“Meet the Experts” session

Drs Huib Caron (The Netherlands) and Suzanne Shusterman (Boston Childrens/DFCI) presented on MIBG therapy in “Meet the Experts” session Friday Oct 22 and Saturday Oct 23, 2010 at the SIOP meeting in Boston.

Completed and ongoing studies

Dr Caron covered the therapeutic considerations, and Dr Shusterman spoke about the practical and logistic issues surrounding the design of MIBG therapy rooms and handling the radioactive material.

MIBG (meta-iodobenzylguanidine) is a synthetic analogue to norepinephrine, developed in the 1970s at University of Michigan as a potential agent for use in hypertension. It is taken up by 90% of neuroblastomas. The compound (also called iobenguane) is useful for both imaging with I-123 isotope which has a shorter half-life of 13 hours and produces better resolution images, and radiation therapy with I-131 which has a longer half-life of 8 days.

The compound with a radioactive isotope of iodine attached (I-131) is taken up in the NB cell but is not lethal to that cell. The beta particles from I-131 decay kills cells up to 2 mm away, and gamma radiation from decay (as in imaging) reaches 2 m or greater distance, but is not lethal to cells in that path. The resulting beta particle decay “cross-fire” is why MIBG radiation therapy appears to be more effective in clumps of disease rather than in diffuse or trace disease. Dr Caron commented in his presentation that this is why he believes using MIBG radiation therapy at the end of induction with minimal or undetectable disease will have questionable efficacy, and why studies in the Netherlands have used double MIBG treatments at the beginning of induction (1989-1999 in 41 children).[1]   Dr Maris countered in a later conversation that there is evidence of efficacy from a double MIBG therapy study where children who respond completely to the first MIBG therapy receive a second MIBG treatment and do well. He also mentioned that it is very common to see much more disease in a post-MIBG therapy scan, revealing that often the imaging dose of MIBG does not show as much disease, and therefore using MIBG therapy at the end of induction even in children with negative MIBG scans may successfully treat undetectable or trace disease. This question (as well as feasibility) will be addressed by the new frontline pilot study now open in several centers using MIBG at the end of induction with CEM transplant for 49 newly diagnosed high-risk NB (see previous article). The German group GPOH is using MIBG therapy in frontline therapy in the ongoing NB2004 study a the end of induction for children who have remaining MIBG positive primary uptake. This study plan is to accrue 360 children.[2]

Other completed and ongoing studies were reviewed, including an ongoing study using MIBG upfront with topotecan in 15 children, a GPOH study using MIBG + gemcitabine phase I/II for refractory and relapsed NB and should finish within the year. The NANT 2007-03 phase I MIBG + vorinostat trial is based on the fact vorinostat (an HDAC inhibitor) increases the norepinephrine transporter expression, and in mice the combination results showed improved response. In 2006 Matthay et al published in JCO the results of the phase I MIBG + CEM transplant in 24 children where the 3-year event-free survival (EFS) was 30% and the 3-year overall survival (OS) was 60% for primary refractory disease. The dose levels from this study were used in the phase II which was recently completed and preliminary results were presented at ANR in June 2010 in Stockholm by Dr Greg Yanik (OR58). MIBG has been tested at 8 to 18 mCi in various trials. In 2007 a Phase II was published in JCO showing promising effectiveness in 164 relapsed or refractory patients with a median of 3 prior regimens (range 1 – 13).[3]  A study in the UK planned to use topotecan with MIBG for relapsed or refractory NB closed before it accrued. Another NANT phase I study N2004-06 used MIBG with irinotecan and vincristine, and results are pending. In Sweden a study using haploidentical donor transplant with MIBG was completed in 5 children.[4] In France a study is ongoing using topotecan with MIBG in relapsed and refractory children.

Approval status for 131-I MIBG

131-I MIBG is made by Draximage (a division of Draxis Health) in Canada, and another company Molecular Insights makes Azedra (Ultratrace MIBG with no cold contaminants). 131-I MIBG is approved for treatment of neuroblastoma in Europe, but still an investigational new drug (IND) in the US.

