Neuroblastoma Immunotherapy by Paul M. Sondel, MD, PhD

Lecture by Paul M. Sondel, MD, PhD We are pursuing basic, preclinical and clinical mechanisms to induce in vivo activated innate immune effector cells to provide anti-tumor benefit.

COG, Apeiron to conduct APN301 trial in neuroblastoma patients

Children´s Oncology Group (COG) and Apeiron Biologics AG (Apeiron) will jointly investigate Apeiron´s APN301 in a clinical phase II study in pediatric neuroblastoma patients.

APN301 is a recombinant fusion protein consisting of the humanized anti-GD2 monoclonal antibody hu14.18 fused to the cytokine interleukin-2 (IL2).

APN301 will be administered along with GM-CSF and isotretinoin to children with refractory or relapsed neuroblastoma,in the trial.

The study which is based on a recent trial with an anti-GD2 monoclonal antibody will commence in the third quarter of 2011 in hospitals throughout the US and Canada.

Children´s Oncology Group MD Peter C. Adamson said leveraging immunotherapy is a primary strategic initiative in their efforts to improve the outcome for patients with high-risk neuroblastoma.

Source: http://clinicaltrials.pharmaceutical-business-review.com/news/cog-apeiron-to-conduct-apn301-trial-in-neuroblastoma-patients-290911
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PHILADELPHIA, MADISON, Wisconsin and VIENNA, September 29, 2011 /PRNewswire via COMTEX/ -- Children's Oncology Group (COG) and APEIRON Biologics AG (Apeiron) announced today that they will jointly investigate Apeiron's APN301 in a clinical phase II study in pediatric neuroblastoma patients.

APEIRON Biologics AG (Apeiron) and the Children's Oncology Group (COG) today announced a collaboration on conducting a clinical phase II study in neuroblastoma patients. Neuroblastoma, a cancer of the nervous system, can be one of the most difficult to treat childhood cancers with about 650 to 750 children diagnosed each year in the U.S. and the E.U., respectively.

In the course of this new clinical trial, Apeiron's APN301, a recombinant fusion protein consisting of the humanized anti-GD2 monoclonal antibody hu14.18 fused to the cytokine interleukin-2 (IL2), will be administered together with GM-CSF and isotretinoin to children with refractory or relapsed neuroblastoma. The design of this trial is based on a recently concluded study with an anti-GD2 monoclonal antibody, performed by COG, in which clinical activity was shown.

The study is scheduled to start in the third quarter of 2011 and will be conducted in multiple hospitals throughout the United States and Canada.

"We are excited to be working with Apeiron to continue to develop this important new approach to treating children with neuroblastoma," said Peter C. Adamson MD, Chair of the Children's Oncology Group. "Being able to leverage immunotherapy is a primary strategic initiative in our efforts to improve the outcome for patients with high-risk neuroblastoma."

Dr. Paul Sondel, Principal Investigator and Study Co-Chair (with Dr. Suzanne Shusterman): "This agent has demonstrated potent antitumor effects in preclinical work and has shown clinical antitumor activity in our recently completed clinical phase II trial. This next study is designed to provide even greater antitumor activity, to better understand the mechanisms of this activity and identify the characteristics of children most likely to respond."

Dr. Hans Loibner, CEO of Apeiron: "We are proud to collaborate with this renowned co-operative group. COG's expertise and the quality of their clinical network in the U.S. and Canada are most impressive. The study will give important insights into the efficacy of APN301 in high-risk neuroblastoma patients and the results may serve as an important component for the registration of this innovative immunotherapy."

*Original Publication: Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children's Oncology Group (COG) Phase II Study. Suzanne S. Shusterman, Wendy B. London, Stephen D. Gillies, Jacquelyn A. Hank, Stephan D. Voss, Robert C. Seeger, C. Patrick Reynolds, Jennifer Kimball, Mark R. Albertini, Barrett Wagner, Jacek Gan, Jens Eickhoff, Kenneth B. DeSantes, Susan L. Cohn, Toby Hecht, Brian Gadbaw, Ralph A. Reisfeld, John M. Maris, and Paul M. Sondel. Journal of Clinical Oncology (2010) 28: 4969-4975.

About The Children's Oncology Group:

The Children's Oncology Group (childrensoncologygroup.org), a National Cancer Institute supported clinical trials group, is the world's largest organization devoted exclusively to childhood and adolescent cancer research. The Children's Oncology Group (COG) unites more than 7.500 experts in childhood cancer at more than 200 leading children's hospitals, universities, and cancer centers across North America, Australia, New Zealand, and Europe in the fight against childhood cancer. COG research has turned children's cancer from a virtually incurable disease 50 years ago into one with an overall cure rate approaching 80 percent today. Research conducted by the COG is also supported through the generosity of individuals, corporations and private foundations working with The Children's Oncology Group Foundation (TheCOGFoundation.org), which enables philanthropic resources to go directly to COG's worldwide team of researchers committed to turning new discoveries into better treatments.

About Apeiron (as of September 2011):

Apeiron is a privately financed biotech based in Vienna, Austria. Apeiron focuses on biological and immunological treatments against cancer and related conditions. Including the recently closed licence agreement for the phase III project Mab ch14.18/CHO (APN311), Apeiron's project portfolio consists of five projects under clinical evaluation, and four preclinical projects. Clinical projects include the immunocytokine hu14.18-IL2 (APN301) that is about to enter a phase II (for certain neuroblastoma patients) shortly and is also being clinically tested against melanoma. Also in clinical stage is a liposomal formulation of recombinant human Superoxide Dismutase (APN201) to prevent or treat skin damage due to radiation treatment in cancer. A further clinical project, recombinant human Angiotensin Converting Enzyme 2 (APN01), was licensed to GlaxoSmithKline early 2010. It is expected to commence a phase II study for the treatment of Acute Respiratory Distress Syndrome in the near future and has considerable potential in other disease areas. Apeiron is operational since 2006 and employs approx. 25 people.

About APN301:

APN301 (hu14.18-IL2) is a recombinant fusion protein that consists of the humanized 14.18 monoclonal antibody, which recognizes the GD2 disialoganglioside, strongly expressed on virtually all cases of human neuroblastoma, as well as on several other human cancer types (including melanoma, small cell lung carcinoma, osteosarcoma, and soft-tissue sarcoma), linked genetically to human recombinant interleukin-2 (IL2) lymphokine. IL2 has been tested extensively in clinical cancer trials and is approved as an immune activator with documented anti-tumor effects in certain cancers (melanoma and renal cell cancer).

In patients, hu14.18-IL2 localizes to GD2-positive tumor cells via the antibody component. The fused IL2 is designed to stimulate the patient's immune system against the tumor by activation of both NK and T cells, whereas the Fc portion of the antibody is designed to trigger tumor cell killing by ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Hu14.18-IL2 has shown activity in a phase II clinical study in certain children with neuroblastoma* and was also tested in a phase I/II study in late stage malignant melanoma, showing immune activation. Apeiron has obtained a world-wide exclusive licence for hu14.18-IL2 earlier this year from Merck KGaA.

Contact Children's Oncology Group: Elizabeth O'Connor, COO COG Operations Center 440 E. Huntington Drive, 4th Floor Arcadia, CA 91006-3776 T +1(0)626-447-0064 E econnor@childrensoncologygroup.org W http://www.childrensoncologygroup.org Contact Apeiron: Dr. Hans Loibner, CEO Campus-Vienna-Biocenter 5 1030 Vienna Austria T +43(0)1-865-6577 E apeiron@apeiron-biologics.com W http://www.apeiron-biologics.com Copy Editing & Distribution: PR&D - Public Relations for Research & Education Mariannengasse 8 1090 Vienna Austria T +43(0)1-505-70-44 E contact@prd.at W http://www.prd.at

Children With Neuroblastoma Helped by New Chemo Regimen

The trial involved 563 children -- median age 3. After three years, the survival was 60 percent for those receiving busulphan-melphalan compared to 48 percent for the CEM group "and the busulphan group had lower rates of relapse and progression."
"The study's results are important for patients with this extremely difficult to treat disease," said lead author Ruth Ladenstein of the University of Vienna and St. Anna Children's Cancer Research Institute in Vienna, Austria.

