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

Phase I Study of Donor Derived,Gene Modified, Multi-virus-specific, Cytotoxic T-Lymphocytes Redirected to GD2 for Relapsed/Refractory Neuroblastoma Post-allo Stem Cell Transplantation With Submyeloblative Conditioning

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.

Study Overview

• Status: Completed
• Conditions: Neuroblastoma
• Intervention / Treatment: Biological: GD2 CAR modified Tri-virus specific cytotoxic t-cells

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: 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.

Biological: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks	Immediate: Patients were monitored following infusion to assess for toxicity related to infusion. Potential toxicities related to cellular therapy infusions, such as allergic reaction to the cellular product or cryopreservation media, hemolytic reactions, volume overload, and hemodynamic instability, were monitored. Short Term: Patients were monitored for 8 weeks for short term toxicity related to infusion. Such adverse reactions monitored were acute graft versus host disease and cytokine release syndrome.	Post infusion week 8
Peak Transgene Copy Number Per 1000ng PBMC DNA	Peak Transgene Copy Number per 1000ng PBMC DNA from peripheral blood samples measured during study participation.	1 year
Death Within 8 Weeks of Infusion		8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well	The following analyses were performed on peripheral blood samples from patients at protocol assigned time points (pre-infusion, post-infusion at 4 hrs, weeks 1,2,4,6 and 8, month 3, 6 and 12: ELISPOT assay for CMV, Adenovirus and EBV specific CTL reported as SFU (spot forming unit) per 2x10e5 mononuclear cells	up to 1 year
Maximum Tumor Response (RECIST 1.1)	Pre and post-therapy evaluation by modalities consistent with prior disease evaluation in each patient. When possible, tumors were assessed per Response Evaluation Criteria In Solid Tumors (RECIST v1.0): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >/=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD) neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Bone marrow aspirations and biopsies were evaluated by histopathology and appropriate immunohistochemistry; Modified Curie score was used for MIBG evaluation.	1 year

Collaborators and Investigators

• Sponsor: Children's Mercy Hospital Kansas City
• Collaborators: Center for Cell and Gene Therapy, Baylor College of Medicine
• Investigators: Principal Investigator: Doug Myers, MD, Children's Mercy Hospital Kansas City

Publications and helpful links

Helpful Links

• Children's Mercy Hospitals and Clinics

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (ACTUAL): January 1, 2015
• Study Completion (ACTUAL): January 1, 2015

Study Registration Dates

• First Submitted: October 25, 2011
• First Submitted That Met QC Criteria: October 26, 2011
• First Posted (ESTIMATE): October 27, 2011

Study Record Updates

• Last Update Posted (ACTUAL): July 23, 2019
• Last Update Submitted That Met QC Criteria: July 22, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Relapsed; Refractory; Neuroblastoma
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Neuroblastoma
• Other Study ID Numbers: STALLONe; 00038 (OTHER: Production Assistance for Cellular Therapy (PACT))