Future focus

Conclusions drawn from this session include the fact that MIBG therapy is obviously an important agent in the treatment of neuroblastoma, with a long history of studies completed since the 1980s. An important challenge for all researchers involved is figuring out the optimum way to use this agent. An excellent review published in 2008 by Drs Matthay and Dubois provides more information.[5]

References

1. Eur J Cancer. 2008 Mar;44(4):551-6. Epub 2008 Feb 11. Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age. PMID: 18267358

2.  Randomized Study of Standard Induction Chemotherapy Versus Topotecan Hydrochloride-Containing Induction Chemotherapy Followed by Myeloablative Autologous Stem Cell Transplantation and Consolidation Therapy With Isotretinoin in Pediatric Patients With High-Risk Neuroblastoma GPOH-NB2004-HR

3. J Clin Oncol. 2007 Mar 20;25(9):1054-60. Phase II study on the effect of disease sites, age, and prior therapy on response to iodine-131-metaiodobenzylguanidine therapy in refractory neuroblastoma. PMID: 17369569

4. Biol Blood Marrow Transplant. 2009 Sep;15(9):1077-85. Epub 2009 Jul 8. High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma. PMID: 19660720

5. Q J Nucl Med Mol Imaging. 2008 Dec;52(4):403-18. Radiolabeled metaiodobenzylguanidine for imaging and therapy of neuroblastoma. PMID: 19088694

Travel to this meeting was supported by:

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

.

Dr Frank Saran from The Royal Marsden in the UK presented on neuroblastoma during the Paediatric Radiation Oncology Society (PROS) education session Wednesday October 20 at the SIOP meeting in Boston. Prior to his presentation we heard from other specialists on the challenges of using radiation for poor-prognosis brain tumors, particularly high-grade glioma. Other brain tumors discussed were ependymoma, supratentorial primitive neuroectodermal tumors (sPNET), and the emerging use of proton radiation. The difficulty of minimizing neurocognitive damage and the grim prognosis for some of these tumors are very sobering. There was no discussion in this session of treatment for brain metastases for non-CNS tumors. There was also a presentation on radiation for Wilm’s tumor.

Dr Saran gave a short history of studies showing why today radiation is a part of standard therapy for high-risk neuroblastoma (but use of TBI was not discussed). Local failure accounted for a large percentage of relapses when chemo-only regimens were used. In unpublished data supplied by Dr Andrew Pearson,  40% of all stage 4 over 1 year relapsed at the primary site in the ENSG5 study. By contrast in 2001 Memorial-Sloan Kettering (MSKCC) published a series of 99 children with only 10% local failure rate. MSKCC uses hyperfractionated radiation 21 Gy in 14 fractions, usually given in two fractions per day to primary sites and additional radiation to some metastases.  The current SIOP NB trial uses 21 Gy in 14 fractions given over 3 weeks.

Dr Saran also listed current efforts to determine the optimum way to give 131-I MIBG radiation. Some investigations address maintaining oxygenation, fractionating treatment, using radiosensitizers, use of carrier-free (Ultratrace), and adding chemotherapy. A recent European trial showed good results when MIBG radiation therapy was given concurrently with topotecan. Several combination trials (chemo with MIBG) are ongoing in the US and in Europe.

Travel to this meeting was supported by:

• Lighthouse Laboratories

• Max’s Ring of Fire

• Magic Water

• Friends of Will

• Solving Kids’ Cancer

• Children’s Neuroblastoma Cancer Foundation

The World of Childhood Cancer

This year Boston MA and Dana-Farber/Boston Children’s will host the 42nd Annual Conference of the International Society of Paediatric Oncology (SIOP) October 20 – 24, 2010. This is the first time this meeting has been held in the US in 17 years.

Next week will be my first return to Boston since my son was treated there for neuroblastoma 1991-1993. I am deeply indebted to the foundations (from AUS, US, and UK) who support this endeavor and have generously granted travel scholarships for me to attend and report on this meeting:

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

Last year the meeting was held October 5-9, 2009 in Sao Paulo Brazil. There were 31 symposia lectures, 174 oral presentations, 535 posters, and 40 publications.[1]

The Société Internationale d’Oncologie Pédiatrique (SIOP) has continental branches for Europe, South America (nations south of Mexico), North America, Asia, Australia, and Africa. ESIOP (Europe) conducts large studies on neuroblastoma in 20 countries including UK and Israel. The first annual general meeting was held in Madrid in 1969 and began with a distinct focus on neuroblastoma among other pediatric cancers. St Jude’s cure4kids site provides access to presentations and education books from each SIOP conference.

The meeting program includes parallel tracks of the following affiliated societies:

• International Confederation of Childhood Cancer Parent Organisations (ICCCPO)
• International Society of Paediatric Surgical Oncology – IPSO
• Paediatric Oncology Developing Countries Committee
• Paediatric Radiation Oncology Society
• SIOP Paediatric Psycho-Oncology Committee
• The SIOP Nurses Committee

This year’s meeting will have over 2000 attendees from 95 countries:

A sampling of the interesting presentations are highlighted below, taken from the 58 page program.

