinical Cancer Research August 1997 3; 1277 Phase IB trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients.

New donor transplant trial open for relapsed or refractory neuroblastoma

Dr Sandeep Soni spoke at CNCF (Children’s Neuroblastoma Cancer Foundation) Parent Conference in Chicago July 10, 2010. Dr Soni is a member of the Pediatric Blood and Marrow Transplant program at Nationwide Children’s Hospital and an Assistant Professor of Clinical Pediatrics at Ohio State University College of Medicine in Columbus.

Dr Soni presented the novel allogeneic transplant trial now open for relapsed and refractory neuroblastoma in Columbus:

Fludarabine, Busulfan, and Antithymocyte Globulin Followed By Donor Stem Cell Transplant in Treating Young Patients With High-Risk Neuroblastoma That Has Relapsed or Not Responded to Treatment

This is a phase II study with a planned accrual of 25 children 1 to 18 years old. The goals of this study are to determine the feasibility of this protocol using a reduced-intensity conditioning regimen, engraftment, transplant-related mortality, and development of acute and chronic graft-vs-host disease. Secondary goals are to learn about the role of natural killer (NK) cells as effectors of graft-vs-tumor effect in these patients, and the role of killer immunoglobulin-like receptor (KIR) mismatches in the donor-recipient pairs on the outcomes of these patients.

Dr Soni explained that the role of NK cells are much better understood today, and recently the potential importance of mismatch in KIR is being explored. He also noted that depleting T-cells reduces the risk of graft-versus-host disease (GVHD) whereas in leukemia T-cells are required for graft-versus-tumor effect. In neuroblastoma, there is evidence that NK cells are more important for graft-versus-tumor. Modified T-cells have also been explored by investigators at CHOP (Children’s Hospital of Philadelphia).

History of allogeneic transplants in neuroblastoma

While allogeniec transplants have been used much less frequently in solid tumors, research continues to explore the potential for graft-versus-tumor effect seen in liquid tumors, primarily leukemia.

In February 2010 Dr Stephen Grupp and colleagues from CHOP published a review of “Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors” including the work on modified T-cells:

Chimeric immunoreceptor (CIR). The CIR is an engineered T-cell receptor (TCR) comprised of an antibody-like extracellular domain fused to an intracellular, functional TCR domain. The CIR was first described by Eshhar in 1993, and has been developed and extended over the last 15 years. The first report of CIR-modified T cells specific for neuroblastoma was published in 2001, and research since that time has led to an early-phase clinical trial published in 2007. To redirect T cells safely against a tumor, the CIR must target a tumor-specific antigen that is minimally expressed on normal tissues.

These trials, and others examining the use of CIR-modified T cells in other malignancies, have shown the feasibility of using genetic modification to redirect autologous T cells against malignancies. As technologies improve, and the experience with CIRs increases, harnessing a patient’s own immune system in the treatment for high-risk pediatric cancers will likely become a promising new therapeutic frontier.[1]

Dr Grupp also published a review of transplants for neuroblastoma in January 2008 (fulltext is available):

Finally, as an alternative to autologous SCT, some groups have studied allogeneic SCT in an attempt to harness an immunotherapeutic effect. A graft-versus-malignancy effect has been well described in allogeneic transplant for liquid tumors, but has not yet been convincingly demonstrated in the setting of solid tumors. Although initial studies of conventional allogeneic SCT for high-risk neuroblastoma failed to show clear benefit, the advent of nonmyeloablative conditioning regimens has provided hope that reduced intensity conditioning will reduce TRM and allow for the detection of a therapeutic benefit. As a result, institutions are beginning to explore the possibility of an allogeneic effect in neuroblastoma. At this point, this is still an investigational and unusual application of allogeneic transplant, with 38 such cases reported to the EBMT from 1991 to 2002. Some recent case reports have provided preliminary evidence for a graft-versus-tumor effect in neuroblastoma. A 2003 case report described a patient who underwent allogeneic SCT after a relapse. Although the patient received further chemotherapy after the allogeneic transplant and response could not be correlated to GVHD, the patient did enter a CR sustained for at least 4 years. In a more recent report, development of GVHD correlated temporally with disease response in a patient who had undergone a reduced-intensity allogeneic bone marrow transplant. In a similar regard, the group at Columbia has been testing reduced intensity allogeneic cord blood transplants in patients with a wide range of diagnoses, including neuroblastoma.[2]

The use of allogeneic transplants may hold promise in neuroblastoma, with progress being made in reducing the risk of acute graft-versus-host disease and reduced treatment-related mortality with reduced intensity regimens. Families who are interested in pursuing this treatment choice for a child with relapsed or refractory neuroblastoma should be aware that some therapies available in current clinical trials prohibit prior donor transplants as part of the eligibility, but many current clinical trials do allow prior allogeneic transplant.

1. Pediatr Clin North Am. 2010 Feb;57(1):47-66. Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors. PMID: 20307711

2. Bone Marrow Transplant. 2008 January; 41(2): 159–165. Stem cell transplantation for neuroblastoma. PMCID: PMC2892221 [fulltext]

C10 (p. 80) “Late effects in neuroblastoma”

Dr Lisa Diller (Boston Children’s/Dana-Farber Cancer Institute) reviewed recent published data on late effects and presented new data in the Neuroblastoma Update Course on June 21st, 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden. The session was organized by Sue Cohn and Andrew Pearson and chaired by Sue Cohn and Rani George.

The Childhood Cancer Survivor Study provided long-term survivorship data for those treated for neuroblastoma between 1970 and 1986, and results on 954 5-year survivors were published in Journal of the National Cancer Institute August 2009.[1]

Of the 954 children, 832 records were abstracted, and only about 10% were stage 4 survivors, so the vast majority (~90%) of the survivor data most likely represented low and intermediate risk survivors.  Only 38% of the survivors had surgery + chemotherapy + radiation.  Of all the survivors, at least 90% had 15 years of follow-up. Of 1358 there were 84 deaths (41 recurrences)  and higher risk of death if diagnosed over the age of 5 and had multimodal therapy. The children treated for neuroblastoma were compared to a cohort of 3899 siblings to determine if there was a higher incidence of health problems. There was a higher incidence of chronic health conditions involving the neurological, sensory, endocrine, and musculoskeletal systems in children treated for neuroblastoma.

Dr Diller also mentioned evidence from soon-to-be published institutional data that advanced bone age or epiphyseal closure is more common in children treated with cis-retinoic acid than children who did not have cis-retinoic acid. There is a theoretical toxicity proposed related to cis-retinoic acid given with anti-GD2 antibody (ch14.18) because of clearance issues, but this has yet to be verified.[2]

References

1. J Natl Cancer Inst. 2009 Aug 19;101(16):1131-40. Epub 2009 Jul 31. [fulltext]

2. ANR 2010 “Neuroblastoma Update Course” ANR 2010 Abstract Programme, p 80.