The results were presented in Chicago at the 47th annual conference of the American Society of Clinical Oncology. More than 30,000 researchers and representatives of pharmaceutical companies participated in the forum.

The phase 3 trial showed better overall survival with a combination of the myeloablative chemotherapy drugs busulphan and melphalan (BuMel) compared to a different myeloablative regimen of three chemotherapy drugs, carboplatin, etoposide and melphalan (CEM).

Previously, only 30 percent of children with high-risk neuroblastoma survive long-term.

The study's results show that survival can increase by 20 percent.

"We could potentially improve overall prognosis by up to 35 percent in the future," Ladenstein said.

"Thus, we overcome the 50 percent threshold in survival rates by choosing the right high-dose myeloablative regimen for these patients," she added.

Myeloablative chemotherapy is high-dose chemotherapy that kills cells in the bone marrow, including cancer cells.

Neuroblastoma is rare, but is the most common cancer in the first year of life and accounts for approximately 15 percent of childhood cancer deaths.

About 650 cases are diagnosed each year in the United States, with 40 percent considered high-risk, meaning they are "very likely to recur or progress, despite therapy," the study said.

"Based on the results, the randomization was stopped early," the study said.

The treatment-related death rate was 3 percent for the busulphan regimen and 5 percent for CEM, the study said.Publish Post

Source-AFP

Targeted Therapy for Neuroblastoma on the Anvil After Detection of Genetic Glitch

Research News
A genetic glitch responsible for the development of the fatal childhood cancer, neuroblastoma, has been identified by scientists from University of Florida.



They hope that the new discovery may provide a novel approach for developing treatments that target the disease also known as neuroblastoma. 


"What makes our study so important is that although neuroblastoma accounts for 7 percent of childhood cancers, it is responsible for 15 percent of deaths in children with cancer," Nature quoted Dr Wendy London, a research associate professor of epidemiology, biostatistics and health policy research at the UF College of Medicine and a member of the UF Shands Cancer Centre as saying. 


"This paper adds yet another gene in the pathway that could lead to tumorigenesis (tumour formation) of neuroblastoma," she added. 


Under the supervision of Dr John J. Maris, director of the Cancer Centre at The Children's Hospital of Philadelphia, researchers team conducted a genome-wide study to identify errors in DNA that could be associated with neuroblastoma. 


They looked at the genetic makeup of 846 patients with neuroblastoma and 803 healthy patients in a control group and found that a glitch called a "copy number variation" in a single chromosome is associated with neuroblastoma. 


The copy number variation has to do with the gain, loss or duplication of snippets of DNA. 


"This is part of series of papers that creates the bigger picture, an understanding of the genetic mechanisms that lead to neuroblastoma," said London. 


"We are searching for genetic targets to treat with therapy," she added. 


The researchers have also found gene called BARD1, six single-nucleotide polymorphisms - variations in tiny pieces of DNA - were also associated with neuroblastoma.


Source-ANI
RAS

Chromosome 6p22 Locus Associated with Clinically Aggressive NeuroblastomaMaris

Chromosome 6p22 Locus Associated with Clinically Aggressive NeuroblastomaMaris J. M., Mosse Y. P., Bradfield J. P., Hou C., Monni S., Scott R. H., Asgharzadeh S., Attiyeh E. F., Diskin S. J., Laudenslager M., Winter C., Cole K. A., Glessner J. T., Kim C., Frackelton E. C., Casalunovo T., Eckert A. W., Capasso M., Rappaport E. F., McConville C., London W. B., Seeger R. C., Rahman N., Devoto M., Grant S. F.A., Li H., Hakonarson H. Abstract FREE Full Text PDF N Engl J Med 2008; published at www.nejm.org on May 7, 2008 (10.1056/NEJMoa0708698).