Wednesday

Role of Surgical Resection in the Cure of Neuroblastoma ~ Mike La Quaglia, United States

Neuroblastoma ~ Frank Saran, United Kingdom

Thursday

Traumatic Stress as a Model for Understanding Patient and Parent ~ Plenary Discussion,  Andrea Patenaude, United States

Response to Childhood Cancer ~ Sean Phipps and Anne Kazak, United States

Incidents and Complication of Totally Implanted Vascular Access Devices: A Prospective Study (O017) ~ Jean-Marc Joseph, Christophe Gapany, Stephane Tercier, Manuel Diezi, Switzerland

Communication With Patients About Challenging Topics ~ Chair: Gerry Koocher, United States, Lori Wiener, United States, Helena Kondryn, United Kingdom, Tim Eden, United States, Katryn Cantrell, United States

Role of SIOP in Integrating Psychosocial Care into Routine Pediatric Oncology Treatment and Fostering Pediatric Psycho-Oncology Research on a Global Level ~ Jimmie Holland, United States

Friday

Therapeutic MIBG ~ Huib Caron, The Netherlands and Suzanne Shusterman, United States

Update on Children’s Oncology Group (COG) Studies ~ Thomas Merchant, United States

Update on SIOP Studies ~ Roger Taylor, United Kingdom

Neuroblastoma (OP2) ~ Chairs: Angelika Eggert, Germany and Purna Arun Kurkure, India

Accumulation of Segmental Alterations Determines Progression in Neuroblastoma (O024) ~ Gudrun Schleiermacher, Isabelle Janoueix-Lerosey, Agnès Ribeiro, Jerzy Klijanienko, Jerome Couturier, Gaelle Pierron, Veronique Mosseri, Alexander Valent, Nathalie Auger, Dominique Plantaz, Hervé Rubie, Dominique Valteau-Couanet, Franck Bourdeaut, Valerie Combaret, Christophe Bergeron, Jean Michon, Olivier Delattre,  France

Tumor Cell Detection in Autologous Stem Cell Harvests in Patients with High-Risk Neuroblastoma (O025) ~ Janine Stutterheim1, Florentien E.M. Vree1, Barbara Hero2, Lily Zappeij-Kannegieter1, Carlijn Voermans1, Roswitha Schumacher-Kuckelkorn2, Ulrike Koehl2, Johannes H. Schulte2, Felix Niggli3, Michael C. Fruhwald2, Max M. van Noesel1, Charlotte M. Niemeyer1, Udo Bode2, Freimut H. Schilling2, Christian Schultz2, Norbert Graf2, Michaela Nathrath2, Irene Schmid2, Hubert N. Caron1, Ellen C. van der Schoot1, Godelieve A.M. Tytgat1 ~ 1The Netherlands, 2Germany, 3Switzerland

Validation of Survivin as a Therapeutic Target in Neuroblastoma (O026) ~ Fieke Lamers, Fieke Lamers, Linda Schild, Ida van der Ploeg, Marli Ebus, Jan Koster, Rogier Versteeg, Huib Caron, Jan Molenaar, The Netherlands

Identification of New Candidate Genes in Progression of Neuroblastoma Using Omics Analysis (O027) ~ Eiso Hiyama, Naomi Kamei, Arata Kamimatsuse, Yukina Hirai, Keiko Hiyama, Tsutomu Masujima, Japan

Keynote Lecture: Psycho-Oncology Late Effects in Survivors ~ Mark Chesler, United States
Chairs: Carmen Auste, The Phillipines and Benson Pau, China

Opening Keynote Lecture: Cancer Survival Need Not Be Determined by Income: Lessons from Developing Countries and Focusing on Children ~ Felicia Knaul, United States
Chairs: Gabriele Calaminus, Germany and Lisa Diller, United States

Neuroblastoma: A 20-Year Experience in a UK Regional Center (O057) ~ Adeline Salim, Dhanya Mullassery, Barry Pizer, Heather McDowell, Paul Losty, United Kingdom

Opening Plenary Session: What About the Rest of the Family? ~ Chairs: Melanie Goldish, United States and Simon Lala, New Zealand

Doubled and Silenced: Grandparents’ Experiences of Childhood Cancer (ICCCPO001) ~ Nancy Moules, Doug Strother, Catherine Laing, Dianne Tapp, Canada

The Benefits of Group Psychosocial Activities for Siblings of Cancer Patients: Results of a 7 Year Qualitative Study (ICCCPO003) ~ Deborah Berk, United States

Emotional Difficulties Experienced by Childhood Cancer Patients’ Siblings (PS007) ~ Shubha Maudgal, Veena Shukla, Maitreyl Nigwekar, India

