GINAKIT Cells for Neuroblastoma

(GINAKIT2 Trial)

Overseen By Gengwen Tian, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must be taking: Etanercept

Must not be taking: Immunosuppressants, Investigational drugs

Disqualifiers: Rapidly progressive disease, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 5 weeks

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for children with difficult-to-treat neuroblastoma, a type of cancer. The study combines special white blood cells, called NKT cells, with a protein that helps these cells locate and destroy cancer cells. Known as GINAKIT Cells (or GD2-CAR NKT cells), this treatment aims to determine the safest and most effective dose of these modified cells and assess their impact on the cancer. Children whose neuroblastoma has returned or not responded to treatment and who meet specific health criteria might be suitable candidates. As a Phase 1 trial, this 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 are not currently taking immunosuppressive drugs like corticosteroids, tacrolimus, or cyclosporine, unless the corticosteroid dose is less than 0.5mg/kg/day of prednisone equivalent. If you are on these medications, you may need to stop or adjust them before participating.

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

In previous studies, researchers found that GD2-CAR NKT cells, like those used in GINAKIT cells, are generally safe for patients and can effectively fight cancer. No serious safety issues have been reported with these cells. Adding Interleukin-15 (IL-15), which extends the cells' lifespan, appears effective without increasing side effects.

Etanercept, a medicine used in children for illnesses like rheumatoid arthritis, is usually well-tolerated. However, its safety in combination with GINAKIT cells remains uncertain due to limited data. Overall, GINAKIT cells and Etanercept appear relatively safe, but further research is needed to fully understand their combined safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about GINAKIT cells for treating neuroblastoma because they offer a novel approach that differs from standard treatments like chemotherapy, surgery, and radiation. Unlike traditional methods, GINAKIT cells are engineered to specifically target and attack cancer cells, potentially improving precision and reducing damage to healthy tissue. Additionally, in one experimental approach, GINAKIT cells are combined with Etanercept, an anti-inflammatory drug, which may enhance the treatment's effectiveness by modulating the immune response. This innovative combination aims to provide a more effective and targeted treatment option for patients with neuroblastoma.

What evidence suggests that GINAKIT cells might be an effective treatment for neuroblastoma?

Research has shown that GD2-specific CAR NKT cells, known as GINAKIT cells, offer a promising new approach to treating neuroblastoma, a type of cancer. These cells are engineered to locate and destroy neuroblastoma cells by recognizing a molecule called GD2, present on most of these cancer cells. Early results suggest that these modified cells can slow tumor growth by also targeting other cells that support the tumor. In animal studies, adding a gene for a protein called IL-15 extended the lifespan of these cells and enhanced their cancer-fighting ability. In this trial, some participants will receive GINAKIT cells alone, while others will receive them in combination with Etanercept. Although GINAKIT cells have not yet been tested in humans, their design and early research indicate they might effectively target and shrink neuroblastoma tumors. ^{1 2 3 4 5}

Who Is on the Research Team?

Gengwen Tian, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for children and young adults (1-21 years old) with high-risk neuroblastoma that has relapsed or not responded to treatment. They must weigh over 12kg, have a life expectancy of at least 12 weeks, and be able to undergo leukocyte apheresis. Their kidney function, blood counts, liver enzymes, and heart/lung health should meet specific criteria. Those who are pregnant or breastfeeding, have HIV infection or severe disease progression cannot participate.

Inclusion Criteria

My white blood cell count is healthy without needing medication for at least 2 days.

My blood cell counts meet the required levels for treatment.

My treatment involves NKT cells modified to target my cancer more effectively.

Exclusion Criteria

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

My tumor is blocking my airways.

I had severe side effects from cyclophosphamide or fludarabine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Participants receive cyclophosphamide and fludarabine intravenously for 2 days and fludarabine alone for one more day before GINAKIT cell infusion.

3 days

In-patient stay for chemotherapy administration

Treatment

Participants receive GINAKIT cells infusion and ETANercept subcutaneously once per week for 5 doses.

5 weeks

Weekly visits for ETANercept administration

Initial Follow-up

Participants are monitored for side effects and tumor response with follow-up visits at weeks 1, 2, 3, 4, and 8.

8 weeks

Weekly visits for monitoring

Long-term Follow-up

Participants are monitored for long-term safety and effectiveness with visits every 3 months for the first year, every 6 months for the next 4 years, and then annually for the next 10 years.

15 years

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• GINAKIT Cells

Trial Overview The study tests GINAKIT cells in patients with neuroblastoma. These cells are the patient's own Natural Killer T (NKT) cells genetically modified to express GD2-CAR targeting cancer cells and IL-15 for improved survival. The goal is to find the highest safe dose that can effectively target the tumor.

How Is the Trial Designed?

Group I: GINAKIT cells Experimental Treatment 1 Intervention

GINAKIT cells will be administer to patients with Neuroblastomas on Day 0.

Group II: Experimental: GINAKIT cells + Etanercept. Experimental Treatment 1 Intervention

GINAKIT cells will be administer to patients with Neuroblastomas on Day 0 in combination of Etanercept.

