Study of Donor Derived, Multi-virus-specific, Cytotoxic T-Lymphocytes for Relapsed/Refractory Neuroblastoma

NCT ID: NCT01460901

Last Updated: 2019-07-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-31
• Study Completion Date: 2015-01-31

Brief Summary

This is a single-center, investigator-initiated, single-arm, pilot study of post-allogeneic transplant, adoptive immunotherapy for the treatment of patients with relapsed/refractory neuroblastoma expressing the mesenchymal tumor marker GD2. Three patients will be treated. The study will focus on the safety and efficacy of allogeneic, donor derived viral specific cytotoxic T-lymphocytes, retrovirally transduced to express a chimeric antigen receptor specific for disialoganglioside, GD2, expressed on neuroblastoma.

Detailed Description

Neuroblastoma (NB) is the most common extracranial tumor of childhood and prognosis for patients with relapsed or refractory disease is < 10% and there is no standard therapy for these patients. Research toward immunotherapeutic agents has intensified as monoclonal antibody targeting GD2, when incorporated into upfront NB therapy, prolongs survival. Allogeneic Hematopoietic stem cell transplantation (HSCT) has been utilized in patients with NB with evidence of a graft versus tumor (GVT) effect but transplant related mortality (TRM) has nullified the survival benefit. In an effort to harness the GVT effect of allogeneic transplant and lower TRM, harvested viral specific cytotoxic T-cells from the donor will be infused early post-HSCT to the HSCT recipient to shorten the recovery of immunity toward the most significant viral infections. The investigators will also retrovirally transduce the viral specific CTL with a chimeric antigen receptor (CAR) gene complex such that the tV-CTL can expand, via their native T-cell receptors in response to viral infections post-HSCT and carry the capability of killing tumor cells through their transduced receptor which, on the extracellular component of the CAR, has specificity for GD2 expressed on the surface of NB. In essence, the investigators intend to take the specificity of the monoclonal antibody to GD2, already utilized in therapy for NB, and combine this specificity with the cytotoxicity of T-cells to target NB. The investigators hypothesize that the infusion will be safe and viral specificity of the tV-CTL will provide long term immunity to both viral infections and the investigators will see anti-tumor effects.

Conditions

Neuroblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

GD2 CAR modified Tri-virus CTL infusion

A single infusion of 2x10e6 cells per meter squared was performed 30 to 120 days following allogeneic stem cell transplant.

Group Type: EXPERIMENTAL

GD2 CAR modified Tri-virus specific cytotoxic t-cells

Intervention Type: BIOLOGICAL

This is a feasibility study to assess safety of an infusion of chimeric-antigen receptor gene modified allogeneic virus specific T lymphocytes after reduced intensity allogeneic stem cell transplant. Three patients were treated and safety was evaluated. Patients received a single infusion of 2x10e6/m2 donor derived, GD2 CAR modified, tri-virus specific CTL performed 30-120 days after allogeneic stem cell transplantation

Interventions

GD2 CAR modified Tri-virus specific cytotoxic t-cells

This is a feasibility study to assess safety of an infusion of chimeric-antigen receptor gene modified allogeneic virus specific T lymphocytes after reduced intensity allogeneic stem cell transplant. Three patients were treated and safety was evaluated. Patients received a single infusion of 2x10e6/m2 donor derived, GD2 CAR modified, tri-virus specific CTL performed 30-120 days after allogeneic stem cell transplantation

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• Allogeneic transduced tV-CTLs with >15% expression of 14g2a.zeta chimeric antigen receptor
• Patient or responsible person must be able to understand and sign a permission/assent or consent form for infusion
• Age 18 months through 17 years at time of relapse/progression
• Life expectancy >8weeks
• Karnofsky score 60% or greater if 10 yrs old or older. Lansky score 60% or greater if under 10 yrs old
• Patient must be HIV negative
• ANC >500
• Pulse ox>90% on room air
• AST/ALT/direct bili <5x upper limit of normal
• Recovered from toxic effects of all prior chemotherapy
• Absence of human/anti-mouse antibody (HAMA) (patients who have received prior therapy with murine antibodies)
• >50% donor engraftment

Exclusion Criteria

• Patient pregnant or lactating or refuses birth control methods
• HIV positive
• Uncontrolled intercurrent infection
• Renal failure (creatinine clearance <40ml/min/1.73m2)
• Active hepatitis or cirrhosis with bilirubin, AST, ALT >5xnormal
• Rapidly progressive disease
• Currently receiving any investigational drugs
• Tumor potentially causing airway obstruction
• Cardiomegaly or bilateral pulmonary infiltrates on CXR
• Receiving >0.25mg/kg/day methylprednisolone or equivalent systemic steroid. Topical steroid therapy is acceptable
• Receiving more than one lymphocyte inhibiting agent (ex. Tacrolimus/CSA and MMF or other similar agent
• Patients relapsing or progressing before the age of 18 months from Stage I/II disease, and/or those who, in the opinion of their oncologist, may benefit from further conventional therapy
• Donor lymphocyte infusion in last 28 days
• Evidence of GvHD greater than or equal to grade 2

• Minimum Eligible Age: 18 Months
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Center for Cell and Gene Therapy, Baylor College of Medicine

OTHER

Sponsor Role: collaborator

Children's Mercy Hospital Kansas City

OTHER

Sponsor Role: lead

Responsible Party

Doug Myers

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Doug Myers, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Mercy Hospital Kansas City

Locations

Children's Mercy Hospital

Kansas City, Missouri, United States

Countries

United States

Related Links

http://www.childrensmercy.org/

Children's Mercy Hospitals and Clinics

Other Identifiers

00038

Identifier Type: OTHER

Identifier Source: secondary_id

STALLONe

Identifier Type: -

Identifier Source: org_study_id