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Important research into neuroblastoma is being done right now in many university hospitals, medical centers, and other research institutions around the world. Each year, scientists find out more about what causes the disease and how to improve treatment.

Genetics of neuroblastomas

Researchers now have better tests to look for changes in the genes of neuroblastoma cells. Researchers might know that a change has happened on a certain chromosome (a strand of DNA inside the cell, which contains its genes), but they still need to learn more about that gene or what part of a gene has been affected. There are a few different ways that genes change in neuroblastoma cells:

• Sometimes there are extra copies of the same gene (called amplification) on a chromosome.
• Sometimes a chromosome can have missing pieces of DNA (called deletions) or extra pieces of DNA (called gains or additions), which can affect which genes the chromosome has.
• Sometimes genes have mutations (changes in the DNA) or other changes that can turn the gene on or off, which can affect how the cell grows and divides.

Understanding the gene changes in neuroblastoma helps researchers understand which neuroblastomas are likely to be cured with less intense treatment, and which will need more aggressive treatment. Some of these gene changes are being used now to help cancer care teams determine a child's neuroblastoma stage and risk group. Other gene changes might help researchers find new treatments that work on certain types of neuroblastoma cells.

Here are some specific DNA and gene changes currently being studied:

• DNA changes on the short arm of chromosome 6 (6p22) are more likely to be seen in neuroblastomas that grow more aggressively.
• Neuroblastoma cells in older children are more likely to have changes in the ATRX tumor suppressor gene. Tumors with this gene change tend to grow more slowly, but they are also harder to cure. This may help explain why older children tend to have high-risk neuroblastomas (which are often harder to treat), while younger children tend to have low- or intermediate-risk neuroblastomas (which are often easier to treat).
• Changes in or having more than one copy (amplification) of the ALK and MYCN genes are features used to help decide a child's risk group. Some drugs that target cells with ALK gene changes are already used to treat other types of cancer, and they are now being studied for use against neuroblastomas with ALK gene changes (see below). Some scientists also are studying how ALK gene changes might be related to extra copies of the MYCN gene in neuroblastoma cells.

Treatment

Survival rates for neuroblastoma have gotten better as doctors have found ways to improve on current treatments, but survival rates for children with high-risk neuroblastoma are not as good as they are for children with low- or intermediate-risk disease.

Most clinical trials of high-risk neuroblastoma (more aggressive and hard-to-treat tumors) are focused on finding the best combinations of chemotherapy (chemo) drugs, stem cell transplant regimens, immunotherapies and other new treatments to try to cure more children. Current studies of low- and intermediate-risk neuroblastoma are trying to figure out if children can get less treatment and still do as well.

Chemotherapy

The search continues for the best combinations of chemo drugs to treat neuroblastoma.

Several chemo drugs that are already used to treat other cancers, such as topotecan, irinotecan, and temozolomide, are now being studied in combination with other kinds of therapies for use against high-risk neuroblastoma or neuroblastoma that has come back.

Other studies are looking to see if some children with low- or intermediate-risk neuroblastoma can be treated with less (or even no) chemotherapy. The goal is to still have the same good results, but with fewer side effects from treatment.

Stem cell transplants

Doctors are also trying to improve the success rate for children with aggressive neuroblastoma with high-dose chemotherapy and stem cell transplants, using different combinations of chemotherapy, radiation therapy, retinoids, immunotherapy, and other treatments. For example:

• Recent research has suggested that giving two stem cell transplants (tandem transplants) to children with high-risk neuroblastoma works better than giving just one stem cell transplant.
• Doctors are studying whether using different combinations of chemo drugs, such as busulfan and melphalan, might work better than the chemo combinations currently being used before a stem cell transplant.
• Other studies are looking at whether using stem cells donated from another person (an allogeneic stem cell transplant), instead of from the patient (an autologous stem cell transplant), might help some children with hard-to-treat tumors.

Retinoids

Retinoids such as 13-cis-retinoic acid (isotretinoin) can reduce the risk of recurrence after treatment in children with high-risk neuroblastoma, especially when they are given with certain immunotherapy treatments. Giving 13-cis-retinoic acid in combination with different types of chemotherapy drugs, immunotherapies called monoclonal antibodies, and targeted drugs is being studied in a number of clinical trials to help determine the combinations that might work best.

Targeted drugs

Knowing what makes neuroblastoma cells different from normal cells might lead to new approaches to treating this disease. Newer drugs that target neuroblastoma cells more specifically than standard chemo drugs are now being studied in clinical trials. For example:

In some neuroblastomas, the cells have changes in the ALK gene that help them grow. Drugs that target cells with changes in the ALK gene, such as crizotinib (Xalkori), have already been shown to be helpful in treating some other types of cancer. Crizotinib is now being studied as part of the treatment for children with high-risk neuroblastoma when the cells have ALK gene changes. Other drugs that target cells with ALK changes, such as lorlatinib (Lorbrena) and ceritinib (Zykadia), are also being studied.

In some neuroblastomas, the cells have an overactive Aurora A kinase signaling pathway, which helps the cells grow. Drugs that target the Aurora A kinase pathway, such as LY3295668 erbumine, are now being studied in clinical trials for use against neuroblastoma.

Doctors are also looking more closely at the gene changes inside neuroblastoma cells to see if other targeted drugs might be helpful. Some of the targeted drugs being studied in this way include sorafenib, dasatinib, and vorinostat.

Many other targeted drugs are now being studied for use against neuroblastoma as well.

Immunotherapy

Immunotherapy is the use of medicines to help a patient’s own immune system fight cancer. Several different kinds of immunotherapy are now being tested or used against neuroblastoma.

Anti-GD2 monoclonal antibodies

The monoclonal antibodies dinutuximab (Unituxin) and naxitamab (Danyelza), which target GD2 on neuroblastoma cells, are now being used in the United States for some children with high-risk neuroblastoma, to help immune system cells find and destroy the cancer cells. These antibodies are typically used after a stem cell transplant, but studies are now being done to see if they might be helpful earlier in the course of treatment as well.

Other antibodies that target GD2 are also being studied. For example, Hu14.18K322A is a modified antibody that might work as well as other GD2 antibodies without some of the side effects. And dinutuximab beta (Qarziba), which is similar to dinutuximab, is now being used in Europe.

Vaccines

Several cancer vaccines are also being studied for use against neuroblastoma. For these vaccines, injections of modified neuroblastoma cells or other substances are given to try to get the child’s own immune system to attack cancer cells. These treatments are still in the early stages of clinical trials.

CAR T-cell therapies

CAR T-cell therapy is a promising new way to get a patient's own immune cells called T cells to fight cancer by changing them in the lab so they can find and destroy cancer cells. The T cells used in CAR T-cell therapies get changed in the lab by adding a gene for a lab-made receptor (called a chimeric antigen receptor or CAR), which helps them attack specific cancer cells.

Studies are now being done to see if CAR T-cells that target GD2 (or other substances) on neuroblastoma cells can be helpful in treating this disease. Most of these are very early clinical trials that are ongoing or still in the planning phase.

Several other types of immunotherapy are also being studied for use against neuroblastoma. Many of these are in very early clinical trials. If you have questions about these or other investigational treatments for neuroblastoma, talk to your child’s cancer care team.