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+

Published Research Related to This Trial

Combining activated invariant natural killer T (iNKT) cells with anti-GD2 antibodies enhances the effectiveness of the treatment for neuroblastoma by increasing the cytotoxicity of natural killer (NK) cells, which is crucial for fighting cancer.

This combination therapy works by upregulating important cytokines like granzyme A, granzyme B, and interferon gamma (IFNγ), suggesting that iNKT cells can improve the immune response against neuroblastoma while potentially minimizing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells. Mise, N., Takami, M., Suzuki, A., et al.[2021]

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]

IL-2 significantly enhances the effectiveness of anti-GD2 antibodies in promoting antibody-dependent cell-mediated cytotoxicity (ADCC) against neuroblastoma cells, potentially allowing for lower doses of antibodies and reduced toxicity.

The study identified that licensed NK cells with specific receptor mismatches against tumor HLA showed the highest degranulation and cytotoxic activity, suggesting that individual variations in NK cell characteristics could influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of interleukin-2, all-trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma. Nguyen, R., Houston, J., Chan, WK., et al.[2022]

Dinutuximab, an immunotherapy targeting GD2 on neuroblastoma cells, improves survival in children with high-risk neuroblastoma, but many still experience disease progression, highlighting the need for better strategies against immune suppression.

Research using TH-MYCN transgenic mice shows that these tumors express GD2 at levels similar to human cases, and treatment with a murine anti-GD2 antibody significantly extends survival, suggesting that GD2-targeted therapies could be more effective than previously thought.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TH-MYCN tumors, but not tumor-derived cell lines, are adrenergic lineage, GD2+, and responsive to anti-GD2 antibody therapy. McNerney, KO., Karageorgos, S., Ferry, GM., et al.[2023]

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]

In a study of 169 children with stage 4 neuroblastoma, the combination of anti-GD2 monoclonal antibody 3F8 with GM-CSF and 13-cis-retinoic acid significantly improved progression-free survival (PFS) and overall survival (OS) rates compared to 3F8 alone, with 5-year OS rates of 81% for the most effective regimen.

The presence of minimal residual disease (MRD) after treatment was identified as a negative prognostic factor, while the absence of certain immune response markers and the use of the most effective treatment regimen (regimen C) were associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. Cheung, NK., Cheung, IY., Kushner, BH., et al.[2021]

The genetically engineered NK-92-scFv(ch14.18)-zeta cell line effectively targets and kills GD2-positive neuroblastoma cells, including those that are partially or multidrug-resistant, demonstrating its potential as a powerful immunotherapy.

In vivo studies in a drug-resistant neuroblastoma mouse model showed that NK-92-scFv(ch14.18)-zeta can elicit a significant anti-tumor response, highlighting its promise for future clinical applications in treating high-risk neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma. Seidel, D., Shibina, A., Siebert, N., et al.[2021]

The combination of dinutuximab beta (DB) and subcutaneous interleukin-2 (scIL2) after haploidentical stem cell transplantation (haplo-SCT) in patients with relapsed high-risk neuroblastoma showed a 54.4% success rate, indicating it is a feasible treatment option.

Long-term outcomes were promising, with a 5-year event-free survival rate of 43% and overall survival rate of 53%, particularly among patients in complete or partial remission before immunotherapy, suggesting enhanced antineuroblastoma activity from donor-derived immune cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial. Flaadt, T., Ladenstein, RL., Ebinger, M., et al.[2023]

In a phase 1 trial involving 12 children with neuroblastoma, GD2-CAR.15 NKTs were found to be safe, with no dose-limiting toxicities and only one case of mild cytokine release syndrome that was manageable with treatment.

The treatment showed an objective response rate of 25%, including one complete response, suggesting that GD2-CAR.15 NKTs can effectively target neuroblastoma, and their anti-tumor activity may be further improved by targeting the BTG1 protein.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. Heczey, A., Xu, X., Courtney, AN., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03294954

NCT03294954 | GD2 Specific CAR and Interleukin-15 ... The purpose of this study is to find the largest effective and safe dose of GD2-CAR NKT cells (GINAKIT cells), to evaluate their effect on the tumor and how ...

2. texaschildrens.org texaschildrens.org/departments/cancer-and-hematology-center/clinical-trials-and-novel-therapies/gd2-specific-car-and

Cancer and Hematology Center GD2 Specific CAR and ... The purpose of this study is to find the largest effective and safe dose of GD2-CAR NKT cells (GINAKIT cells), to evaluate their effect on the tumor.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37188782/

Anti-GD2 CAR-NKT cells in relapsed or refractory ... Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with ...

4. targetedonc.com targetedonc.com/view/safety-efficacy-results-boost-the-use-of-nkt-cells-in-pediatric-neuroblastoma

Safety, Efficacy Results Boost the Use of NKT Cells in ... Safety and efficacy data for natural killer T (NKT) cells bolster the use of this cellular therapy in patients with stage IV relapsed/refractory ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02439788

Study Details | NCT02439788 | 3RD GENERATION GD2 ... Natural Killer T cells are a special subset of innate lymphocytes that can effectively go into tumor tissues of neuroblastoma. Inside the tumor, there are ...