Gamma Delta T Cell Immunotherapy + Chemoimmunotherapy for Neuroblastoma

(Aflac-NBL-2002 Trial)

Overseen By Kelly Goldsmith, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Emory University

Must not be taking: T cell therapy

Disqualifiers: Pregnancy, CNS disease, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

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

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments to determine a safe dose for children with difficult-to-treat neuroblastoma or osteosarcoma, both types of cancer. The trial evaluates how well a special immune cell, called γδ T cells (a type of immunotherapy), works with existing cancer drugs. The researchers aim to find the optimal dose that minimizes side effects. Eligible participants include children with neuroblastoma that recurs or resists treatment, or osteosarcoma that does not improve with standard care. As a Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

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

Research has shown that ex vivo expanded allogeneic γδ T cells, a type of immune cell treatment, have potential in early studies. These cells, grown from healthy donors, appear safe. However, researchers are still determining the best dose and monitoring for side effects.

Dinutuximab, another treatment in the trial, has FDA approval for children with high-risk neuroblastoma, indicating general safety, though some side effects may occur.

Irinotecan, a chemotherapy drug, often causes side effects like diarrhea, so patients require monitoring.

Temozolomide has been well-tolerated in past studies, even when combined with irinotecan, but some patients may experience blood-related issues.

Zoledronate is typically used to manage calcium levels in cancer patients. It is considered safe but requires careful use in individuals with kidney problems due to potential effects on kidney function.

Overall, each treatment in this trial has been studied before, but their combined use is new. The trial aims to find the safest way to combine them while monitoring side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for neuroblastoma because it combines traditional chemoimmunotherapy with a cutting-edge approach using γδ T cells. Unlike most treatments that rely solely on chemotherapy and antibodies like dinutuximab, this therapy harnesses the power of ex vivo expanded allogeneic γδ T cells, a type of immune cell that can target cancer cells more specifically. Additionally, the treatment includes zoledronate, which may enhance the effectiveness of γδ T cells. This combination could potentially offer a more targeted attack on cancer cells, reducing the risk of disease progression and improving outcomes for patients.

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

Research shows that certain treatments hold promise for fighting neuroblastoma, a type of cancer. This trial includes an approach using specially grown immune cells, called γδ T cells, which early studies found effective in killing cancer cells. Another treatment option is dinutuximab, a medicine that helps patients with high-risk neuroblastoma live longer by targeting a specific protein on cancer cells. Irinotecan, a chemotherapy drug in this trial, successfully eliminated cancer cells in lab tests and remained effective for up to 12 weeks. When combined with temozolomide, it showed some success in treating patients. Zoledronate, also part of this trial, is a different drug that stops cancer cells from growing and makes them die more easily. Together, these treatments aim to attack neuroblastoma in various ways, increasing their chances of effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

Kelly Goldsmith, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Dinutuximab
• Ex Vivo Expanded Allogeneic γδ T Cells
• Irinotecan
• Temozolomide
• Zoledronate

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.

How Is the Trial Designed?

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

Subjects are assigned a cell therapy dose level at registration. Entry dose is Level 1, with escalation to Level 3 using a 3+3 design. If no progression, up to 4 courses may be given. Each course includes two γδ T cell infusions, one week apart. Toxicity for dose escalation and MTD will be assessed in Course 1. Disease response will be evaluated after Courses 2 and 4. Dinutuximab (17.5 mg/m²), temozolomide (100 mg/m²), irinotecan (50 mg/m²), and zoledronate (0.0125 mg/kg) are consistent across dose levels. Same γδ T cell donor will be used for both infusions per course. Due to stock supply, this may not always be possible. In each cohort, the first two subjects are staggered; the second is enrolled only after the first completes the DLT observation (≥21 days).

Dinutuximab is already approved in United States, European Union for the following indications:

Approved in United States as Unituxin for:

• Neuroblastoma

Approved in European Union as Dinutuximab for:

• High-risk neuroblastoma

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

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 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 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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10729685/

Safety and efficacy of dinutuximab in the treatment of ...

Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen.

2.

unituxin.com

unituxin.com/hcp/about-unituxin/clinical-trial-data/

Efficacy and Clinical Trial Data

5-year EFS was 57±4.7% for patients randomized to the Unituxin group (n=114) vs 46±5.1% for those randomized to the RA-only group (n=112; P=0.042).4. 5-year EFS ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8046731/

Long-term follow-up of a Phase III Study of ch14.18 ...

Conclusions: Immunotherapy with dinutuximab improved outcome for patients with high-risk neuroblastoma. Early stoppage for efficacy resulted in a smaller sample ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05421897

Rapid Administration Pilot for Infusing Dinutuximab

Studies have shown that the anti-GD2 human-mouse chimeric monoclonal antibody dinutuximab has contributed significantly to the improvement of treatment for ...

5.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.e22000

Efficacy and safety of dinutuximab in the management ...

Conclusions: Our findings suggest that dinutuximab is linked to a significant reduction in overall mortality and a noteworthy improvement in the ...

6.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/26917818/

Dinutuximab: An Anti-GD2 Monoclonal Antibody for High- ...

Dinutuximab is the first anti-GD2 monoclonal antibody approved in combination with GM-CSF, IL-2, and RA for maintenance treatment of pediatric patients with ...

7.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/nda/2015/125516Orig1s000PharmR.pdf

125516Orig1s000 - accessdata.fda.gov

Dinutuximab is a chimeric mouse/human IgG1 monoclonal antibody produced in the SP2/0 cell line that binds to the GD2 disialonganglioside. GD2 is ...

8.

unituxin.com

unituxin.com/hcp/

Healthcare Professionals Home

FDA approved. The first antibody therapy FDA-approved for children with high-risk neuroblastoma.2,5. 200+ children's hospitals.

9.

aetna.com

aetna.com/cpb/medical/data/800_899/0895.html

Dinutuximab (Unituxin) - Medical Clinical Policy Bulletins

The authors concluded that dinutuximab is the 1st anti-GD2 monoclonal antibody (MAb) approved in combination with GM-CSF, IL-2, and RA for maintenance treatment ...

10.

journals.lww.com

journals.lww.com/jrms/fulltext/2023/09290/safety_and_efficacy_of_dinutuximab_in_the.71.aspx

Safety and efficacy of dinutuximab in the treatment of...

Dinutuximab, which is a monoclonal antibody targeting GD2 expressed in neuroblasts, improves survival when included in the therapy regimen.