Alex's Lemonade Stand Foundation for Childhood Cancer

Neuroblastoma, which arises from the developing sympathetic nervous system, is the most common type of solid tumor in childhood outside of the brain and spine. The sympathetic nervous system is the part of the body’s nervous system that manages the reaction to stress or danger—the flight or fight response. It begins as immature nerve cells called neuroblasts. These neuroblasts are supposed to mature into regular nerve cells, but sometimes they stop changing into normal cells and continue to proliferate, forming tumors. Neuroblastoma tumors are most commonly found in the adrenal glands on the top of the kidneys or in the nerve tissue along the spine in the neck, chest, abdomen, or pelvis.

Treatment for neuroblastoma has evolved significantly over the last two decades, with the 5-year survival rates for low- and intermediate-risk neuroblastoma now above 95%.¹¹⁰ This has been achieved by more precise molecular “risk assessment” at the time of diagnosis, which allows clinicians to design treatment plans that reduce or eliminate chemotherapy and radiation therapy, thus reducing the toxic side effects affiliated with those treatments.

Children with high-risk neuroblastoma have long-term survival rates of about 60% despite an increase in the amount of treatment given as part of standard of care in the past two decades.¹¹¹ Advances in other treatments, such as MIBG (meta-iodobenzylguanidine) radiotherapy, immunotherapies, and targeted therapies, have inspired hope that progress can continue to be made in this devastating disease.

Breakthroughs and Research Milestones:

1. MIBG radiotherapy (1980s)
   MIBG is a medicine that can be absorbed by nerve cells, including neuroblastoma cells. When combined with radioactive iodine, it delivers radiation directly into those cancer cells. Because only the cells that absorb MIBG receive radiation, this treatment is less harmful to the rest of the body.116 Despite MIBG being used in neuroblastoma for over 40 years, no company has commercialized this drug. As a result, patient access is a problem around the world.
2. Small molecule inhibitors (2000-present)
   Small molecule inhibitors are drugs that can enter cancer cells to block a specific target. Some notable breakthroughs in this drug class include:
   • In 2009, the Children’s Oncology Group Phase 1 trial of crizotinib opened primarily for neuroblastoma and also included other cancers driven by the ALK mutation (see sidebar). The ALK diseases with gene fusions were much more sensitive to crizotinib than neuroblastomas, leading to FDA approvals for ALK+ anaplastic large cell lymphoma and ALK+ unresectable/relapsed inflammatory myofibroblastic tumors.
   • Another ALK-inhibitor, lorlatinib was tested in a clinical trial beginning in 2017. The trial showed that lorlatinib was generally well tolerated, shrank tumors in many patients on its own, and may work even better when combined with chemotherapy, especially in patients with high-risk tumors driven by ALK mutations and MYCN amplification.¹¹⁷
   • Eflornithine (DFMO) is a small molecule inhibitor that blocks the formation of essential polyamines, which are small molecules that help neuroblastoma cells grow. This drug was approved by the FDA in 2023 as a continuation treatment option for patients with high-risk neuroblastoma.¹¹⁸ This FDA approval was based on a comparison of patients who received DFMO more recently to those who did not over a decade ago, and despite the FDA approval, many pediatric oncologist do not prescribe it because they are not convinced by the data.
   • Retinoids are a class of drugs made from vitamin A. One retinoid called isotretinoin has been a standard treatment for children with the high-risk neuroblastoma since the early 2000s.¹¹⁹
3. Proton therapy (2010)
   The expansion of proton radiation centers in the United States has allowed for this newer form of radiation therapy to be expanded to neuroblastoma with the goal of reducing radiation-induced side effects (see more in Section 3, page 46).¹²⁰
4. Immunotherapy (2010-present):
   Immunotherapy harnesses the body’s immune system, activating it to kill cancer cells. Neuroblastoma is the only pediatric solid tumor with FDA-approved immunotherapies—antibodies targeting GD2. This therapy is painful and quite toxic because GD2 is also found on nerves/pain fibers. Combining these antibodies with lower dose chemotherapy can be very effective for relapsed disease but is generally not curative. Many centers are now testing GD2 directed immunotherapies for newly diagnosed patients.
   • Dinutuximab was the first FDA approved immunotherapy for neuroblastoma. The initial trial with this drug that was given after standard upfront therapy showed 61% of patients that received this drug were cancer free after five years.¹²³
   • Naxitamab is an additional GD2 targeting monoclonal antibody that has received FDA approval and demonstrated success in neuroblastoma clinical trials.¹²⁴
   • CAR T-cell therapies that are currently FDA-approved for leukemias show promise for neuroblastoma, as do other CAR T-cell therapies being developed.
   • Antibody-drug conjugates are a hybrid of targeted therapies and immunotherapy. ADCs could be available to relapsed high-risk neuroblastoma patients in the coming years.