Clinical trial NCT01460901: Study of Donor Derived, Multi-virus-specific, Cytotoxic T-Lymphocytes for Relapsed/Refractory Neuroblastoma
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neuroblastoma
Keywords: Neuroblastoma
Relapsed
Refractory
Lead sponsor: Children's Mercy Hospital Kansas City
Sponsor class: OTHER
Collaborators: name: Center for Cell and Gene Therapy, Baylor College of Medicine
First posted: 2011-10-27
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks
timeFrame: Post infusion week 8
measure: Peak Transgene Copy Number Per 1000ng PBMC DNA
timeFrame: 1 year
measure: Death Within 8 Weeks of Infusion
timeFrame: 8 weeks
Secondary outcomes:
measure: Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well
timeFrame: up to 1 year
measure: Maximum Tumor Response (RECIST 1.1)
timeFrame: 1 year
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
Study officials:
affiliation: Children's Mercy Hospital Kansas City
name: Doug Myers, MD
role: PRINCIPAL_INVESTIGATOR
References: