Immunotherapy for Neuroblastoma

Not currently recruiting at 11 trial locations

Overseen By Araz Marachelian, MD, MS

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: New Approaches to Neuroblastoma Therapy Consortium

Must not be taking: Thalidomide

Disqualifiers: Pregnancy, Breastfeeding, CNS metastasis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the safest dose of a new treatment that combines immune cells, a cancer drug, and another medication for children with neuroblastoma, a cancer that forms in nerve tissue. The researchers are testing a specific mix of natural killer (NK) cells with dinutuximab (an immunotherapy drug) and may add lenalidomide to evaluate its effectiveness and tolerability. Children with high-risk neuroblastoma that does not respond well to previous treatments or has recurred might be suitable for this study. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot receive other anti-cancer agents or radiotherapy while participating in the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining natural killer (NK) cells with the drugs dinutuximab and lenalidomide appears promising for safety. Dinutuximab has been studied with NK cells before and helps activate these cells to fight cancer. In past studies, patients tolerated this combination well, with manageable side effects.

Lenalidomide also supports NK cells by blocking certain substances in the body that might weaken them, potentially enhancing the treatment's effectiveness. Previous research has demonstrated the safe use of lenalidomide.

This trial is in its early stages and aims to determine the optimal dose of these treatments together. As an early-stage trial, it is still assessing the safety of these treatments. However, past studies suggest that any side effects might be mild and manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for neuroblastoma because they combine the power of immunotherapy with innovative approaches. Unlike traditional chemotherapy, which attacks cancer cells directly, this study uses a combination of Ch14.18, also known as Dinutuximab, and NK (natural killer) cells to boost the body's own immune response against cancer. The addition of Lenalidomide offers an exciting enhancement by further stimulating the immune system. This multifaceted approach promises a more targeted attack on cancer cells, potentially improving effectiveness and reducing side effects compared to standard treatments.

What evidence suggests that this trial's treatments could be effective for neuroblastoma?

Research has shown that natural killer (NK) cells can find and destroy cancer cells, including those in neuroblastoma. In this trial, participants will receive NK cells combined with dinutuximab, a medicine that helps the immune system attack cancer. This combination has shown promising results, with some patients experiencing complete or partial improvements. Additionally, lenalidomide may strengthen the immune response and enhance this combination's effectiveness. This method is under study to help children with hard-to-treat neuroblastoma. ^{1 2 3 5 6}

Who Is on the Research Team?

Araz Marachelian, MD, MS

Principal Investigator

Children's Hospital Los Angeles

Are You a Good Fit for This Trial?

This trial is for children with neuroblastoma that hasn't responded to initial treatments or has come back. They must have a certain type of tumor activity visible on specific scans, be under 30 years old, and have an expected lifespan of at least 12 weeks. Their heart, kidney, liver, and blood functions need to meet set levels. Pregnant or breastfeeding individuals can't join.

Inclusion Criteria

My disease is either coming back, not responding, or has never fully gone away.

My neuroblastoma is classified as high-risk according to COG.

I am expected to live at least 12 weeks and can do some daily activities on my own.

Exclusion Criteria

I do not have any ongoing or uncontrolled infections.

I have chosen not to participate in the NANT 2004-05 study.

My cancer has spread to my brain.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive NK cells on Day 5 and dinutuximab on Days 1-4, with lenalidomide added for Dose Level 4 from Day -6 through 14

3 weeks

Multiple visits for administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of toxicities and response

4 weeks

Regular follow-up visits

Extension

Optional continuation of treatment to further assess long-term effects and safety

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Ch14.18
• Dinutuximab
• Lenalidomide
• NK Cells

Trial Overview The study tests the highest dose kids can handle of NK cells (a type of immune cell) combined with dinutuximab (an antibody therapy). It also looks at adding lenalidomide (a cancer drug) to this mix for those who've had no luck with standard treatments for their aggressive neuroblastoma.

How Is the Trial Designed?

Group I: NK cells with Dinutuximab & Lenalidomide Experimental Treatment 3 Interventions

Patients in this arm will receive a designated dose of NK cells on Day 5 and 17.5 mg/m2/dose of dinutuximab on Day 1-4. Patients on Dose Level 4 will also receive 25mg/m2/dose of Lenalidomide during Day -6 through 14 of treatment.

Who Is Running the Clinical Trial?

