GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma

NCT03294954 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: H-41033 GINAKIT2
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

This research study combines two different ways of fighting cancer: antibodies and Natural Killer T cells (NKT). Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special white 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. Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. In a previous clinical trial, investigators made artificial genes called a chimeric antigen receptors (CAR), from an antibody called 14g2a that recognizes GD2, a molecule found on almost all neuroblastoma cells (GD2-CAR). Investigators put these genes into the patients' own T cells and gave them back to patients that had neuroblastoma. NKT cells are another special subgroup of white blood cells that can specifically go into tumor tissue of neuroblastoma. Inside the tumor, there are other white blood cells called macrophages which help the cancer cells to grow and recover from injury. NKT cells can specifically kill these macrophages and slow the tumor growth. We will expand NKT cells and add GD2-specific chimeric antigen receptors to the cells. We think these cells might be better able to attack NB since they also work by destroying the macrophages that allows the tumor to grow. The chimeric antigen receptor will also contain a gene segment to make the NKT cells last longer. This gene segment is called CD28. In addition, to further improve the antitumor activity of the GINAKIT cells we added another gene expressing a molecule called Interleukin -15 (IL-15). The combination of these 3 components showed the most antitumor activity by CAR expressing NKT cells and improved these cells' survival in animal models. We also found that a medicine called ETANercept can slow down neuroblastoma growth, which might enhance the effects of the modified cells. In this part of our study, we aim to treat children with hard-to-treat neuroblastoma using these modified NKT cells along with ETANercept. Though ETANercept has been used to treat other diseases, such as rheumatoid arthritis in children, there is limited information about the safety, efficacy, and risk of ETANercept treatment in combination with cellular therapies. GD2-CAR expressing NKTs have not been tested in patients so far. 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 long they can be detected in the patient's blood and what affect they have on the patient's neuroblastoma.

Conditions

Neuroblastoma

Keywords

Neuroblastoma; Natural Killer T-Cells; Chimerical Antigen Receptor

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose of autologous NKTs expressing a 2nd generation GD2-specific chimeric antigen receptor administered to patients with relapsed or refractory neuroblastoma in combination with Etanercept.

  Defined as the highest dose level that will have at most a 33% chance of inducing the following NKT-cell-related dose limiting toxicities (DLTs) within 28 days after infusion of NKTs in combination with Etanercept.

  28 days

Secondary Outcomes (1)

• Anti-tumor response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma and compare the anti-tumor response in patients treated with and without Etanercept.

  15 years

Other Outcomes (1)

• Immunologic response of autologous GINAKIT cells with and without Etanercept in patients with relapsed/refractory neuroblastoma.

  15 years

Study Arms (2)

GINAKIT cells

EXPERIMENTAL

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

Genetic: GINAKIT Cells

Experimental: GINAKIT cells + Etanercept.

EXPERIMENTAL

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

Biological: GINAKIT cells + Etanercept

Interventions

GINAKIT Cells GENETIC

Six dose levels of GINAKIT cells will be studied. Dosing will be based on the actual number of transduced cells. All doses are per m2. * Dose Level 1 = 3 x 10\^6 * Dose Level 2 = 1 x 10\^7 * Dose Level 3 = 3 x 10\^7 * Dose Level 4 = 1 x 10\^8 * Dose Level 5 = 3 x 10\^8 * Dose Level 6 = 1 x 10\^9

GINAKIT cells

GINAKIT cells + Etanercept BIOLOGICAL

Four dose levels of GINAKIT cells in combination of Etanercept will be studied. Dosing will be based on the actual number of transduced cells. All doses are per m2. * Combination Dose level 1: 3 x 10\^6 + Etanercept\* * Combination Dose level 2: 1 x 10\^7 + Etanercept\* * Combination Dose level 3: 3 x 10\^7 + Etanercept\* * Combination Dose level 4: 1 x 10\^8 + Etanercept

Experimental: GINAKIT cells + Etanercept.

