CAR T-Cell Therapy for Neuroblastoma

(GRAIN Trial)

Recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must be taking: Pembrolizumab

Must not be taking: Immunosuppressive drugs

Disqualifiers: Rapidly progressive disease, others

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

Compensation: Varies

Number of Visits: 4

11 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you do not take immunosuppressive drugs like corticosteroids, tacrolimus, or cyclosporine. If you are on these medications, you will need to stop them to participate in the trial.

What data supports the effectiveness of the treatment CAR T-Cell Therapy for Neuroblastoma?

Research shows that GD2-directed CAR T cells helped shrink tumors in 17 out of 27 children with neuroblastoma, and some patients experienced disease regression without severe side effects, indicating potential effectiveness and safety. ^{1 2 3 4 5}

Is CAR T-cell therapy for neuroblastoma safe?

CAR T-cell therapy for neuroblastoma has been shown to be safe in early clinical trials, with some patients experiencing mild to moderate side effects like cytokine release syndrome (a condition where the immune system becomes overly active). The therapy has not shown on-target off-tumor toxicity, meaning it does not harm healthy tissues. ^{2 3 4 5 6}

What makes the CAR T-Cell Therapy for Neuroblastoma unique?

This treatment uses specially engineered T cells to target and attack neuroblastoma cells, featuring a safety switch and two costimulatory domains to enhance effectiveness and safety. It is designed to overcome challenges like low antigen density and the tumor's ability to suppress the immune response, which are significant barriers in treating neuroblastoma with traditional therapies. ^{1 2 3 5 7}

What is the purpose of this trial?

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.

Research Team

Andras A. Heczey, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

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.

Inclusion Criteria

Pulse Ox greater than or equal to 90% on room air

Absence of HAMA prior to enrollment (only in patients that have been previously treated with murine antibodies)

Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who have received prior therapy with murine antibodies

Exclusion Criteria

You have had an allergic reaction in the past to products containing murine protein.

Patients who are pregnant, lactating, or unwilling to use birth control

My cancer is growing quickly.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Patients receive cyclophosphamide and fludarabine for lymphodepletion before T cell infusion

3 days

3 visits (in-person)

T Cell Infusion

Patients receive an infusion of iC9-GD2 T cells and pembrolizumab

1 day

1 visit (in-person)

Initial Monitoring

Patients are monitored for side effects and receive a second dose of pembrolizumab if treatment is well tolerated

4 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with visits every 1-2 weeks during the first 2 months, then spaced out over 15 years

15 years

Optional Additional Doses

Eligible patients may receive up to 2 additional doses of iC9-GD2 T cells if disease has not worsened

6 weeks between doses

Treatment Details

Interventions

• Cyclophosphamide
• Fludarabine
• iC9-GD2-CD28-OX40 T Cells
• Pembrolizumab

Trial Overview 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.

Participant Groups

Group I: iC9-GD2 T cells,Cytoxan,Fludara,Keytruda Experimental Treatment 4 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 - CLOSED Experimental Treatment 1 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 - CLOSED Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Solving Kids' Cancer

Collaborator

Trials

11

Recruited

200+

The Evan Foundation

Collaborator

Trials

5

Recruited

240+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Kids Cancer Research Foundation

Collaborator

Trials

1

Recruited

10+

Findings from Research

Despite the integration of anti-GD2 monoclonal antibody therapy, the 5-year overall survival rate for high-risk neuroblastoma patients remains around 50%, highlighting the need for improved treatment options.

CAR T cell therapy has shown promise in early clinical trials for neuroblastoma, demonstrating safety and feasibility, but challenges such as T cell persistence and an immunosuppressive tumor environment need to be addressed to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy for Neuroblastoma. Richards, RM., Sotillo, E., Majzner, RG.[2023]

In a phase 1 study involving 12 children with relapsed/refractory neuroblastoma, treatment with GD2-directed CAR-T cells showed some clinical activity, with three patients experiencing regression of their disease despite no objective clinical responses at the 28-day evaluation point.

The study reported that while two patients experienced significant cytokine release syndrome, there was no on-target off-tumor toxicity, indicating that targeting neuroblastoma with CAR-T cells is a safe approach, although further modifications are needed to enhance the effectiveness and longevity of the CAR-T cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. Straathof, K., Flutter, B., Wallace, R., et al.[2021]

A 3rd generation CAR T-cell construct targeting GD2 showed improved anti-tumor efficacy in neuroblastoma compared to other constructs, highlighting the importance of the 4-1BB costimulatory domain in enhancing T-cell characteristics like persistence and tumor control.

The inclusion of an inducible safety switch (iC9) in the CAR construct allows for the controlled elimination of CAR T cells if necessary, without compromising their anti-tumor activity, making it a safer option for treating pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma. Quintarelli, C., Orlando, D., Boffa, I., et al.[2021]

References

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

CAR T Cells Offer Hope for Neuroblastoma. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T Cell Therapy for Neuroblastoma. [2023]

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

Antitumor activity without on-target off-tumor toxicity of GD2-chimeric antigen receptor T cells in patients with neuroblastoma. [2021]

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

Tumor infiltrating lymphocytes expanded from pediatric neuroblastoma display heterogeneity of phenotype and function. [2021]

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

CAR T Cells Engineered to Target Low-Density Antigens Show Efficacy and Safety. [2022]

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

Choice of costimulatory domains and of cytokines determines CAR T-cell activity in neuroblastoma. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

αβ-T Cells Engineered to Express γδ-T Cell Receptors Can Kill Neuroblastoma Organoids Independent of MHC-I Expression. [2021]