For two decades, the neuroblastoma team at Memorial Sloan Kettering has been at the forefront of the effort to develop innovative drugs and treatments that prolong survival but do not cause debilitating long-term side effects.
Chimeric and Humanized Antibodies
Immunotherapy is the cornerstone of our treatment program for high-risk neuroblastoma. Our protocols for metastatic disease (monoclonal antibody 3F8) and central nervous system relapse (monoclonal antibodies 8H9 and 3F8) have shown promise. At present, our monoclonal antibodies are produced in mice. While they have been effective in treating neuroblastoma in some patients, mouse-derived proteins are foreign to the human body and stimulate neutralizing antibodies (human anti-mouse antibody, or HAMA). When HAMA develops, the treatment stops working, which is of particular concern for patients who did not receive a sufficient number of doses of 3F8. Technology exists to “humanize” or “chimerize” 3F8 — i.e., to engineer them so that they are more like human antibodies. Chimeric antibodies are almost half human and should substantially reduce the incidence of early HAMA. These human-like forms can also be made to bind more strongly to white cell receptors. We are actively pursuing both the chimeric and humanized forms, and hope to make them available to patients in the near future.
Monoclonal antibodies can be trained to deliver liquid radiation. When linked to a particular form of radioactive iodine (124I), these antibodies enable us to use a positron emission tomography (PET) scanner to accurately detect tumors that spread to the central nervous system (CNS) and the leptomeninges. Having detected tumor cells, we can then link the antibodies to another form of radioactive iodine (131I) and use the antibodies to deliver lethal doses of radiation to the tumor cells without damaging normal cells. Monoclonal antibodies can also be linked to alpha emitters (e.g., 213Bismuth and 225Actinium), which may kill tumor cells with even greater precision and efficiency than iodine. We are working on applying these antibodies to treat tumors in compartments besides those in the CNS.
Like monoclonal antibodies, cancer vaccines can train the body's immune system to fight cancer. These vaccines instruct the body's immune cells to recognize and destroy existing cancer cells and any cancer cells that may subsequently develop. Cancer vaccines are specific to particular types of cancer. We are currently doing preclinical testing of several neuroblastoma-specific vaccines. While some vaccines stimulate the body to make antibodies against neuroblastoma, other vaccines activate lymphocytes to fight the tumor. These vaccines will likely be most effective for patients with only minimal residual tumor in their body.
We are also investigating new ways to attack neuroblastoma, in part by taking advantage of new drugs already in clinical trials for adult patients. Some of these drugs can enhance the effectiveness of chemotherapy without added toxicities, especially in patients whose tumor has become resistant to standard treatment. Others are made to block the ability of neuroblastoma cells to spread. We are also doing an exhaustive large-scale screening of nonstandard medicines and chemicals to find new drugs to treat neuroblastoma. We are committed to the rapid translation of these promising drugs from the test tube to clinical trials.