Adoptive Cellular Immunotherapy Following Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma
Primary Purpose
Myeloma, Transplant-eligible Patients
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ex-vivo expanded effector cells
Sponsored by
About this trial
This is an interventional treatment trial for Myeloma
Eligibility Criteria
Inclusion Criteria:
Multiple Myeloma:
- Patients must meet criteria for diagnosis of Multiple Myeloma.
Patient must meet either criterion listed below:
- Stage I, II, or III newly diagnosed multiple myeloma
- Progressive or relapsed disease in partial response (PR) or complete response (CR)
- Primary refractory disease.
- Relapsed refractory disease.
- Patients may have received a prior autologous transplant.
- The patients must have recovered from all serious and life threatening effects of previous treatment at the time of study entry (unless this abnormality is believed to be due to the underlying myeloma).
- The patient must have adequate bone marrow function, i.e. a total white blood cell count (WBC) of > 2,000/ul, a Hemoglobin (Hgb) of > 7 gm/dl, and a platelet count of > 50,000/ul, unless this abnormality is believed to be due to the underlying myeloma.
- The patient must have adequate liver function, i.e. bilirubin <2.0 mg/dl, aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT) not greater than 2 times the upper normal limit (unless this abnormality is believed to be due to the underlying myeloma).
- The patient must have adequate renal function, i.e. serum creatinine < 3.0 mg/dl, and/or creatinine clearance >50 ml/min. This eligibility criterion is excluded if renal insufficiency is believed to be secondary to myeloma.
- Age >18 years and < 75 years old
- The patient must have a Karnofsky status > 80%
- Patients must have a life expectancy of at least 12 weeks
- Left ventricular ejection fraction of > 45% by radionuclide scan or echocardiography
- Pulmonary function tests: forced vital capacity, Diffusing capacity of the lungs for carbon monoxide (DLCO) and expiratory volume in one second (FEV1) must be > 50% of predicted
- No significant co-morbid medical or psychiatric illness which would significantly compromise the patient's clinical care and chances of survival.
- Informed written consent must be obtained. Patients must be able to give informed consent as a prerequisite to this procedure. The Informed Consent form will become part of his/her permanent record and a copy will be given to the patient
Exclusion Criteria:
- Medical, social, or psychological factors which would prevent the patient from receiving or cooperating with the full course of therapy.
- Evidence on physical exam, lumbar puncture, computed tomography (CT), or magnetic resonance imaging (MRI) scan of central nervous system (CNS) involvement with malignancy
- Any clinically significant cardiac disease (angina, myocardial infarction, congestive heart failure, ventricular arrhythmias requiring therapy) or clinically significant obstructive/restrictive pulmonary disease
- Serology positive for human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLVI)
- Active hepatitis B or C
- History of seizures
- Concurrent or expected need for therapy with corticosteroids
- Active connective tissue disease
- Current "clinically significant" pleural effusion, pericardial effusion, or ascites
- Positive pregnancy test or presence of lactation
- Collection of fewer than 1 x 106 cluster of differentiation 34 positive (CD34+) cells/kg (peripheral blood stem cells). If the apheresis collection is inadequate based on this criteria, the patient will be removed from protocol and a marrow harvest may be performed
- A history of a second malignancy (other then squamous cell/ basal cell carcinoma of the skin or cervical dysplasia) must be reviewed by the Principal Investigator, before inclusion or exclusion in the study. Based upon the PI's review, this patient may be eligible (i.e., distant past history of a malignancy)
Sites / Locations
- Dartmouth-Hitchcock Medical Center
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Ex-vivo expanded effector cells
Arm Description
Infusing IL-2 and GM-CSF post-Hematopoietic Stem Cell Transplant (HSCT)
Outcomes
Primary Outcome Measures
Number of Participants With Adverse Events in All Subjects
To establish the safety (toxicity) of myeloma patients treated with high dose melphalan, autologous peripheral blood stem cell transplantation (APBSCT) & adoptive transfer of cytotoxic effector cells with Interleukin-2 (IL-2) and Recombinant Human Granulocyte Colony Stimulating Factor (GM-CSF).
Secondary Outcome Measures
Count of Participants With Increased CD3+CD8+, CD8+ and CD56+ Concentrations Between Day 15 Post-Transplant and Days 21 to 28 Post-transplant
To demonstrate that the effector cell infusions result in a clinical effect, phenotypic analyses of blood samples using flow cytometry will be performed prior to, and after each infusion, focusing on the CD8 + populations (CD3+CD8+, CD8+CD56+). As a complement to flow cytometry, the following assays will be used to identify cell subset precursor frequencies, subset proliferation, and cytokine production:
Dye Dilution Proliferation Assay (DDPA) 36 - Evaluation of CD8+ T Cell Precursors
ELISPOT-Quantifying cytokine producing T cells:
Time to Recovery of Absolute Neutrophil Count
To establish the time to engraftment of myeloma patients treated with high dose melphalan, APBSCT& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.
Time to Recovery of Platelet Count
To establish the time to engraftment of myeloma patients treated with high dose melphalan, APBSCT& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.
Assessment of Disease Response to Treatment
To establish the disease response of myeloma patients treated with high dose melphalan, APBSCT& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.
Number of Participants With Increased Expression of DAP10 and NKG2D on the CD8 Cell Population
Isolate CD3+CD8+ and CD8+CD56+ from patients' blood following transplant.
Identify NKG2D and DAP10 expression.
Determine the mechanism of tumor cell killing and the relationship to NKG2D or DAP 10 expression.
After isolating CD8+ cells from patient's blood samples using the AutoMACS, we will evaluate the expression of NKG2D and DAP10 on all CD8+ cells (CD3+CD8+ and CD8+CD56+cells) pre-transplant (Baseline) and following the third and fourth cellular infusions using phenotypic analysis. We postulate the increased expression of both DAP10 and NKG2D on the CD8 population immediately following APSCT and effector cell infusions when compared to baseline.
Determine the Methods of Tumor Cell Killing of the in Vivo CD8+ Cells: Cytotoxicity Assays, Blocking Experiments, Analysis of T-cell Receptor (TCR)
We will isolate the CD8+ populations (CD3+CD8+, CD8+CD56+) using the Auto MACS (Miltenyi) and then identify the mechanisms of tumor cell killing by the CD8+ cells obtained pre-transplant (Baseline) and following the third and fourth cellular infusions. We will examine mechanisms of tumor cell killing through NKG2D receptor, major histocompatibility complex (MHC) Class I molecules or through the T cell receptor. We postulate the CD8+ cells obtained from patient's blood will kill tumor cells both via MHC Class I and through the NKG2D receptor.
Full Information
NCT ID
NCT00439465
First Posted
February 21, 2007
Last Updated
March 1, 2019
Sponsor
Dartmouth-Hitchcock Medical Center
Collaborators
The Leukemia and Lymphoma Society
1. Study Identification
Unique Protocol Identification Number
NCT00439465
Brief Title
Adoptive Cellular Immunotherapy Following Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma
Official Title
Adoptive Cellular Immunotherapy Following Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
January 2007 (undefined)
Primary Completion Date
October 15, 2012 (Actual)
Study Completion Date
November 30, 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Dartmouth-Hitchcock Medical Center
Collaborators
The Leukemia and Lymphoma Society
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to determine whether the administration of highly effective "killer" cells (cytotoxic T cells), along with Interleukin-2 (IL-2) and Recombinant Human Granulocyte Colony Stimulating Factor (GM-CSF) immediately following Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) will enhance anti-tumor immune reconstitution and improve outcome of Multiple Myeloma patients.
