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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Neuroblastoma

Intervention / Treatment
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* Biological: GD2 CAR modified Tri-virus specific cytotoxic t-cells


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GD2 CAR modified Tri-virus CTL infusion<br>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<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroblastoma, Relapsed, Refractory