Physician-scientist Nai-Kong Cheung focuses on engineering of antibodies and immune cells to treat solid tumors in children. We spoke to him in 2003.
In pediatric oncology, we face a particular kind of challenge. When treating a child with a cancer such as neuroblastoma, which originates from primitive cells of the sympathetic nervous system, we have to deal with the immediate threat of the disease, but then we also have to consider the long-term effects of the treatment — these patients have their whole lives ahead of them. What we call a “success” is a qualified statement. Some neuroblastoma tumors are metastatic and require intensive treatments; others are less threatening and can actually disappear or remain unchanged with minimal or no treatment.
Four years before I joined the Center in 1987, I began to devote my professional life, from the laboratory bench to the patient’s bedside, to the treatment of neuroblastoma. For two decades, I have witnessed the heavy toll on children and families affected by this cancer. Our priority is to identify the 50 percent of patients who do not need cytotoxic treatment such as radiation or chemotherapy, while for the other 50 percent, to design treatments that are not only more effective, but also more specific.
With the help of sophisticated imaging and the tools of molecular pathology, our neuroblastoma team can now, with 95 percent certainty, identify those patients whose tumors do not need cytotoxic therapy and achieve a greater than 90 percent survival rate. This is a substantial improvement compared to a decade ago, and we are excited by a worldwide effort to validate these approaches in large clinical trials.
Sparing children unnecessary therapy is always a blessing, since treatment-related issues (medical cost, out-of-pocket expenses, time away from work, issues with other children in the family, and marital problems) can cripple even the strongest family. However, the five percent of patients whose tumors only masquerade as low-risk is a constant reminder that further understanding of tumor biology is necessary. We are hopeful that mapping the genetic makeup of these tumors will eventually eliminate these uncertainties and allow more accurate classifications and treatment choices.
For the other 50 percent of neuroblastoma patients, those who do need aggressive therapy, we have also made substantial progress in recent years. For more than a decade, we have utilized monoclonal antibodies to deliver therapy more selectively to these tumors. We take advantage of the ability of these antibodies to activate white cells and complement proteins, as well as to carry radioisotopes to deliver radiation to kill tumor cells.
We continue to optimize the combination of chemotherapy, surgery, radiation, and immunotherapy for high-risk metastatic neuroblastoma. More recently, we demonstrated that the combination of monoclonal antibody 3F8 plus GM-CSF (granulocyte macrophage colony stimulating factor) is highly effective in destroying residual tumor cells in the bone marrow. While an antibody alone can prolong survival for high-risk patients in their first or second remission, the addition of GM-CSF can further improve their odds.
Back in the laboratory, we continue to explore methods to increase the effectiveness and selectivity of antibody-based treatment strategies. For example, we have identified beta-glucan derived from barley as a potential enhancer of antibody action against human tumors.
We have also genetically engineered monoclonal antibodies to improve their therapeutic ratio using a “two-step” targeting strategy, utilizing a fusion protein called scFv-streptavidin that has two binding sites, one for the tumor and the second for a small molecule to carry therapeutic agents such as radioisotopes, drugs, or biologics. We hope to test these scFv fusion proteins in the clinic in the very near future.
Because more than ten percent of treated patients return to us with isolated tumors in the brain or the surrounding cerebrospinal fluid, we are developing more effective methods to treat or to prevent such occurrences. By injecting antibodies or antibody conjugates directly into the fluid, we can kill tumor cells that hide there and thus escape chemotherapy. In early clinical studies, there were few serious side effects and some patients have lived longer than expected.
In an effort to further increase the selectivity and efficacy of such an approach, David Scheinberg and I, both members of Memorial Sloan Kettering’s new Experimental Therapeutics Center, have teamed up to investigate the use of “nanogenerators” carried by antibodies to kill tumor cells circulating in the cerebrospinal fluid. This method has great potential, and it is a good example of how Memorial Sloan Kettering researchers work together.
We continue to bridge our laboratory findings to the clinic, constructing new treatment protocols and offering hope for families whose children have unusually aggressive tumors. Besides monoclonal antibodies and new chemotherapeutic agents, we are testing new classes of drugs, such as arsenic trioxide. We are encouraged by its potential clinical benefit and the relatively mild side effects.
When I left my home in Hong Kong to attend college and eventually medical school in the United States, I embarked on a journey of hope for a healthier world. Seeing children and their families stricken by neuroblastoma is heart-wrenching. Together, these special people and a large team of health professionals at Memorial Hospital will continue to orchestrate a “Symphony of Hope,” the theme of our recent neuroblastoma survivors reunion celebration.