The overall hypothesis of this proposal is that immediately following APBSCT the immune reconstitution is optimal to administer "killer" cells, combined with the administration of IL-2 and GM-CSF.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myeloma, Transplant-eligible Patients
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
23 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ex-vivo expanded effector cells
Arm Type
Other
Arm Description
Infusing IL-2 and GM-CSF post-Hematopoietic Stem Cell Transplant (HSCT)
Intervention Type
Biological
Intervention Name(s)
Ex-vivo expanded effector cells
Intervention Description
This trial will test if the combination of infusing ex vivo expanded cytotoxic effector cells with IL-2 and GM-CSF post-transplant will accelerate immune reconstitution, resulting in an effector cell-versus-myeloma effect and, possibly, improved clinical outcomes.
Primary Outcome Measure Information:
Title
Number of Participants With Adverse Events in All Subjects
Description
To establish the safety (toxicity) of myeloma patients treated with high dose melphalan, autologous peripheral blood stem cell transplantation (APBSCT) & adoptive transfer of cytotoxic effector cells with Interleukin-2 (IL-2) and Recombinant Human Granulocyte Colony Stimulating Factor (GM-CSF).
Time Frame
From initiation of treatment on protocol until Day 100
Secondary Outcome Measure Information:
Title
Count of Participants With Increased CD3+CD8+, CD8+ and CD56+ Concentrations Between Day 15 Post-Transplant and Days 21 to 28 Post-transplant
Description
To demonstrate that the effector cell infusions result in a clinical effect, phenotypic analyses of blood samples using flow cytometry will be performed prior to, and after each infusion, focusing on the CD8 + populations (CD3+CD8+, CD8+CD56+). As a complement to flow cytometry, the following assays will be used to identify cell subset precursor frequencies, subset proliferation, and cytokine production:
Dye Dilution Proliferation Assay (DDPA) 36 - Evaluation of CD8+ T Cell Precursors
ELISPOT-Quantifying cytokine producing T cells:
Time Frame
Day 15 post-transplant and between days 21 to 28 post-transplant
Title
Time to Recovery of Absolute Neutrophil Count
Description
To establish the time to engraftment of myeloma patients treated with high dose melphalan, APBSCT& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.
Time Frame
From initiation of treatment on protocol until Day 100
Title
Time to Recovery of Platelet Count
Description
To establish the time to engraftment of myeloma patients treated with high dose melphalan, APBSCT& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.
Time Frame
From initiation of treatment on protocol until Day 100
Title
Assessment of Disease Response to Treatment
Description
To establish the disease response of myeloma patients treated with high dose melphalan, APBSCT& adoptive transfer of cytotoxic effector cells with IL-2 and GM-CSF.
Time Frame
From initiation of treatment on protocol until Day 100
Title
Number of Participants With Increased Expression of DAP10 and NKG2D on the CD8 Cell Population
Description
Isolate CD3+CD8+ and CD8+CD56+ from patients' blood following transplant.
Identify NKG2D and DAP10 expression.
Determine the mechanism of tumor cell killing and the relationship to NKG2D or DAP 10 expression.
After isolating CD8+ cells from patient's blood samples using the AutoMACS, we will evaluate the expression of NKG2D and DAP10 on all CD8+ cells (CD3+CD8+ and CD8+CD56+cells) pre-transplant (Baseline) and following the third and fourth cellular infusions using phenotypic analysis. We postulate the increased expression of both DAP10 and NKG2D on the CD8 population immediately following APSCT and effector cell infusions when compared to baseline.
Time Frame
Pre-transplant and following the third and fourth cellular infusions
Title
Determine the Methods of Tumor Cell Killing of the in Vivo CD8+ Cells: Cytotoxicity Assays, Blocking Experiments, Analysis of T-cell Receptor (TCR)
Description
We will isolate the CD8+ populations (CD3+CD8+, CD8+CD56+) using the Auto MACS (Miltenyi) and then identify the mechanisms of tumor cell killing by the CD8+ cells obtained pre-transplant (Baseline) and following the third and fourth cellular infusions. We will examine mechanisms of tumor cell killing through NKG2D receptor, major histocompatibility complex (MHC) Class I molecules or through the T cell receptor. We postulate the CD8+ cells obtained from patient's blood will kill tumor cells both via MHC Class I and through the NKG2D receptor.
