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

Phase 1

Completed

Conditions: Neuroblastoma

Interventions: Biological: GD2 CAR modified Tri-virus specific cytotoxic t-cells

Registration Number: NCT01460901

Lead Sponsor: Children's Mercy Hospital Kansas City

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 5

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
GD2 CAR modified Tri-virus CTL infusion	GD2 CAR modified Tri-virus specific cytotoxic t-cells	A single infusion of 2x10e6 cells per meter squared was performed 30 to 120 days following allogeneic stem cell transplant.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks	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.
Peak Transgene Copy Number Per 1000ng PBMC DNA	1 year	Peak Transgene Copy Number per 1000ng PBMC DNA from peripheral blood samples measured during study participation.
Death Within 8 Weeks of Infusion	8 weeks

Secondary Outcome Measures

Name	Time	Method
Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well	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
Maximum Tumor Response (RECIST 1.1)	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.