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SU2C-St. Baldrick’s Dream Team Progress Update

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The SU2C-St. Baldrick’s Dream Team Progress Report

Immunogenomics to Create New Therapies for High-Risk Childhood Cancers

Funding: $14,500,000

Leader: John M. Maris, M.D., The Children’s Hospital of Philadelphia
Co-Leader: Crystal L. Mackall, M.D., National Cancer Institute

Fast Facts on Childhood Cancer:

  • Every year an estimated 263,000 new cases of cancer affect children under the age of 20 worldwide.
  • Childhood cancer is the leading cause of death by disease in children under the age of 15 in the United States.
  • Unlike many adult cancers, the causes of most childhood cancers are unknown and are not strongly linked to lifestyle or environmental risk factors.


Project Background

The Pediatric Cancer Dream Team’s Research Project
Curative chemotherapy for cancer was first realized in children and survival rates for many childhood cancers improved dramatically through the latter quarter of the 20th century. However, those cure rates have plateaued since the 1990s, and for some childhood cancers, there has been little to no improvements. Furthermore, current therapies can’t win the battle against childhood cancer when they often lead to side effects that reduce the quality of life for young patients as they grow into adulthood. New classes of therapeutics are needed to improve survival of children with cancer and decrease the physical, emotional, and financial life-altering costs of curative therapies.

Investigators on the Pediatric Cancer Dream Team (PCDT) have used new technologies in the field of cancer genomics to discover the fundamental biology involved in the most aggressive childhood cancers. These genomic studies have provided new scientific insights into, but have not yet revolutionized therapies. In parallel, investigators on the Team have also led efforts to harness the body’s own immune system to eradicate cancer. Stunning recent advances in this field have resulted in unmatched enthusiasm for immunotherapy as a potent new weapon in the fight against childhood cancer. However, use of these immunotherapies remains limited, since they are available for only a few disease types and in very few institutions. Shockingly, the fields of cancer genomics and immunotherapy have come to age separately, with essentially no cross-fertilization and little collaboration until the formation of the PCDT 30 months ago.

The team brings the fields of genomics and immunotherapy together through collaborative projects focused on developing new, targeted immunotherapies for the most difficult to cure childhood cancers. The team is accelerating progress by bridging the gaps between genomics and immunology across the spectrum of discovery to potentially curative therapies:

  • Discovery:  The team has employed recent technologic advances to identify new targets for immunotherapy.
  • Drug Development: The multidisciplinary team is developing new drugs based on these new targets. These new drugs will be tested first in the laboratory before they are considered for clinical trials
  • Therapy: PCDT clinical trials consortium currently is conducting 14 clinical trials that have enrolled 279 patients, with stunning and sustained remissions in the majority of their relapsed acute lymphoblastic leukemia patients.

This PCDT is revolutionizing the approach to childhood cancer and are now focused on finding a way to continue their work and progress beyond the four years of SU2C-SBF funding.


Status Update:

6 Month:
During the first 6 months, the Stand Up To Cancer-St. Baldrick’s Pediatric Dream Team has laid the foundation for executing their proposed studies. They have:

  • Collected samples of the most lethal pediatric cancers and analyzed the molecules on the surface of the cancer cells.
  • Optimized technologies to analyze and store the collected data regarding the identity of molecules on the surface of different cancer cells.
  • Started testing surface markers identified to be preferentially expressed in pediatric cancer cells compared with normal cells to see if they are good candidates for drug development.
  • Developed and tested newly identified immunotherapeutics.
  • Developed a platform to share results in real-time with all participating institutions.
  • Continued ongoing safety/efficacy studies of lead immunotherapeutics to ultimately expand to other institutions.

By the end of year 1, the Dream Team expects to a) create computing infrastructure, database, and analytic pipeline; b) complete the creation of pediatric cancer and normal tissue microarrays, which are necessary for screening cell surface proteins; c) continue identifying and analyzing candidate cell surface targets; d) conduct preclinical studies on immunotherapies generated based on the identified cell surface targets; and e) expand immunotherapeutic clinical trials that have been shown to be safe in patients.