New Approaches to Neuroblastoma Therapy Consortium

Lead Sponsor

Trials

19

Recruited

1,700+

United Therapeutics

Industry Sponsor

Trials

112

Recruited

14,500+

Dr. Martine Rothblatt

United Therapeutics

Chief Executive Officer since 1996

PhD in Medical Ethics from the Royal London College of Medicine and Dentistry, JD and MBA from UCLA

Dr. Michael Benkowitz

United Therapeutics

Chief Medical Officer since 2023

MD from Harvard Medical School

Nationwide Children's Hospital

Collaborator

Trials

354

Recruited

5,228,000+

Published Research Related to This Trial

Dinutuximab is a monoclonal antibody that targets GD2, a glycolipid overexpressed in neuroblastoma, and has been approved by the US FDA for treating high-risk neuroblastoma in children when used in combination with other therapies.

The drug works by inducing immune responses that kill cancer cells, and its development has progressed through multiple phases, with ongoing regulatory reviews in the EU and other countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinutuximab: first global approval. Dhillon, S.[2019]

Galunisertib enhances the effectiveness of the anti-GD2 antibody dinutuximab by suppressing SMAD2 activation in neuroblastoma cells and restoring the cytotoxic functions of activated natural killer (aNK) cells, which are crucial for targeting neuroblastoma tumors.

In preclinical models, combining galunisertib with aNK cells and dinutuximab significantly reduced tumor growth and improved survival rates in mice, indicating a promising strategy for improving immunotherapy outcomes in high-risk neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. Tran, HC., Wan, Z., Sheard, MA., et al.[2022]

In a phase 3 trial involving 406 children and young people with high-risk neuroblastoma, the addition of subcutaneous IL-2 to dinutuximab beta did not improve event-free survival rates compared to dinutuximab beta alone, with 3-year event-free survival rates of 60% and 56% respectively.

The combination treatment with subcutaneous IL-2 resulted in significantly higher toxicity, leading to a lower treatment completion rate (62% vs. 87% for dinutuximab beta alone), indicating that dinutuximab beta with isotretinoin should remain the standard care for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Ladenstein, R., Pötschger, U., Valteau-Couanet, D., et al.[2022]

Combining the anti-GD2 antibody dinutuximab with ex vivo-activated human natural killer (aNK) cells after surgical removal of neuroblastoma tumors significantly improved survival rates in a mouse model, indicating a promising approach for treating residual disease.

In vitro studies showed that this combination not only increased cytotoxicity against neuroblastoma cells but also reduced their invasiveness, suggesting a dual mechanism of action that could enhance the effectiveness of immunotherapy in high-risk neuroblastoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma. Barry, WE., Jackson, JR., Asuelime, GE., et al.[2020]

In a study involving 28 children with high-risk neuroblastoma, the monoclonal antibody dinutuximab produced by United Therapeutics (UTC) showed pharmacokinetic comparability to the National Cancer Institute's (NCI) version, indicating similar drug exposure levels.

Both UTC and NCI products had comparable safety profiles and adverse events, suggesting that UTC's dinutuximab can be used interchangeably with NCI's version without compromising efficacy or safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative pharmacokinetics, safety, and tolerability of two sources of ch14.18 in pediatric patients with high-risk neuroblastoma following myeloablative therapy. Marachelian, A., Desai, A., Balis, F., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02573896

Immunotherapy of Relapsed Refractory Neuroblastoma ... Natural killer cells are lymphocytes of the innate immune system that have the ability to recognize and kill malignant cells, including neuroblastoma.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11554946/

Natural killer cells in neuroblastoma - PubMed Central - NIH Adoptive NK cell therapy along with m3F8, an anti-GD2 antibody, but with higher affinity than Dinutuximab, led to a complete or partial response ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6082365/

Anti-GD2 immunotherapy for neuroblastomas - PMC Anti-GD2 monoclonal antibodies are associated with improved survival in patients in their first remission and are increasingly being used for chemorefractory ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01711554

Lenalidomide and Dinutuximab With or Without Isotretinoin ... Monoclonal antibodies, such as dinutuximab, may interfere with the ability of tumor cells to grow and spread. Giving more than one drug (combination ...

5. cell.com cell.com/cancer-cell/abstract/S1535-6108(25)00405-2

Engineered natural killer cells for cancer therapy In this review, we summarize findings from early-phase clinical trials and discuss emerging synthetic biology and engineering approaches to ...

6. cincinnatichildrens.org cincinnatichildrens.org/service/c/clinical-trials/studies/NANT-2013-01

Immunotherapy of Relapsed Refractory Neuroblastoma ... This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded natural killer (NK) cells when combined with standard dosing of ch14.18 ...