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

1 mars 2019 uppdaterad av: Kenneth Meehan, Dartmouth-Hitchcock Medical Center

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.

Studieöversikt

Status

Avslutad

Studietyp

Interventionell

Inskrivning (Faktisk)

23

Fas

  • Fas 2

Kontakter och platser

Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.

Studieorter

    • New Hampshire
      • Lebanon, New Hampshire, Förenta staterna, 03756
        • Dartmouth-Hitchcock Medical Center

Deltagandekriterier

Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.

Urvalskriterier

Åldrar som är berättigade till studier

18 år till 75 år (Vuxen, Äldre vuxen)

Tar emot friska volontärer

Nej

Kön som är behöriga för studier

Allt

Beskrivning

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)

Studieplan

Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.

Hur är studien utformad?

Designdetaljer

  • Primärt syfte: Behandling
  • Tilldelning: N/A
  • Interventionsmodell: Enskild gruppuppgift
  • Maskning: Ingen (Open Label)

Vapen och interventioner

Deltagargrupp / Arm
Intervention / Behandling
Övrig: Ex-vivo expanded effector cells
Infusing IL-2 and GM-CSF post-Hematopoietic Stem Cell Transplant (HSCT)
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.

Vad mäter studien?

Primära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Number of Participants With Adverse Events in All Subjects
Tidsram: 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).
From initiation of treatment on protocol until Day 100

Sekundära resultatmått

Resultatmått
Åtgärdsbeskrivning
Tidsram
Count of Participants With Increased CD3+CD8+, CD8+ and CD56+ Concentrations Between Day 15 Post-Transplant and Days 21 to 28 Post-transplant
Tidsram: 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:
Day 15 post-transplant and between days 21 to 28 post-transplant
Time to Recovery of Absolute Neutrophil Count
Tidsram: 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.
From initiation of treatment on protocol until Day 100
Time to Recovery of Platelet Count
Tidsram: 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.
From initiation of treatment on protocol until Day 100
Assessment of Disease Response to Treatment
Tidsram: 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.
From initiation of treatment on protocol until Day 100
Number of Participants With Increased Expression of DAP10 and NKG2D on the CD8 Cell Population
Tidsram: 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.

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

Samarbetspartners och utredare

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Studieavstämningsdatum

Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.

Studera stora datum

Studiestart

1 januari 2007

Primärt slutförande (Faktisk)

15 oktober 2012

Avslutad studie (Faktisk)

30 november 2012

Studieregistreringsdatum

Först inskickad

21 februari 2007

Först inskickad som uppfyllde QC-kriterierna

22 februari 2007

Första postat (Uppskatta)

23 februari 2007

Uppdateringar av studier

Senaste uppdatering publicerad (Faktisk)

26 mars 2019

Senaste inskickade uppdateringen som uppfyllde QC-kriterierna

1 mars 2019

Senast verifierad

1 mars 2019

Mer information

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