Gamma Delta T Cell Immunotherapy + Chemoimmunotherapy for Neuroblastoma

(Aflac-NBL-2002 Trial)

Overseen by Kelly Goldsmith, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Emory University

Must not be taking: T cell therapy

Disqualifiers: Pregnancy, CNS disease, HIV, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment combining existing cancer drugs with special immune cells and a booster drug in children with aggressive neuroblastoma. The goal is to see if this combination can more effectively fight the cancer.

Do I have to stop taking my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must have recovered from the effects of any prior treatments before joining the study.

What data supports the effectiveness of the treatment Gamma Delta T Cell Immunotherapy + Chemoimmunotherapy for Neuroblastoma?

Research shows that combining the anti-GD2 antibody dinutuximab with γδ T cells and chemotherapy drugs like temozolomide and irinotecan can effectively reduce tumor size and improve survival in neuroblastoma models. This combination enhances the immune system's ability to target and kill cancer cells, supporting its potential use in treating high-risk neuroblastoma. ^{1 2 3 4 5}

Is the combination of gamma delta T cell immunotherapy and chemoimmunotherapy safe for treating neuroblastoma?

The combination of gamma delta T cell immunotherapy with chemoimmunotherapy, including drugs like dinutuximab, temozolomide, and irinotecan, has been studied in patients with high-risk neuroblastoma. Dinutuximab, in particular, has been approved by the FDA for use in children with high-risk neuroblastoma, indicating it has been evaluated for safety in this context. However, as with any treatment, there may be side effects, and it is important to discuss these with your healthcare provider. ^{1 2 3 4 6}

What makes the treatment with Gamma Delta T Cell Immunotherapy and Chemoimmunotherapy unique for neuroblastoma?

This treatment is unique because it combines the use of dinutuximab, a monoclonal antibody targeting GD2 on tumor cells, with ex vivo expanded γδ T cells, which have direct tumor-killing abilities. The combination enhances the immune system's ability to attack neuroblastoma cells, potentially improving outcomes compared to traditional therapies. ^{1 2 3 4 7}

Research Team

Kelly Goldsmith, MD

Principal Investigator

Profesor

Eligibility Criteria

This trial is for children over 12 months old with high-risk neuroblastoma that's relapsed or not responded to treatment. They need normal heart, kidney, liver, and bone marrow function and can't have had prior T cell therapy or stem cell transplant. No major organ system diseases, active infections, or uncontrolled cardiac issues are allowed.

Inclusion Criteria

My neuroblastoma is classified as high risk by the Children's Oncology Group.

My neuroblastoma has not improved after 4 treatment cycles.

My cancer is in the soft tissues.

Exclusion Criteria

Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.

I do not have an active infection or I am on antifungal treatment but meet health criteria.

I am currently receiving hemodialysis.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of γδ T cells, Dinutuximab, Temozolomide, Irinotecan, and Zoledronate. γδ T cells are administered on Day 6 and potentially on Day 13 if criteria are met.

4 courses, each course includes two administrations of γδ T cells one week apart

Multiple visits for drug administration and monitoring

Dose Escalation

Dose escalation follows a 3+3 design to determine the maximum tolerated dose (MTD) of γδ T cells.

21 days per dose level

Follow-up

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

30 days following end of protocol therapy

Treatment Details

Interventions

• Dinutuximab (Monoclonal Antibodies)
• Ex Vivo Expanded Allogeneic γδ T Cells (CAR T-cell Therapy)
• Irinotecan (Anti-tumor antibiotic)
• Temozolomide (Anti-metabolites)
• Zoledronate (Other)

Trial Overview The study tests a new combination of treatments for aggressive childhood cancer: γδ T cells from donors plus standard drugs (dinutuximab, temozolomide, irinotecan) and zoledronate. It aims to find the safest dose and see how well it works in kids with tough-to-treat neuroblastoma.

Participant Groups

Group I: Dose Escalation Phase I cohort Experimental Treatment 1 Intervention

Subjects will be assigned a cell therapy dose level at time of registration. The entry dose level is Dose Level 1, with escalation up to Dose Level 3 following a 3 + 3 dose escalation design. If there is no evidence of progression, patients may receive up to a maximum of 4 courses. Each course includes two administrations of γδ T cells, administered one week apart. Toxicity, for deciding dose escalation and defining the MTD, will be evaluated during Course 1. Disease response assessment will be done after Courses 2 and 4. Dinutuximab (17.5 mg/m2), temozolomide (100 mg/m2), irinotecan (50 mg/m2) and zoledronate (0.0125 mg/kg/dose) will be consistent across all dose levels.The same donor for γδ T cell will be used for both cell therapy product infusions per course. Treatment of the first two subjects in each dose escalation cohort will be staggered. The second subject will not be enrolled until the first subject completes the DLT observation interval (minimum of 21 days).

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Dr. R. Donald Harvey

Emory University

Chief Medical Officer

MD from Emory University School of Medicine

Dr. George Painter

Emory University

Chief Executive Officer since 2013

PhD in Synthetic Organic Chemistry from Emory University

Findings from Research

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]

The combination of γδ T cells with the anti-GD2 antibody dinutuximab significantly enhances tumor cell lysis in neuroblastoma, showing a 30% increase in effectiveness compared to γδ T cells alone.

In preclinical models, the treatment regimen of dinutuximab, temozolomide, and expanded γδ T cells effectively reduced tumor burden and improved survival in mice with neuroblastoma, supporting further testing of this chemo-immunotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model. Zoine, JT., Knight, KA., Fleischer, LC., et al.[2021]

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]

Dinutuximab, an antibody targeting the GD2 antigen on neuroblastoma cells, is FDA-approved for treating high-risk neuroblastoma in patients who have responded to initial therapy, showing significant clinical efficacy when combined with other treatments like cytokines and isotretinoin.

The effectiveness of dinutuximab can be limited by the presence of GD2-negative neuroblastoma cells and factors affecting the immune response, which may lead to resistance against this targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy. Keyel, ME., Reynolds, CP.[2023]

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 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]

The combination of Zoledronate (ZOL) and Interleukin-2 (IL-2) was well tolerated in a Phase I trial involving 4 patients aged 2 to 21 with refractory neuroblastoma, showing no unexpected severe toxicities.

This treatment successfully expanded circulating Vγ9Vδ2+ T cell counts to levels comparable to healthy controls, indicating a potential immunotherapeutic strategy for solid tumors, although increases in regulatory CD4+ T cells may limit the overall effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study. Pressey, JG., Adams, J., Harkins, L., et al.[2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Dinutuximab: first global approval. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Ex vivo expanded patient-derived γδ T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model. [2021]

3. England 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. [2022]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy. [2023]

5. United States 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. [2022]

6. Germany 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. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study. [2021]