Autologous CD117+ Progenitor Cell Mobilization for Lung Transplantation
Condition: COPD; Cystic Fibrosis; Pulmonary Fibrosis
MeSH terms: Cystic Fibrosis; Pulmonary Fibrosis; Fibrosis
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine if the drug Plerixafor (Mozobil) can lead to
      clinically relevant efflux of CD117+ stem cells from the bone marrow to the peripheral blood
      of normal controls and patients awaiting lung transplantation. The investigator's hypothesis
      is that Plerixafor (Mozobil) will lead to significant mobilization of CD117+ stem cells to
      the peripheral blood.
    

Detailed description: 
      The investigators have developed a new therapy utilizing a stem cell found in the bone marrow
      that is defined by cell surface expression of the protein "cluster of differentiation antigen
      117" (CD117). Studies utilizing these stem cells in a mouse heart transplant model have
      demonstrated significantly improved survival of transplanted hearts, (as much as more than 5
      times that seen with untreated heart transplants). In vitro studies in mice also show that
      these cells work to inhibit the immune system by inhibiting T cell activation/proliferation
      by both paracrine (primary) and contact-dependent (lesser) mechanisms. Importantly, these
      stem cells are taken from the intended transplant recipient (autologous) and since these
      cells are part of their own body normally (in small numbers); these cells are theoretically
      without risk to the patient. This is very different from other stem cell therapies, which are
      taken from the donor and as such put the patient at significant risk of developing
      potentially life-threatening immune reactions. Because the use of our own stem cells is
      potentially safe - the rapid study, development, and implementation of autologous CD117 stem
      cell (SC) therapy in human transplant patients is theoretically possible. Therefore, these
      cells have high impact potential for the field of tissue and organ transplantation as well as
      auto-immunity - to potentially improve tissue/cellular engraftment, decrease acute rejection,
      and/or to promote organ transplant tolerance (lack of rejection despite no concomitant
      immune-suppression). Prior to full clinical development (efficacy trials in humans), the next
      step is to develop a safe and efficacious means for obtaining relatively large quantities of
      these cells from potential human recipients. As bone marrow biopsy for cell capture is not
      without risk (especially to ill potential lung transplant recipients), the investigators
      propose to use Plerixafor (Mozobil), a CXC-chemokine receptor 4 (CXCR4)-inhibitor to cause
      efflux of bone marrow-derived CD117+ cells to the peripheral blood for capture by
      apheresis/positive selection. If successful, the next step will be to perform initial safety
      studies in human patients awaiting transplantation and normal controls (not a goal of this
      initial protocol however). These studies have the potential to lead to large-scale clinical
      efficacy trials and ultimate indication/implementation for human disease(s).

      Primary Outcome Measure: The number of circulating CD117+ cells per milliliter (ml) of
      peripheral blood at baseline and following Plerixafor (Mozobil) treatment (change in
      peripheral blood CD117+ cells per ml).

      Secondary Outcome Measures:

      i.) The number of Plerixafor (Mozobil) related adverse events (AEs). ii.) The number of
      patients with Plerixafor (Mozobil) related AEs iii.) The number of Plerixafor (Mozobil)
      related serious adverse events (SAEs). iv.) The number of patients with Plerixafor (Mozobil)
      related serious adverse events (SAEs).

      As listed in the package insert, the most common adverse reactions (≥10%) during
      hematopoietic stem cell mobilization were: diarrhea (37%), nausea (34%), fatigue (27%),
      injection site reaction (34%), headache (22%), arthralgia (13%), dizziness (11%), and
      vomiting (10%). It should be noted that the majority of these occurred in patients also
      undergoing apheresis.

      Outcome Measure Time Frame:

      Primary Outcome Measure Time Frame: At baseline and at 8 hours post-Plerixafor (Mozobil)
      treatment

      Secondary Outcome Measures Time Frame:

      i.): Continuously for the first 30 minutes post-Plerixafor (Mozobil) treatment, at 1 week
      post-Plerixafor (Mozobil) treatment, and up to 1 year post treatment.

      ii.): For the first 30 minutes post administration, at 1 week post-Plerixafor (Mozobil)
      treatment and up to 1 year post treatment, at 1 week post-Plerixafor (Mozobil) treatment, and
      up to 1 year post treatment.

      iii.): For the first 30 minutes post administration, at 1 week post-Plerixafor (Mozobil)
      treatment and up to 1 year post treatment, at 1 week post-Plerixafor (Mozobil) treatment, and
      up to 1 year post treatment.

      iv.): For the first 30 minutes post administration, at 1 week post-Plerixafor (Mozobil)
      treatment and up to 1 year post treatment, at 1 week post-Plerixafor (Mozobil) treatment, and
      up to 1 year post treatment.

      Primary Study Goals:

      To determine whether Plerixafor (Mozobil) will mobilize CD117+ progenitor cells from the bone
      marrow in patients with chronic lung diseases on the lung transplant waiting list (versus
      normal controls). We will compare baseline counts of CD117+ cells with cell counts 8 hrs
      after Plerixafor to determine the efficacy of mobilization.

      The primary results will be used to determine the number of rounds of apheresis that may be
      required to isolate sufficient cells for reinfusion at later timepoints in a future study.

      Significance:

      If the investigators can mobilize a sufficient number of autologous CD117+ cells, they will
      eventually re-infuse them at the time of transplant to determine whether we can abrogate
      acute rejection following human lung transplantation (future study). The investigators
      believe these are safer than allogeneic stem cells as there is no risk for graft versus host
      disease (GVHD) with autologous cells.

      Hypothesis:

      These experiments should demonstrate the effectiveness of CD117+ stem cell mobilization from
      the bone marrow to the peripheral blood (PB) via CXCR4 antagonism (Plerixafor) and whether
      end-stage lung disease affects the ability to mobilize stem cells. Additionally, these
      results will be used to mathematically extrapolate approximately how many rounds of
      peripheral blood apheresis will be required to attain adequate stem cell numbers for clinical
      infusion (10e7) for a future study.

      Methods:

      Experiments will involve taking blood from consented patients awaiting lung transplantation
      (as well as normal controls) prior to Plerixafor (Mozobil) treatment (240mcg/kg
      subcutaneously) and then 8 hours after treatment as in Table 1.

      TABLE 1:

      Patient Category PB baseline analysis Plerixafor (Mozobil) Rx PB analysis 8hrs post-Rx

      Awaiting Tx (n=15, 5 chronic obstructive pulmonary disease (COPD), 5 Cystic Fibrosis (CF),
      and 5 Pulmonary Fibrosis (PF)) CD117 isolation/analysis by Flow Cytometry Yes - 240 mcg/kg
      CD117+ stem cell isolation/analysis by Flow Cytometry

      Normal Control (n=5) CD117 isolation/analysis by Flow Cytometry Yes - 240mcg/kg CD117+ stem
      cell isolation/analysis by Flow Cytometry
    

Intervention name(s): Plerixafor mobilization of autologous CD117 stem cells
Intervention type(s): Drug
Intervention description(s): Peripheral mobilization of autologous CD117+ stem cells from the bone marrow in patients awaiting lung transplantation versus normal controls
Other intervention name(s): Mozobil
Intervention MeSH terms: Plerixafor
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Stem Cell Mobilization; Stem Cells; Transplantation; Autologous