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Relapsed or refractory high risk neuroblastoma
• Life expectancy of at least 12 weeks
• Age greater than 1 year and less than 21 years old
• Karnofsky/Lansky score of 60% or greater
• Absence of HAMA prior to enrollment (only in patients that have been previously treated with murine antibodies)
• Ability to tolerate leukocyte apheresis
• Informed consent and assent (as applicable) obtained from parent/guardian and child.
• Patients must have an ANC greater than or equal to 500/µl, platelet count greater than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count greater than or equal to 20,000/µl.
• Pulse Ox greater than or equal to 90% on room air
• Serum AST less than 3 times the upper limit of normal
• Total Bilirubin less than 1.5 times the upper limit of normal
• Creatinine \< 1.5 times the upper limit of normal
• Recovered from the acute toxic effects of all prior chemotherapy based on the enrolling physician's assessment (if some effects of chemotherapy are expected to last long term, patient is eligible if meeting other eligibility criteria).
• Weight greater than 12kg
• Negative QuantiFERON-TB or T-SPOT testing within 3 months prior to procurement

You may not qualify if:

• Rapidly progressive disease
• History or hypersensitivity to murine protein-containing products
• Tumor causing airway obstruction
• Currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine
• Severe previous toxicity from cyclophosphamide or fludarabine based on the enrolling physician's assessment
• HIV infection
• History of hypersensitivity, anaphylaxis, and/or adverse event with Etanercept
• Relapsed or refractory high risk neuroblastoma
• Life expectancy of at least 12 weeks
• Age greater than 1 year and less than 21 years old
• Karnofsky/Lansky score of 60% or greater
• Patients must have an ANC greater than or equal to 500/µl, platelet count greater than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count greater than or equal to 20,000/µl.
• Pulse Ox greater than or equal to 90% on room air
• Serum AST less than 3 times the upper limit of normal
• Total Bilirubin less than 1.5 times the upper limit of normal

Sponsors & Collaborators

• Baylor College of Medicine: lead
• Center for Cell and Gene Therapy, Baylor College of Medicine: collaborator

Study Sites (1)

Texas Children's Hospital

Houston, Texas, 77030, United States

RECRUITING

Related Publications (3)

• Heczey A, Xu X, Courtney AN, Tian G, Barragan GA, Guo L, Amador CM, Ghatwai N, Rathi P, Wood MS, Li Y, Zhang C, Demberg T, Di Pierro EJ, Sher AC, Zhang H, Mehta B, Thakkar SG, Grilley B, Wang T, Weiss BD, Montalbano A, Subramaniam M, Xu C, Sachar C, Wells DK, Dotti G, Metelitsa LS. Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results. Nat Med. 2023 Jun;29(6):1379-1388. doi: 10.1038/s41591-023-02363-y. Epub 2023 May 15.

  PMID: 37188782 DERIVED

• Heczey A, Courtney AN, Montalbano A, Robinson S, Liu K, Li M, Ghatwai N, Dakhova O, Liu B, Raveh-Sadka T, Chauvin-Fleurence CN, Xu X, Ngai H, Di Pierro EJ, Savoldo B, Dotti G, Metelitsa LS. Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis. Nat Med. 2020 Nov;26(11):1686-1690. doi: 10.1038/s41591-020-1074-2. Epub 2020 Oct 12.

  PMID: 33046868 DERIVED

• Xu X, Huang W, Heczey A, Liu D, Guo L, Wood M, Jin J, Courtney AN, Liu B, Di Pierro EJ, Hicks J, Barragan GA, Ngai H, Chen Y, Savoldo B, Dotti G, Metelitsa LS. NKT Cells Coexpressing a GD2-Specific Chimeric Antigen Receptor and IL15 Show Enhanced In Vivo Persistence and Antitumor Activity against Neuroblastoma. Clin Cancer Res. 2019 Dec 1;25(23):7126-7138. doi: 10.1158/1078-0432.CCR-19-0421. Epub 2019 Sep 4.

  PMID: 31484667 DERIVED

MeSH Terms

Conditions

Neuroblastoma

Interventions

Etanercept

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins

Study Officials

• Gengwen Tian, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gengwen Tian, MD

CONTACT

832-454-2642; gxtian1@texaschildrens.org

Ramy Sweidan

CONTACT

832-824-4234; rxsweida@texaschildrens.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: September 20, 2017
• First Posted: September 27, 2017
• Study Start: January 18, 2018
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): August 10, 2040
• Last Updated: September 19, 2025

Record last verified: 2025-09

Locations

US (1)