Treatment

In the 1980s, fewer than 5% of children diagnosed with high risk neuroblastoma survived.

Although intensified chemotherapy and radiation treatments improved the chances of killing this vicious cancer, many children suffered severe side effects–including developing other forms of cancer caused by the treatments themselves.

In 1987, the MSKCC team began treating children with 3F8, a monoclonal antibody developed by Dr. Cheung. 3F8 can attach to neuroblastoma cells and kill them, and can also train the child’s own immune system to attack and kill neuroblastoma. In the last 2 decades, 3F8 treatment notably improved survival, without lasting side effects.

Today, 80 percent of children with high risk neuroblastoma treated at MSKCC from diagnosis achieve remission. More than 50% of these patients are expected to remain in remission after consolidation with 3F8/GMCSF immunotherapy. In this section you will find links to information about MSKCC and their expertise in treating children with neuroblastoma.

Symptoms

Neuroblastoma’s first symptoms are often vague and may include fatigue and loss of appetite. Later on, symptoms depend on where the tumor takes root within the body.

Diagnosis & Staging

Diagnosis is made using either a biopsy of the tumor or the results of urine and bone marrow tests. The treatment each child receives depends on the age at diagnosis, tumor location, stage of disease, and tumor biology.

Treatment

Neuroblastomas are highly diverse in their behavior. Some will go away without any treatment, and others can be cured by surgery alone. But half of these tumors spread quickly to the bone and bone marrow and may require chemotherapy, radiation therapy, stem cell transplantation, or immunotherapy.

Innovative Treatments

The MSKCC team has a great deal of experience using the latest therapies to treat all stages and types of neuroblastoma, including the most advanced and aggressive forms.

MSKCC Clinical Trials

A continually updated listing of Memorial Sloan-Kettering’s current clinical trials for neuroblastoma.

Treatments Offered at Memorial Sloan-Kettering Q & A

Frequently asked questions about the various treatment options for children with neuroblastoma. (more)

The 3F8 Antibody in Brief

3F8 is a mouse derived monoclonal antibody developed by Dr. Cheung at Case Western Reserve University in the 1980’s, and later tested extensively at Memorial Sloan-Kettering Cancer Center. It is directed toward sugar containing molecules called GD2 found on the surface of neuroblastoma cells. GD2 is also found on the surface of nerve cells. This fact is responsible for the great pain it causes while it is being infused each day. Its name, 3F8, refers to the tray, row and column it was found in when the monoclonal antibodies were screened. 3F8 has been used in clinical trials for neuroblastoma for more than 20 years.

What kinds of monoclonal antibodies are available?

Most monoclonal antibodies are produced in mice but they have also been developed in other animals. Because of problems associated with using animal proteins in humans, researchers using chemical and genetic engineering techniques have developed monoclonal antibodies that are more like human antibodies, and in fact researchers can now produce completely human antibodies.

Murine antibodies are entirely mouse derived and contain no human components. In chimeric antibodies 67% of the antibody has been replaced by human antibody. In humanized antibodies the human portion is increased to 90%-95%. Human antibodies by definition are 100% human, although near human antibodies can also be generated in a genetically modified mouse.

Why are humanized monoclonal antibodies necessary?

There are two main problems that occur with current monoclonal antibodies. 1.The initial hopes for monoclonal antibody therapy in cancer were dampened when patients began developing their own antibodies against the animal antibodies being given. These antibodies the patients produced called HAMA (Human anti-mouse antibodies) bind up all of the monoclonal antibodies neutralizing them and preventing them from binding to and killing cancer cells. As a result patients often must stop therapy after a few treatments even though the treatment may have previously been very effective.

2.The stem of the Y-shaped antibody (the Fc portion) binds to receptors (Fc Receptors) on a variety of immune cells. The ability to bind to these immune cells is critical in killing cancer cells. Cells from different patients have slightly different FC receptors and different abilities to bind different antibodies, whether mouse or human. As a result current antibody therapy may work well for some, but not for all patients. During the process of humanizing the monoclonal antibody, the Fc portion can be genetically modified to enhance its binding to receptors of more patients.

Is HAMA always a bad thing?

Not all patients develop HAMA. The development of HAMA can be delayed by several months by administering certain kinds of chemotherapy in high doses prior to initiating treatment. HAMA forces patients to stop treatment with monoclonal antibodies since it neutralizes the antibodies and the disease is left untreated. On average patients who develop HAVA actually do better than those who do not so long as they are disease free at the start of treatment and complete at least 40 doses. The proposed reason for the better outcome in patients who develop HAMA is a complicated mechanism called idiotype networking. Simply put HAMA’s (Ab2) are antibodies against mouse derived antibodies (Ab1). These may bind to any part of the antibody. A few will bind to the idotype of Ab1. In order for this to happen the shape of the idotype of Ab2 must be very similar though not identical to the protein (GD2) on the cancer cell. Since this is a new shape to the patient, the patient may make antibodies (Ab3) against that idiotype. The result is that the patient is producing his or her own antibodies that can bind directly to the GD2 protein on the cancer cell and kill it. It is likely that this series of events requires time to develop, and if HAMA is made too soon, this idotype network cannot materialize. At the present time many children who would benefit form 3F8 had to stop therapy because they developed HAMA early.

Would humanizing 3F8 eliminate the HAMA problem?

Yes and No. It would not eliminate HAMA since 5-10% of the antibody is still derived form mouse genes, but it could eliminate it as a “problem.” The only part of a humanized antibody remaining that is derived form mouse genes is the idotype. If the patient did develop HAMA it would more likely be against the idotype and the chances of developing an idotype network and their own antibodies against the tumor would be even greater.

Why humanize the antibody rather than create a fully human antibody from scratch?

The strength of binding to the cancer cell is very important and is a function of the shape and electrical charge on the idotype. Designing and producing the ideal idotype is beyond present day technology. Achieving a strongly binding idotype is often a result of luck in addition to special techniques. Humanizing an antibody is achieved by taking a B-cell which produces mouse antibodies and replacing the genes for the entire antibody with the exception of the portion of the genes that produce the idotype. The result is an antibody that is 95% human protein and the original idiotype is preserved. Alternatively, an entirely human antibody can be achieved by starting with a mouse whose antibody genes have been replaced by human antibody genes. To create an antibody against neuroblastoma, researchers may have to start back where they were 20 years ago and create a new antibody and hope for the same good luck in creating such a strongly binding idotype as 3F8.