Neuroblastoma
Conditions
Keywords
Neuroblastoma, Relapsed, Refractory
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.
Interventions
BIOLOGICALGD2 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
Sponsors
Center for Cell and Gene Therapy, Baylor College of Medicine
Children's Mercy Hospital Kansas City
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Months to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Patients were consented and screened in the outpatient clinic. First consent was 10/2012 and last consent was signed 2/2014.
Pre-assignment details
Patients could withdraw at their discretion or were withdrawn for rapid disease progression.
Participants by arm
| Arm | Count |
|---|---|
| GD2 CAR Modified Tri-virus CTL 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. The intent is to treat three patients and evaluate safety.
A single infusion of 2 million cells per meter squared was dosed.
Tri-virus specific cytotoxic t-cells: Infusion of donor derived tri-virus specific cytotoxic t-cell post allogeneic stem cell transplantation | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | GD2 CAR Modified Tri-virus CTL | — |
|---|---|---|
| Age, Categorical <=18 years | 5 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 0 Participants | — |
| Age, Continuous | 7.7 years STANDARD_DEVIATION 1.9 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 5 participants | — |
| Sex: Female, Male Female | 2 Participants | — |
| Sex: Female, Male Male | 3 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 3 |
| other Total, other adverse events | 2 / 3 |
| serious Total, serious adverse events | 3 / 3 |
Outcome results
Primary
Death Within 8 Weeks of Infusion
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GD2 CAR Modified Tri-virus CTL Infusion | Death Within 8 Weeks of Infusion | 1 participants |
Primary
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.
Time frame: Post infusion week 8
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| GD2 CAR Modified Tri-virus CTL Infusion | Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks | Immediate Infusion Toxicity | 0 Participants |
| GD2 CAR Modified Tri-virus CTL Infusion | Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks | Short Term Toxicity (Week 8) | 0 Participants |
| GD2 CAR Modified Tri-virus CTL Infusion | Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks | No Toxicity | 3 Participants |
Primary
Peak Transgene Copy Number Per 1000ng PBMC DNA
Peak Transgene Copy Number per 1000ng PBMC DNA from peripheral blood samples measured during study participation.
Time frame: 1 year
Population: Evaluable patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GD2 CAR Modified Tri-virus CTL Infusion | Peak Transgene Copy Number Per 1000ng PBMC DNA | Participant 1 | 10562 Transgene Copy per 1000ng PBMC DNA |
| GD2 CAR Modified Tri-virus CTL Infusion | Peak Transgene Copy Number Per 1000ng PBMC DNA | Participant 3 | 44 Transgene Copy per 1000ng PBMC DNA |
| GD2 CAR Modified Tri-virus CTL Infusion | Peak Transgene Copy Number Per 1000ng PBMC DNA | Participant 5 | 1464 Transgene Copy per 1000ng PBMC DNA |
Secondary
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.
Time frame: 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GD2 CAR Modified Tri-virus CTL Infusion | Maximum Tumor Response (RECIST 1.1) | Non-complete Response | 3 Response |
| GD2 CAR Modified Tri-virus CTL Infusion | Maximum Tumor Response (RECIST 1.1) | Progressive Disease | 0 Response |
| GD2 CAR Modified Tri-virus CTL Infusion | Maximum Tumor Response (RECIST 1.1) | Complete Response | 0 Response |
Secondary
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
Time frame: up to 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GD2 CAR Modified Tri-virus CTL Infusion | Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well | Participant 1 | 180 SFU/2x10e5 Mononuclear Cells |
| GD2 CAR Modified Tri-virus CTL Infusion | Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well | Participant 3 | 175 SFU/2x10e5 Mononuclear Cells |
| GD2 CAR Modified Tri-virus CTL Infusion | Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well | Participant 5 | 150 SFU/2x10e5 Mononuclear Cells |