ABSTRACT

Background Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known.
Methods We performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations.
Results We observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms (SNPs) at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180 (P=1.71x10–9 to 7.01x10–10; allelic odds ratio, 1.39 to 1.40). Homozygosity for the at-risk G allele of the most significantly associated SNP, rs6939340, resulted in an increased likelihood of the development of neuroblastoma (odds ratio, 1.97; 95% confidence interval, 1.58 to 2.45). Subsequent genotyping of the three 6p22 SNPs in three independent case series confirmed our observation of an association (P=9.33x10–15 at rs6939340 for joint analysis). Patients with neuroblastoma who were homozygous for the risk alleles at 6p22 were more likely to have metastatic (stage 4) disease (P=0.02), amplification of the MYCN oncogene in the tumor cells (P=0.006), and disease relapse (P=0.01).

Conclusions A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.

Source: http://content.nejm.org/cgi/reprint/NEJMoa0708698v2.pdf

Lytic Bone Lesions in Human Neuroblastoma Xenograft Involve Osteoclast Recruitment and Are Inhibited by Bisphosphonate

Yasuyoshi Sohara, Hiroyuki Shimada, Miriam Scadeng, Harvey Pollack, Shinya Yamada, Wei Ye,
C. Patrick Reynolds, and Yves A. DeClerck2

Abstract
Neuroblastoma is the second most common solid tumor in childhood and frequently metastasizes to the bone marrow and the bone matrix. The mechanism involved in bone metastasis and destruction in neuroblastoma is poorly understood. Using a model of bone invasion in immunodeficient mice, we demonstrated that neuroblastoma cells recruited osteoclasts to generate osteolytic lesions and invade the bone matrix. In further support of a contributory role for osteoclasts in neuroblastoma bone invasion, we demonstrated that treatment with the bisphosphonate compound, ibandronate, significantly delayed the progression of osteolytic lesions. The data suggest that bisphosphonates may be clinically effective in the treatment of bone metastases in neuroblastoma.

Source: http://cancerres.aacrjournals.org/cgi/reprint/63/12/3026.pdf

Curcumin induces apoptosis in human neuroblastoma cells via inhibition of NFkappaB.

Institut für Anatomie II: Experimentelle Morphologie, Universitätsklinikum Hamburg-Eppendorf 20246 Hamburg, Germany. c.freudlsperger@uke.uni-hamburg.de 2008 Jan-Feb;28(1A):209-14. Anticancer Res

BACKGROUND: Metastasised neuroblastoma is a largely incurable neoplasia in children over one year of age using current treatment protocols. After dissemination to the bone, the survival rate is <7%,>

MATERIALS AND METHODS: Proliferation of neuroblastoma cell lines Lan-5, SK-N-SH and Kelly under the treatment of curcumin over a broad concentration range (1 x 10(-5) to 1 x 10(2) microM) was assessed using XTT cell proliferation assays. Possible induction of apoptosis through curcumin treatment was assessed by detection of DNA fragmentation. To investigate the effect of curcumin on NFkappaB activation, the protein levels of the NFkappaB subunit p65 of curcumin-treated cells were compared to untreated cells using Western blots.

RESULTS: Curcumin showed a significant dose-dependent antiproliferative effect on all three neuroblastoma cell lines starting at a concentration of 1 x 10(-3) microM. The highest concentration of 1 x 10(2) microM significantly reduced the viable cell count to 8-48% depending on the cell line. This antiproliferative effect was mediated through an increased induction of apoptosis by inhibition of NFkappaB, corroborating earlier findings indicating an antiapoptotic effect of NFkappaB.

CONCLUSION: Our results suggest that curcumin might hold promise in the treatment of patients suffering from neuroblastoma

Source: Meryl Witmer [meryl@EAGLECAPITAL.NET]; The Neuroblastoma (Cancer) Online Support Group [N-BLASTOMA@LISTSERV.ACOR.ORG];
Date: Sat 4/5/2008 8:01 AM