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

• ClinicalTrials.gov Identifier: NCT01460901
• Recruitment Status: Completed
• First Posted: October 27, 2011
• Results First Posted: July 23, 2019
• Last Update Posted: July 23, 2019
• Sponsor: Children's Mercy Hospital Kansas City
• Collaborator: Center for Cell and Gene Therapy, Baylor College of Medicine
• Information provided by (Responsible Party): Doug Myers, Children's Mercy Hospital Kansas City

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Neuroblastoma	Biological: GD2 CAR modified Tri-virus specific cytotoxic t-cells	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: October 2012
• Actual Primary Completion Date: January 2015
• Actual Study Completion Date: January 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks [ Time Frame: Post infusion week 8 ]

   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.

2. Peak Transgene Copy Number Per 1000ng PBMC DNA [ Time Frame: 1 year ]
   Peak Transgene Copy Number per 1000ng PBMC DNA from peripheral blood samples measured during study participation.
3. Death Within 8 Weeks of Infusion [ Time Frame: 8 weeks ]

Secondary Outcome Measures :

1. Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well [ Time Frame: up to 1 year ]

   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

2. Maximum Tumor Response (RECIST 1.1) [ Time Frame: 1 year ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Months to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Missouri

Children's Mercy Hospital

Kansas City, Missouri, United States, 64108

Sponsors and Collaborators

Children's Mercy Hospital Kansas City

Center for Cell and Gene Therapy, Baylor College of Medicine

Investigators

• Principal Investigator: Doug Myers, MD; Children's Mercy Hospital Kansas City

More Information

Additional Information:

Children's Mercy Hospitals and Clinics 

• Responsible Party: Doug Myers, Principal Investigator, Children's Mercy Hospital Kansas City
• ClinicalTrials.gov Identifier: NCT01460901
• Other Study ID Numbers: STALLONe; 00038 ( Other Identifier: Production Assistance for Cellular Therapy (PACT) )
• First Posted: October 27, 2011
• Results First Posted: July 23, 2019
• Last Update Posted: July 23, 2019
• Last Verified: July 2019

Keywords provided by Doug Myers, Children's Mercy Hospital Kansas City:

Neuroblastoma; Relapsed; Refractory

Additional relevant MeSH terms:

Neuroblastoma; 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