Angiogenesis (S5)
Chairs: Mark Kieran, United States and Stefan Pfister, Germany
Anti-Angiogenesis: Emerging Paradigms and Biomarkers
Rakesh Jain, United States

Tumor Microenvironment Controls the Rate of Cancer Progression and Metastasis
Raghu Kalluri, United States

Matrix Metalloproteinases and Associated Proteins as Biomarkers of Angiogenesis, Tumor Growth and Progression
Marsha Moses, United States

Phase II Study of Low Dose Metronomic (LDM) Cyclophosphamide (CTX) and Vinorlebine (VN) for Recurrent or Resistant Pediatric Tumors (O045)
Odile Oberlin, Annie Rey, Gisele Goma, Daniel Orbach, Anne-Sophie Defachelles, Jean-Claude Gentet, Francoise Mechinaud, Claude Linassier, Pascal Chastagner, Didier
Cupissol, Guy Leverger, Christophe Bergeron, France

Transition of AdV-tk Gene Transfer Approach from Adult to Pediatric Oncology (O046)
Laura Aguilar, Andrea Manzanera, Claudia Moran, Mark Kieran, John Goldberg, Jana Portnow, Pamela New, E. Antonio Chiocca, Estuardo Aguilar-Cordova, Jill Brace-O’Neill, United States

Cancer Patients’ and Parents’ Attitudes towards Banking of Tissues for Research (O047) ~ Steven Joffe, Julie Najita, United States

Late Effects ~ Chairs: Louis Constine, United States and Edward Halperin, United States
Lung ~ Giovanni Scarzello, Italy
Endocrinology ~ Laurie Cohen, United States
Fertility ~ Valerie Bernier, France
Neurocognitive Function ~ Laetitia Padovani, France
Second Malignancies ~ Louis Constine, United States

Nurses Oral Papers II: Parental Perspectives – and Listening to Children and Young People
Chairs: Faith Gibson, United Kingdom and Lisa Morrisey, United States

Children, Parents, and Healthcare Professionals Perspectives on Children’s Participation in Shared Decision Making (O089) ~ Imelda Coyne1, Aislinn Amory1, Faith Gibson2, Gemma Kiernan1, 1Ireland, 2United Kingdom

Adolescent-Parent-Clinician Communication Regarding Cancer-Related Symptoms (O090) ~ Christina Baggott, United States

Weblogs of Parents with a Child Treated for Cancer: Their Intentions and Experiences (O091) ~ Veronique Van de Velde, Ilse Demares, Patricia De Vos, Johan De Porre, Barbara De Moerloose, Yves Benoit, Gino Verleye, Belgium

IPSO – Translational Research and Surgical Strategies of Childhood Solid Tumors
Sponsored by Children’s Hospital Boston
Dietrich von Schweinitz, Germany
Chairs: Jan Godzinski, Poland and Robert Shamberger, United States

Accurate Prediction of Neuroblastoma Outcome Based on miRNA Expression Profiles (O099)
Johannes Schulte1, Benjamin Schowe1, Pieter Mestdagh2, Lars Kaderali1, Prabhav Kalaghatgi1, Stefanie Schlierf1, Joelle Vermeulen2, Bent Brockmeyer1, Kristian Pajtler1, Theresa Thor1, Katleen de Preter2, Frank Speleman2, Katharina Marik1, Angelika Eggert1, Jo Vandesompele2, Alexander Schramm1, 1Germany, 2Belgium

Saturday

Therapeutic MIBG ~ Huib Caron, The Netherlands and Suzanne Shusterman, United States

Workshop on Ototoxicity ~ Chairs: Penelope Brock, United Kingdom and Edward Neuwelt, United States

Predictors of Independent Living after Childhood Cancer: A Report from the Childhood Cancer Survivor Study (O104)
Alicia Kunin-Batson, Nina Kadan-Lottick, Liang Zhu, Cheryl Cox, Veronica Bordes, Deo Kumar Srivastava, Lonnie Zeltzer, Leslie Robison, Kevin Krull, United States

Fatigue, Vitality, Sleep and Neurocognitive Functioning in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study (O106)
Nancy Clanton, James Klosky, Zhenyu Pan, E. Brannon Morris, Neelam Jain, Deo Kumar, Srivastava, Daniel Mulrooney, Lonnie Zeltzer, Marilyn Stovall, Leslie Robison, Kevin Krull, United States

Immunotherapy in Solid Tumors (S12)
Co-Sponsored by Texas Children’s Hospital and the Dunbar Foundation
Chairs: Lisa Diller and Robert Seeger, United States

