04:51pm Wednesday 20 September 2017

A new immunotherapy targets pediatric malignant brain tumors

In a research recently reported by Healthcanal, Dr. Sharareh Gholamin and colleagues tested a new immunomodulatory agent, antiCD47 antibody, for its therapeutic potential against childhood brain tumors, the most common malignant solid tumors in children.  The results obtained from this study were promising against five malignant pediatric brain tumors.

Dr. Gholamin, first author of the scientific publication, answered Healthcanal’s questions about her and her colleagues’ important work.

Dr. Gholamin, what inspired you to study potential therapy candidates for childhood brain tumors?

Although low in frequency (roughly 5.47 cases per 100,000 people), pediatric brain tumors account for the most devastating solid tumor in children and the current standard treatments for these tumors come at a great cost of long-lasting neurocognitive disorders, if they are ever effective.

Moreover, Children usually receive the newly developed treatments that are only approved and optimized for adult patients and that may, in part, result in suboptimal therapeutic response in children. Therefore, we were inspired to test potential candidates on childhood tumors at the preclinical level to address this acute and unmet medical need.

What is the current status of treating these devastating conditions?

Pediatric high-grade gliomas (pHGG, including glioblastoma, and diffuse intrinsic pontine glioma) are essentially incurable causing death in 6 months to three years. Diffuse intrinsic pontine glioma, arising in the brainstem is inoperable and resistant to radiotherapy. There has been no chemotherapy developed for this tumor yet. Others, such as medulloblastoma (MB), can be treated in a significant number of children, but the surgery, irradiation, and chemotherapy necessary to achieve these “successes” come at the great cost of permanent physical and intellectual disabilities.

Thus, more effective and safer treatments are urgently needed, as highlighted by off-target effects of current treatments. Our main aim is to develop a drug which would not only be effective but also safe and have limited activity against normal neural cells.

What makes immunomodulatory agents, such as antiCD47 antibodies tested by you, attractive therapeutic candidates for pediatric brain tumors?

In continuation of growing trend to develop immunotherapies and following the recent favorable outcomes in treatment of various type of tumors using myeloid checkpoint inhibitors, we determined to exploit an innate immune system to fight cancer cells. Humanized anti-CD47 antibody–through harnessing the innate immune cells, named macrophages–can detect cancer cells over normal cells and elicit a cascade of events which ultimately leads to death of cancer cells.

In addition to the rareness of these tumors, treatment options are also quite limited and therefore it is must be hard to find models for studying treatment candidates. Can you elaborate on the validity of the chosen models?

When using mouse models to investigate the therapeutic potential of a certain anti-cancer candidate, one can choose either:

1. a syngeneic model, in which mouse tumors cells are used. In this model, the animal’s essential functions are all intact, but the genetic complexity of a human tumor is not fully represented;

or

2. a xenograft model in which patient derived cells are placed in the actual site of the tumor. The mouse’s immune system must be modified to avoid rejection of the foreign tumor cells, but tumor’s complexity is fully represented and the organ environment in which the tumor grows can be reproduced.

The xenograft models were the better choice, as the pediatric brain tumors are very unique in their complexity and distinct from adult tumors in many parameters. Although the immune system is partly compromised, the macrophages as the main involved immune cells modulated by humanized anti-CD47 antibody still exist.

What other preclinical and clinical studies are planned for antiCD47 antibodies?
Anti-CD47 antibody-stimulated macrophages may further prime T cells, thereby activating the adaptive immune response and boost overall anti-tumor effect. To fully exploit them against brain tumor cells, the combination of checkpoint inhibitors along with anti-CD47 antibodies is currently being evaluated in preclinical setting. Dr. Cheshier and his team currently broaden the combinatorial approaches for treatment of such malignancies with the hope that they can further extend them to phase I trial.

In regard to clinical studies, Phase I clinical trials using humanized antiCD47 antibodies are currently underway for non-CNS solid tumors and hematologic malignancies. Clinical trials for Adult and CNS malignancies are planned for 2018.

In summary, can you highlight the most important findings of your study?

  • Blocking the CD47-SIRPa pathway using a monoclonal antibody shows efficacy against five malignant pediatric brain tumors.
  • The humanized antiCD47 antibody is effective against metastatic medulloblastoma, the leading cause of mortality in recurrent disease.
  • The humanized antiCD47 antibody showed negligible toxicity against normal neural cells while it was effective in removal of tumor cells.
  • In the mouse, humanized antiCD47 antibody, despite its relatively large size, can cross the blood-brain-barrier

 

Sharareh Gholamin is currently at California Institute of Technology (Caltech) and developing new immunotherapeutics for brain tumors using single cell technology.

 


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