Adoptive Cellular Immunotherapy Following Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma

• Sponsor: Dartmouth-Hitchcock Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00439465
• Collaborator: The Leukemia and Lymphoma Society (Other)
• Enrollment: 23
• Location: 1
• Arm: 1
• Duration (Months): 71
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Myeloma; Transplant-eligible Patients	Biological: Ex-vivo expanded effector cells	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Adoptive Cellular Immunotherapy Following Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Oct 15, 2012
• Actual Study Completion Date: Nov 30, 2012

Arms and Interventions

Arm	Intervention/Treatment
Other: Ex-vivo expanded effector cells Infusing IL-2 and GM-CSF post-Hematopoietic Stem Cell Transplant (HSCT)	Biological: Ex-vivo expanded effector cells; 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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events in All Subjects [From initiation of treatment on protocol until Day 100]

   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

1. Count of Participants With Increased CD3+CD8+, CD8+ and CD56+ Concentrations Between Day 15 Post-Transplant and Days 21 to 28 Post-transplant [Day 15 post-transplant and between 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:

2. Time to Recovery of Absolute Neutrophil Count [From initiation of treatment on protocol until Day 100]

   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.

3. Time to Recovery of Platelet Count [From initiation of treatment on protocol until Day 100]

   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.

4. Assessment of Disease Response to Treatment [From initiation of treatment on protocol until Day 100]

   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.

5. Number of Participants With Increased Expression of DAP10 and NKG2D on the CD8 Cell Population [Pre-transplant and following the third and fourth cellular infusions]

   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.

6. Determine the Methods of Tumor Cell Killing of the in Vivo CD8+ Cells: Cytotoxicity Assays, Blocking Experiments, Analysis of T-cell Receptor (TCR) [Pre-transplant and following the third and fourth cellular infusions.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756

Sponsors and Collaborators

• Dartmouth-Hitchcock Medical Center
• The Leukemia and Lymphoma Society

Investigators

• Principal Investigator: Kenneth Meehan, MD, Dartmouth-Hitchcock Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kenneth Meehan, Director, Bone Marrow Transplant Program, Dartmouth-Hitchcock Medical Center
• ClinicalTrials.gov Identifier: NCT00439465
• Other Study ID Numbers: D0717
• First Posted: Feb 23, 2007
• Last Update Posted: Mar 26, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

Participant Flow

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing Interleukin-2 (IL-2) and Recombinant Human Granulocyte Colony Stimulating Factor (GM-CSF)post-Hematopoietic stem cell transplant (HSCT) Ex-vivo expanded effector cells: 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.
Period Title: Overall Study
STARTED	23
COMPLETED	19
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing IL-2 and GM-CSF post-HCST Ex-vivo expanded effector cells: 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.
Overall Participants	23
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	17 73.9%
>=65 years	6 26.1%
Age (Years) [Median (Full Range) ]
Median (Full Range) [Years]	60
Sex: Female, Male (Count of Participants)
Female	9 39.1%
Male	14 60.9%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	23 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing IL-2 and GM-CSF post-Hematopoietic Stem-Cell Transplant (HSCT) Ex-vivo expanded effector cells: 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.
Measure Participants	23
Count of Participants [Participants]	11 47.8%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Sixteen out of nineteen subject samples were analyzed. Three subject's samples were not available for analysis.

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing IL-2 and GM-CSF post-HCST Ex-vivo expanded effector cells: 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.
Measure Participants	16
Increase	7 30.4%
No Increase	9 39.1%
Increase	7 30.4%
No Increase	9 39.1%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing IL-2 and GM-CSF post-HCST Ex-vivo expanded effector cells: 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.
Measure Participants	19
Median (Full Range) [Days]	13

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing IL-2 and GM-CSF post-HCST Ex-vivo expanded effector cells: 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.
Measure Participants	19
Median (Full Range) [days]	16

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing IL-2 and GM-CSF post-HCST Ex-vivo expanded effector cells: 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.
Measure Participants	19
Complete Response	12 52.2%
Very Good Partial Response	5 21.7%
Partial Response	1 4.3%
Progressive disease	1 4.3%

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Sixteen out of nineteen participants samples were analyzed. Three participants' samples were not available for analysis.

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing IL-2 and GM-CSF post-Hematopoietic Stem Cell Transplant (HSCT) Ex-vivo expanded effector cells: 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.
Measure Participants	16
Increased abs. NKG2D+CD3+CD8 Tcells	12 52.2%
Increased abs. NKG2D+CD3-CD56+ T cells	12 52.2%

7. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Autologous myeloma cells were isolated for only 4 study participants. There is no information on the remaining participant provided.

Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing Interleukin-2 (IL-2) and Recombinant Human Granulocyte Colony Stimulating Factor (GM-CSF)post-Hematopoietic stem cell transplant (HSCT) Ex-vivo expanded effector cells: 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.
Measure Participants	5
Increased tumor lysis	4 17.4%
Failure of tumor lysis	0 0%
Increased tumor lysis	5 21.7%
Failure of tumor lysis	0 0%

Adverse Events

Time Frame	Adverse event data were collected from the start of treatment until 100 days post-treatment for all subjects. Total time of adverse event collection for the study was January 2007 through March 2010
Arm/Group Title	Ex-vivo Expanded Effector Cells
Arm/Group Description	Infusing IL-2 and GM-CSF post-HCST Ex-vivo expanded effector cells: 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.
All Cause Mortality
	Ex-vivo Expanded Effector Cells
	Affected / at Risk (%)	# Events
Total	0/23 (0%)
Serious Adverse Events
	Ex-vivo Expanded Effector Cells
	Affected / at Risk (%)	# Events
Total	0/23 (0%)
Other (Not Including Serious) Adverse Events
	Ex-vivo Expanded Effector Cells
	Affected / at Risk (%)	# Events
Total	11/23 (47.8%)
Cardiac disorders
Tachycardia	2/23 (8.7%)
Hypotension	2/23 (8.7%)
Gastrointestinal disorders
Nausea	2/23 (8.7%)
Vomiting	2/23 (8.7%)
Mucositis - oral	1/23 (4.3%)
Constipation	1/23 (4.3%)
General disorders
Fever	2/23 (8.7%)
Hepatobiliary disorders
Increased liver function tests	2/23 (8.7%)
Infections and infestations
Moderate infection	3/23 (13%)
Severe infection	1/23 (4.3%)
Metabolism and nutrition disorders
anorexia	3/23 (13%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.