Children’s Healthcare of Atlanta | Children’s Healthcare of Los Angeles

The Weill-Cornell Medical College

Pediatric Brain Tumor Research at the Weill-Cornell Medical College
Principal Investigator: Mark M. Souweidane, MD.

Representative Model of Infiltrative Brain Stem Tumors. Because a reliable model of an infiltrative brain tumor does not currently exist and since that model is needed to show efficacy in the laboratory a novel animal model is being designed. Through collaboration with another laboratory, we have begun to use a novel form of human-derived brain tumor cells, called tumor stem cells, as implants in small animals. These models will be compared with conventional models of animal models using magnetic resonance imaging (MRI) and microscopic tissue analysis.

Distribution of MAbs using Interstitial Delivery. We have investigated the distribution of the MAb, 8H9 following interstitial infusion into normal brain tissue and tissue harboring tumor implants. Ongoing work is focusing on the optimal concentration of the agent, the ideal duration of infusion, and a feasible method for detecting the agent during administration.

Toxicity and Efficacy of the Targeted Toxin, 8H9-PE38. The 8H9 molecule has been linked to genetically engineered cellular toxin, PE38, that confers a tumor killing activity to the molecule. This molecule, 8H9-PE38 is currently being used in varying concentrations to test the tolerance of normal brain tissue and to test the efficacy against human-derived brain tumor models in animals.

Toxicity of the Radiolabled MAb, 8H9-I131. Another therapeutic approach using the tumor specific 8H9 molecule is to attach a radioisotope, a molecule that is responsible for tumor cell death once. I131 is attached to the 8H9 molecule and this agent, 8H9-I131 is being locally administered in normal brain tissue by interstitial infusion to determine the tolerance of various doses.

Laboratory Aims

Our laboratory investigates a therapeutic methodology which addresses all of the aforementioned issues by combining two recent developments in cancer therapy. The first of these promising developments is a method for drug delivery called local interstitial infusion. The second research direction has been the use of tumor specific monoclonal antibodies (MAbs). These approaches are complementary in that they each have a distinct advantage over conventional therapy and the simultaneous use of both accomplishes what was otherwise impracticable.

Intersitial Infusion

Rather than administering the anti-cancer agents through the bloodstream, interstitial infusion delivers the agent though small catheters placed directly in the tumor tissue. This approach has two major advantages over other forms of drug delivery. First, no drug is exposed to the rest of the body thus avoiding the common problem of toxicity to other parts of the body (bone marrow, liver, and kidneys). The second major benefit is the ease of achieving high and uniform drug concentrations in the cancer tissue, a phenomenon which is not as possible with other systemic and local routes of drug delivery. Our laboratory and others have shown local infusion of chemotherapeutic and unconventional tumor-targeting agents to be very safe and applicable for infiltrative brain tumors that are not accessible for tumor removal.

Immunotherapy

A concurrent advancement in tumor therapy has been the design of molecules that possess a high degree of specificity against tumor cells, the aforementioned tumor-targeting agents. These molecules possess the ability to selectively attach to tumor cells while not affecting normal cells; monoclonal antibodies (MAbs) are such molecules. Our collaborators have isolated an MAb, 8H9, that has recently been shown to be very specific against brain tumors with no reactivity with normal brain cells. In addition to their tumor specificity, MAbs are also very appealing since they can be conjugated or attached with molecules that result in cell death. Treatment with tumor-targeting agents has not been routinely used for brain tumors until recently because of the large size of these molecules. This large size of MAbs limits their movement from the bloodstream to the tumor tissue. The use of local infusion ideally overcomes this obstacle since direct delivery bypasses the BBB. This promising therapeutic scheme has been recently introduced in some clinical trials of malignant brain tumors in adults, using a different MAb.