Time Frame
Pre-transplant and following the third and fourth cellular infusions.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Multiple Myeloma:
Patients must meet criteria for diagnosis of Multiple Myeloma.
Patient must meet either criterion listed below:
Stage I, II, or III newly diagnosed multiple myeloma
Progressive or relapsed disease in partial response (PR) or complete response (CR)
Primary refractory disease.
Relapsed refractory disease.
Patients may have received a prior autologous transplant.
The patients must have recovered from all serious and life threatening effects of previous treatment at the time of study entry (unless this abnormality is believed to be due to the underlying myeloma).
The patient must have adequate bone marrow function, i.e. a total white blood cell count (WBC) of > 2,000/ul, a Hemoglobin (Hgb) of > 7 gm/dl, and a platelet count of > 50,000/ul, unless this abnormality is believed to be due to the underlying myeloma.
The patient must have adequate liver function, i.e. bilirubin <2.0 mg/dl, aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT) not greater than 2 times the upper normal limit (unless this abnormality is believed to be due to the underlying myeloma).
The patient must have adequate renal function, i.e. serum creatinine < 3.0 mg/dl, and/or creatinine clearance >50 ml/min. This eligibility criterion is excluded if renal insufficiency is believed to be secondary to myeloma.
Age >18 years and < 75 years old
The patient must have a Karnofsky status > 80%
Patients must have a life expectancy of at least 12 weeks
Left ventricular ejection fraction of > 45% by radionuclide scan or echocardiography
Pulmonary function tests: forced vital capacity, Diffusing capacity of the lungs for carbon monoxide (DLCO) and expiratory volume in one second (FEV1) must be > 50% of predicted
No significant co-morbid medical or psychiatric illness which would significantly compromise the patient's clinical care and chances of survival.
Informed written consent must be obtained. Patients must be able to give informed consent as a prerequisite to this procedure. The Informed Consent form will become part of his/her permanent record and a copy will be given to the patient
Exclusion Criteria:
Medical, social, or psychological factors which would prevent the patient from receiving or cooperating with the full course of therapy.
Evidence on physical exam, lumbar puncture, computed tomography (CT), or magnetic resonance imaging (MRI) scan of central nervous system (CNS) involvement with malignancy
Any clinically significant cardiac disease (angina, myocardial infarction, congestive heart failure, ventricular arrhythmias requiring therapy) or clinically significant obstructive/restrictive pulmonary disease
Serology positive for human immunodeficiency virus (HIV) or human T-lymphotropic virus (HTLVI)
Active hepatitis B or C
History of seizures
Concurrent or expected need for therapy with corticosteroids
Active connective tissue disease
Current "clinically significant" pleural effusion, pericardial effusion, or ascites
Positive pregnancy test or presence of lactation
Collection of fewer than 1 x 106 cluster of differentiation 34 positive (CD34+) cells/kg (peripheral blood stem cells). If the apheresis collection is inadequate based on this criteria, the patient will be removed from protocol and a marrow harvest may be performed
A history of a second malignancy (other then squamous cell/ basal cell carcinoma of the skin or cervical dysplasia) must be reviewed by the Principal Investigator, before inclusion or exclusion in the study. Based upon the PI's review, this patient may be eligible (i.e., distant past history of a malignancy)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kenneth Meehan, MD
Organizational Affiliation
Dartmouth-Hitchcock Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Dartmouth-Hitchcock Medical Center
City
Lebanon
State/Province
New Hampshire
ZIP/Postal Code
03756
Country
United States
12. IPD Sharing Statement
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Adoptive Cellular Immunotherapy Following Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma
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