CAR T-Cell Therapy for Neuroblastoma

(GRAIN Trial)

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new type of T-cell therapy for individuals with neuroblastoma that has recurred or is unresponsive to other treatments. Researchers are enhancing these T-cells with new genes to help them survive longer and attack cancer cells more effectively. Participants will receive a combination of modified T-cells (iC9-GD2-CD28-OX40 T Cells), chemotherapy, and pembrolizumab to potentially enhance the T-cells' effectiveness. This trial may suit those with high-risk neuroblastoma that does not respond to treatment or has returned. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

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

Research shows that CAR T-cell therapy, which modifies T cells to identify and attack cancer cells, has been studied in neuroblastoma cases. Previous studies with GD2-CAR T cells, targeting a specific protein on neuroblastoma cells, found the treatment generally safe for patients. In these studies, patients who received the infusion did not experience severe side effects, and the treatment was well-tolerated.

The new study aims to improve GD2-CAR T cells by adding genes that help the cells survive longer and potentially fight cancer more effectively. These enhanced T cells, called iC9-GD2-CD28-OX40 T cells, are used with chemotherapy drugs like cyclophosphamide and fludarabine to prepare the body and enhance T cell efficacy. Research supports that this combination of drugs, known for reducing immune cells, can make the treatment more effective without increasing safety risks.

Additionally, pembrolizumab, a drug used in the study, boosts the immune response by preventing tumors from shutting down the T cells. Studies have shown this combination to be generally safe and feasible for patients with solid tumors like neuroblastoma.

In summary, research supports that iC9-GD2-CD28-OX40 T cells, both alone and with additional treatments, are well-tolerated with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about iC9-GD2-CD28-OX40 T cells because they represent a cutting-edge approach to treating neuroblastoma, a type of cancer that primarily affects children. Unlike standard treatments like chemotherapy and radiation, which target cancer cells broadly and can harm healthy cells, this therapy uses engineered T cells to specifically target and attack cancer cells expressing GD2, a molecule found on neuroblastoma cells. The addition of the iC9 safety switch allows for control over the T cells, potentially reducing side effects by selectively eliminating the cells if needed. This level of precision and control offers a promising alternative to traditional therapies, with the potential for improved effectiveness and reduced harm.

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

Research has shown that a special type of immune cell treatment, called GD2-directed CAR T cells, effectively shrinks tumors in children with neuroblastoma. In one study, 17 out of 27 children experienced tumor reduction. These modified immune cells target a protein called GD2, found on most neuroblastoma cells, and have shown promise in earlier studies. In this trial, participants will receive iC9-GD2 T cells, which include CD28 and OX40 genes to help these immune cells live longer in the body, potentially enhancing their cancer-fighting ability. Some participants will receive these immune cells with chemotherapy drugs like cyclophosphamide and fludarabine, which may help the immune cells grow and last longer, increasing their effectiveness. Additionally, pembrolizumab is included in this trial to help the immune cells overcome the cancer’s defenses, improving their chances of success. Overall, these findings suggest this treatment approach has strong potential. ^{1 2 6 7 8}

Who Is on the Research Team?

Andras A. Heczey, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02439788

Study Details | NCT02439788 | 3RD GENERATION GD2 ... This research study is for patients that have a cancer called Neuroblastoma that has either come back after treatment or did not respond to the standard ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2772610X24000382

GD2 targeting CAR T cells for neuroblastoma GD2 is a well-recognised and validated target antigen for neuroblastoma. CAR-T cells targeting GD2 are a tractable novel therapeutic approach for refractory ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5980417/

Choice of costimulatory domains and of cytokines determines ... Our data indicate that a 3rd generation CAR incorporating CD28.4-1BB costimulatory domains is associated with improved anti-tumor efficacy as compared with a ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6430125/

Advances in Anti-GD2 Immunotherapy for Treatment of High ... Immunotherapy with ch14.18 was shown in a COG phase III randomized clinical trial to have superior event-free survival (EFS, 66 ± 5% vs 46 ± 5%) and overall ...

5. withpower.com withpower.com/trial/phase-1-neuroblastoma-7-2013-61006

CAR T-Cell Therapy for Neuroblastoma (GRAIN Trial) 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 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6232778/

CAR T Cell Therapy for Neuroblastoma - PMC - PubMed Central In early phase clinical trials, CAR T cell therapy for neuroblastoma has proven safe and feasible, but significant barriers to efficacy remain.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT01953900

Study Details | NCT01953900 | iC9-GD2-CAR-VZV-CTLs/ ... The purpose of this study is to find the largest safe dose of GD2-T cells (also called iC9-GD2-CAR-VZV-CTLs) in combination with a varicella zoster vaccine ...

8. aacrjournals.org aacrjournals.org/clincancerres/article/25/9/2915/82503/Eradication-of-Neuroblastoma-by-T-Cells-Redirected

Eradication of Neuroblastoma by T Cells Redirected with an ... Response rates in patients with neuroblastoma receiving GD2.CAR-Ts remain significantly inferior to those observed in patients with acute lymphoblastic leukemia ...