What side effects are associated with this type of intervention?

Common side effects of treatments for neuroblastoma, particularly those involving genetically modified T cells like iC9-GD2-CD28-OX40, include cytokine release syndrome (CRS) with symptoms such as fever, fatigue, and low blood pressure, and neurotoxicity, which can cause confusion, seizures, or encephalopathy. Lymphodepletion chemotherapy, used to enhance T cell efficacy, can lead to immunosuppression, increased infection risk, and bone marrow suppression. Additionally, pembrolizumab, used to counteract PD1 inhibition, can cause immune-related adverse events such as colitis, hepatitis, and endocrinopathies.

What prior FDA approvals exist?

The FDA has approved several treatments for neuroblastoma, though specific approvals for genetically modified T cells targeting GD2 are limited. Dinutuximab, an anti-GD2 monoclonal antibody, is approved for high-risk neuroblastoma. This therapy targets the GD2 antigen on neuroblastoma cells, similar to the GD2-CAR T cells being studied. Other treatments include chemotherapy agents like cyclophosphamide and fludarabine, often used in combination with immunotherapies to enhance efficacy. While the iC9-GD2-CD28-OX40 T cells represent an advanced approach with enhanced longevity and efficacy, they are still under investigation and not yet FDA-approved.

What other types of research exist?

Promising alternatives to iC9-GD2-CD28-OX40 T cells for neuroblastoma patients include: 1) Pembrolizumab, an anti-PD1 antibody, which can help overcome the inhibitory effects of PD1 in the tumor microenvironment. 2) Adoptive transfer of cytotoxic T lymphocytes (CTLs) induced by CD86-transfected tumor cells, which has shown potential in preclinical studies. 3) Combination therapies involving checkpoint inhibitors like nivolumab or atezolizumab, which have shown efficacy in other cancers and may be applicable to neuroblastoma. These alternatives are based on their ability to enhance T cell activity and persistence in the tumor microenvironment.

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CAR T-cell Therapy

CAR T-Cell Therapy for Neuroblastoma (GRAIN Trial)

Phase 1

Waitlist Available

Led By Andras A. Heczey, MD

Research Sponsored by Baylor College of Medicine

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

PROCUREMENT

Karnofsky/Lansky score of 60% or greater

Must not have

Rapidly progressive disease

Evidence of tumor potentially causing airway obstruction

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 15 years

Awards & highlights

No Placebo-Only Group

Summary

This trial involves treating patients with relapsed or refractory neuroblastoma using specially modified immune cells that can better recognize and attack their cancer. These modified cells are supported by chemotherapy and an additional drug to help them work more effectively. The goal is to see if this approach can safely extend the time these cells stay active in the body and improve their ability to fight cancer.

Who is the study for?

This trial is for children with high-risk neuroblastoma that's come back or didn't respond to treatment. They should have normal liver and kidney function, be stable after previous treatments, not have certain allergies, and must not be on immunosuppressive drugs. A key requirement is having T-cells modified to fight cancer ready for infusion.

What is being tested?

The study tests a new gene therapy using T cells engineered to target neuroblastoma more effectively by living longer in the body. It includes lymphodepletion chemotherapy (cyclophosphamide and fludarabine) followed by these special T cells plus pembrolizumab to counteract substances released by tumors that weaken immune responses.

What are the potential side effects?

Possible side effects include reactions from the genetically modified T cells or chemotherapy like fatigue, nausea, low blood counts leading to infection risk; pembrolizumab can cause immune-related issues such as inflammation of organs but varies among patients.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can care for myself but may need occasional help.

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My kidney function tests are within acceptable limits.

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Pembrolizumab is available for my treatment.

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My neuroblastoma is high risk and has either come back or not gone away.

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My T-cells are modified to target my cancer effectively.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My cancer is growing quickly.

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My tumor might block my airways.

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I am currently taking drugs that suppress my immune system.

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I had a severe reaction to a PD-1 inhibitor like pembrolizumab.

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I had severe side effects from cyclophosphamide or fludarabine.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 15 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~15 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 15 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Dose limiting toxicities at 6 weeks post T cell infusion

Secondary study objectives

Change in serum cytokine and chemokine levels

Time to progression of disease

To evaluate the expansion and persistence of 3rd generation iC9-GD2 T cells

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Group I: iC9-GD2 T cells,Cytoxan,Fludara,KeytrudaExperimental Treatment4 Interventions

Fresh T cells will be given IV over 5-10 mins. There is a possibility for additional doses of iC9-GD2 T cells.

Group II: iC9-GD2 T Cells - frozen - CLOSEDExperimental Treatment1 Intervention

The cells will be given IV over 5-10 minutes. There is a possibility for additional doses of iC9-GD2 T cells.

Group III: iC9-GD2 T Cells - fresh - CLOSEDExperimental Treatment1 Intervention

The cells will be given IV over 5-10 minutes. There is a possibility for additional doses of iC9-GD2 T cells.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Cytoxan

2007

Completed Phase 3

~1460

Fludara

2017

Completed Phase 2

~30

0 / 11Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Genetically modified T cells targeting GD2, such as iC9-GD2-CD28-OX40 T cells, are designed to recognize and kill Neuroblastoma cells by expressing chimeric antigen receptors (CARs) specific to the GD2 protein. Enhancements like CD28 and OX40 are incorporated to increase the T cells' longevity and efficacy. Lymphodepletion with chemotherapy and immune checkpoint inhibitors like pembrolizumab are also used to improve the persistence and effectiveness of these CAR T cells. This targeted approach is crucial for Neuroblastoma patients as it aims to more effectively eliminate cancer cells, potentially prolonging the time to disease progression and improving overall treatment outcomes.

The State of Cellular Adoptive Immunotherapy for Neuroblastoma and Other Pediatric Solid Tumors.Neuroblastoma: molecular pathogenesis and therapy.Surgical excision combined with autologous whole tumor cell vaccination is an effective therapy for murine neuroblastoma.