12 Month:
During this 6-month reporting period, the Pediatric Dream Team has continued its progress on this grant. They have:

  • Identified molecules on the surface of cancer cells in several pediatric cancers that may be useful for drug development.
  • Tested to see if the molecules identified should be developed into a drug to treat the specific cancer.
  • Continued to develop new immune-therapeutics and conducted preliminary testing to see if they work.
  • Developed a standardized diagnosis and management plan for Cytokine Release Syndrome (CRS), a common and potentially fatal complication which occurs with the use of antibody therapies.

This Dream Team is meeting their set goals and will continue their proposed work. During the next six month period, they will continue validating molecules identified on surface of cancer cells and identify new molecules in underrepresented pediatric cancers. They will also work on developing markers that can be used to help improve immunotherapy for patients. This Dream Team is also trying to understand why patients stop responding to treatment with CD19-CAR T cells, which are immune cells engineered to attack tumor cells. In addition, they will be opening five clinical trials by the end of 2014 and will continue to develop new immunotherapies.

18 Month:
During this 6-month reporting period, the Pediatric Dream Team has continued its progress. In particular, they have:

  • Developed computer based platforms to aid with data analysis and the drug discovery pipeline.
  • Identified important cellular changes in several pediatric tumors that may serve as targets for immunotherapy.
  • Made specific and specialized immune targeted drugs and then testing to see if they can inhibit pediatric tumors.
  • Opened three new clinical trials in 2014.
  • Worked on 14 immunotherapy (CAR T-cell based therapy) clinical trials for childhood cancer, with 12 currently open (2 completed), of which 8 focus on B cell malignancies and 4 on high risk solid tumors.

This Dream Team is meeting their set goals and will continue their proposed work. During the next six month period, they will continue to generate new data and bring in collaborators in underrepresented pediatric cancers. They will use the computer-based platforms to identify the best drugs for continued development and movement towards the clinic. The Team will open several new clinical trials that will focus on new targets and novel strategies based on their work.

24 Month:
During this 6-month reporting period, the Pediatric Dream Team has made progress, as highlighted below:

  • Continues to discover, generate, and develop immunotherapeutic candidates targeting cell surface molecules that are specific to different types of pediatric cancers.
  • Continues to investigate strategies to overcome resistance to immunotherapy, specifically after initial CAR T cell treatment.
  • Continues to develop and test antibody drug conjugates that work with the immunotherapeutic proteins to discriminate between healthy and cancerous cells.
  • Continues to work on 12 open clinical trials for childhood cancer with two additional scheduled to open within the next six months.

This Dream Team is meeting their set goals and will continue their proposed work. During the next six month period, they will continue to test their novel discoveries in laboratory experiments and will continue to move current laboratory work to the clinic. Several new clinical trials will open in the next 6 months, with increasing focus on new targets as well as new strategies.

30 Month
All subprojects of this Dream Team continue to progress. The major recent advances are highlighted below:

  • The informatics team continues to develop software to support research initiatives, target identification pipelines, and develop a formal structure to manage data storage and infrastructure.
  • The SU2C-SBF Pathology Core continues to work with all PCDT investigators to prioritize which molecules found on the surface of tumors are the best for development of new immunotherapies.
  • The Dream Team published an important paper in the journal Cancer Cell describing possible new drug targets found on the tumor cells in in rhabdomyosarcoma and osteosarcoma.
  • They reported new information on how some patients with B-cell acute lymphoblastic leukemia relapse after receiving the immune therapy called CD19 CAR T therapy.
  • The team continues to generate new approaches to direct toxic drugs to cancer cells using antibodies against molecules found on the outside of cancer cells.
  • The Dream Team has a total of 15 active pediatric cancer immunotherapy trials, one of which has completed enrollment. Several additional trials are under development.

36 Month
During the 36-month reporting period, this Dream Team continues to achieve their proposed milestones with substantial progress made in all subprojects.

  • The Team has made advances in immunotherapy target discovery, specifically in high risk and rare solid tumors. They are currently validating novel immunotherapeutic targets in tumors of pediatric patients with osteosarcoma and ependymoma.
  • The Team continues to investigate why some patients with B-cell acute lymphoblastic leukemia relapse after receiving the immune therapy CD19 CAR T therapy.
  • The Team is working with a new vaccine that has shown to activate and expand CD19 CAR T cells. A clinical trial using this vaccine is being planned./li>
  • The Team continues to make progress on developing antibody-based therapeutics and anticipate their first clinical trial using antibodies (as opposed to T cell therapy) will open in 2016.
  • There are 15 active clinical trials.

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