GD2 T-Cells + Chemotherapy for Neuroblastoma

(VEGAS Trial)

Recruiting at 1 trial location

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Disqualifiers: Immune deficiency, HIV, Pregnancy, others

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

Compensation: Varies

Number of Visits: 2

26 Participants Needed

Trial Summary

What is the purpose of this trial?

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 and lymohodepleting chemotherapy. Additionally, we will learn what the side effects of this treatment are and to see whether this therapy might help patients with advanced osteosarcoma and neuroblastoma. Because there is no standard treatment for recurrent/refractory osteosarcoma and neuroblastoma at this time or because the currently used treatments do not work fully in all cases, patients are being asked to volunteer to take part in a gene transfer research study using special immune cells. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. Investigators have found from previous research that a new gene can be put into T cells that will make them recognize cancer cells and kill them. Investigators now want to see if a new gene can be put in these cells that will let the T cells recognize and kill sarcoma and neuroblastoma cells. The new gene is called a chimeric antigen receptor (CAR) and consists of an antibody called 14g2a that recognizes GD2, a protein that is found on sarcoma and neuroblastoma cells (GD2-CAR). In addition, it contains parts of the CD28 and OX40 genes which can stimulate T cells to make them live longer. Investigators have found that CAR-T cells can kill some of the tumor, but they don't last very long in the body and so the tumor eventually comes back. T cells that recognize the virus that causes chicken pox, varicella zoster virus (VZV), remain in the bloodstream for many years especially if they are stimulated or boosted by the VZV vaccine. Investigators will therefore insert the GD2-CAR gene into T cells that recognize VZV. These cells are called iC9-GD2-CAR-VZV-specific T cells but are referred to as GD2-T cells for simplicity.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the GD2 T-Cells treatment for neuroblastoma?

Research shows that GD2-directed CAR T cells can lead to tumor regression in some neuroblastoma patients, with three out of eleven patients achieving complete remission in one study. Additionally, anti-GD2 immunotherapy has improved survival rates in high-risk neuroblastoma patients, indicating potential effectiveness of GD2-targeted treatments. ^{1 2 3 4 5}

Is GD2 T-cell therapy safe for humans?

GD2 T-cell therapy has been tested in patients with neuroblastoma, and while some experienced mild to moderate side effects like cytokine release syndrome (a reaction that can cause fever and inflammation), it was generally considered safe without causing damage to healthy tissues. ^{1 3 4 6 7}

How is the GD2 T-Cells + Chemotherapy treatment different from other treatments for neuroblastoma?

The GD2 T-Cells + Chemotherapy treatment is unique because it uses genetically modified T cells to specifically target the GD2 antigen on neuroblastoma cells, aiming to reduce tumor growth without harming healthy tissues. This approach is different from traditional treatments like chemotherapy and surgery, as it focuses on harnessing the body's immune system to fight the cancer, potentially leading to fewer side effects and improved long-term outcomes. ^{1 3 4 8 9}

Research Team

Cliona Rooney, PhD

Principal Investigator

Baylor College of Medicine

Lisa L Wang, MD

Principal Investigator

Baylor College of Medicine

Sarah Whittle, MD

Principal Investigator

Pediatrics, Baylor College of Medicine

Eligibility Criteria

This trial is for patients with relapsed or refractory osteosarcoma or high-risk neuroblastoma that hasn't responded to standard treatments. Participants must have a certain level of physical fitness, adequate organ function, and not be pregnant. They should have had prior exposure to the varicella zoster virus (chickenpox) or been vaccinated against it.

Inclusion Criteria

Procurement:

I have recovered from side effects of my previous cancer treatments.

Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent

Exclusion Criteria

Known primary immune deficiency or HIV positivity

Pregnant or lactating

You have had allergic reactions in the past to products that contain mouse proteins.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-infusion Lymphodepletion

Patients receive 3 daily doses of cyclophosphamide and fludarabine to induce lymphopenia before T cell infusion

3 days

T-cell Infusion

Patients receive GD2-T cells by intravenous line, followed by monitoring for 1 to 4 hours

1 day

1 visit (in-person)

VZV Vaccination

Two weeks after T-cell infusion, patients receive a dose of the VZV vaccine

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with blood tests and tumor measurements

15 years

Treatment Details

Interventions

• GD2 T cells

Trial Overview The study tests a combination therapy using GD2-T cells genetically modified to target cancer cells, alongside lymohodepleting chemotherapy and a varicella zoster vaccine. The goal is to determine the highest safe dose of these T cells and assess their effectiveness in treating advanced sarcomas and neuroblastoma.

Participant Groups

Group I: GD2 T cells plus VZV vaccine Experimental Treatment 4 Interventions

In this study we will be administering from 1 x 10\^6 to 1 x 10\^9 transduced autologous VZV-specific CTLs, derived from VZV-specific memory T cells, so there will be no risk of alloreactivity. 6.1.1 Pre-infusion lymphodepletion for dose levels 9-11: Patients will receive 3 daily doses of cyclophosphamide together with fludarabine to induce lymphopenia, finishing at least 24 hours before T cell infusion. Cyclophosphamide will be given at a dose of 500 mg/m2/day followed by Fludarabine 30 mg/m2/day.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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+

Findings from Research

In a study involving 19 patients with high-risk neuroblastoma, GD2 chimeric antigen receptor (CAR) T cells were able to induce complete remission in 3 out of 11 patients with active disease, demonstrating their efficacy in treating this aggressive cancer.

The persistence of CAR T cells in the patients was linked to better clinical outcomes, with some CAR-ATCs lasting up to 192 weeks, suggesting that longer-lasting CAR T cells may contribute to improved survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Louis, CU., Savoldo, B., Dotti, G., et al.[2023]

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]

In a phase II study involving 102 patients with high-risk neuroblastoma, the GD2/GD3 vaccine combined with oral β-glucan demonstrated a favorable safety profile, with only mild, self-limited side effects and no severe toxicities.

Higher levels of anti-GD2-IgG1 antibodies (≥ 150 ng/mL) by week 8 were linked to better progression-free survival (32% at 5 years) and overall survival (71% at 5 years), indicating that antibody response may be a key factor in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression. Cheung, IY., Cheung, NV., Modak, S., et al.[2022]

References

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

Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with 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. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-GD2 Based Immunotherapy Prevents Late Events in High-Risk Neuroblastoma Patients over 18 Months at Diagnosis. [2021]

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

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

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

Targeting GD2-positive Refractory/Resistant Neuroblastoma and Osteosarcoma with Anti- CD3 x Anti-GD2 Bispecific Antibody Armed T cells. [2023]

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

Survival Impact of Anti-GD2 Antibody Response in a Phase II Ganglioside Vaccine Trial Among Patients With High-Risk Neuroblastoma With Prior Disease Progression. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Anti-GD2 immunotherapy for neuroblastoma. [2021]

9. 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]