Vaccine Therapy for Neuroblastoma ~ Chrystal Louis, United States

Adoptive Immunotherapy for Neuroblastoma ~ Laurence Cooper, United States

Allogeneic Transplant in Neuroblastoma: Lessons from a Mouse Model ~ Shifra Ash, Israel

Solid Tumors (OP17)
Chairs: Scott Macfarlane, New Zealand and Arthur Zimmermann, Switzerland

Integrating Diversity-Oriented Synthesis and Expression-Based Screening to Identify New Inducers of Neuroblastoma Differentiation (O143)
Stacey Frumm, Zi Peng Fan, Kenneth N. Ross, Supriya Gupta, Lynn VerPlank, Byung-Chul Suh, Jeremy Duvall, Lisa Marcaurelle, Nicola Tolliday, Kimberly Stegmaier
United States

Deep Sequencing Reveals Differential Expression of microRNAs in Favourable Versus Unfavourable Neuroblastoma (O144)
Johannes Schulte1, Tobias Marshall1, Marcel Martin1, Philipp Rosenstiel1, Pieter Mestdagh2, Stefanie Schlierf1, Theresa Thor1, Jo Vandesompele2, Angelika Eggert1, Stefan Schreiber1, Sven Rahmann1, Alexander Schramm1, 1Germany, 2Belgium

High Expression of the ALK Receptor Tyrosine Kinase Precedes Mutation as a Determining Factor of Unfavourable Phenotype in Primary Neuroblastoma (O145)
Johannes Schulte, Hagen Bachmann, Bent Brockmeyer, Sandra Nowacki, Yvonne Kahlert, Andre Oberthur, Katleen de Preter, Kristian Pajtler, Jessica Theissen, Frank Westermann, Frank Speleman, Jo Vandesompele, Frank Berthold, Angelika Eggert, Barbara Hero, Alexander Schramm, Matthias Fischer, Germany

Toxicity and Efficacy of HDC with BU/MEL and HSCT in High-Risk Neuroblastoma Patients: A Single Center Study (O146)
Stephanie Proust-Houdemont, Ellen Benhamou, Christelle Dufour, Gisele Goma, Nathalie Gaspar, Veronique Minard-Colin, Cormac Owens, Olivier Hartmann, Dominique Valteau-Couanet, France

New Drug Development for Children with Cancer
Sponsored by Lucile Packard Children’s Hospital at Stanford
Peter Adamson, United States
Chairs: Darren Hargrave, United Kingdom and Michael Link, United States

Sunday

The Voice of the Invisible – The Experiences and Consequences of
Having a Brother or Sister with Cancer During Childhood
Ulrika Kreicbergs, Sweden
Chairs: Patti Byron, Canada and Barbara Cuccovia, United States

World Child Cancer Report
Chairs: Maarten Egeler, The Netherlands and Raul Ribeiro, United States
World Child Cancer (GL001)
Tim Eden, United Kingdom

Posttraumatic Stress, Depression, and Anxiety among Adult Long Term Survivors of Cancer in Adolescence (O179)
Lutz Goldbeck, Tanja Besier, Klaus-Michael Debatin, Desiree Grabow, Ute Dieluweit, Andreas Hinz, Peter Kaatsch, Diana C. M. Seitz, Germany

Emotional, Behavioral and School Difficulties for Siblings of Children with Cancer: A Comparison with Matched Classmates (O180)
Melissa Alderfer, Caroline Stanley, Robert Noll, United States

Challenges for Solid Tumor Diagnosis in a Resource-Limited Setting (O183)
Mariana Kruger, David Reynders, Fareed Omar, Judy Schoeman, Oloko Wedi, South Africa

President’s Symposium
Genomics: Prospects for Genome-Based Personalized Medicine (S14) ~ Huib Caron, The Netherlands and Todd Golub, United States

Integrative and Functional Studies of Human Genomic Cancer ~ Levi Garraway, United States

Towards Personalized Management of Neuroblastoma ~ John Maris, United States

Ballroom B/C Ethical Challenges in Pediatric Oncology Clinical Research (S15) ~ Tim Eden, United Kingdom and Steven Joffe, United States

Best Practices in Informed Consent ~ Leslie Fallowfield, United Kingdom

Ethical Issues in Clinical Trials in the Developing World ~ Mariana Kruger, South Africa

Assent in Pediatric Research ~ Marion Broome, United States

1. (2009), 41st Annual conference of International Society of Paediatric Oncology SIOP 2009, Sao Paulo, Brazil, October 5–9, 2009. Pediatric Blood & Cancer, 53: 701–915. doi: 10.1002/pbc.22234

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

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7. Correspondence with investigators

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