Autologous Ex Vivo Expanded Regulatory T Cells in Ulcerative Colitis
Condition: Ulcerative Colitis; Autoimmune Diseases
MeSH terms: Colitis; Colitis, Ulcerative; Autoimmune Diseases; Ulcer
Study type: Interventional
Phase: Phase 1

Summary: 
      Together with Crohn's disease (CD), ulcerative colitis (UC) is one of the major forms of
      inflammatory bowel diseases (IBD).Currently, no curative therapy is available, since the
      pathophysiology of this disease is incompletely understood (1-3) and clinical practice
      demonstrates that current therapies induce remission in subgroups of patients only.
      Scientific evidence suggests that colitogenic immune responses can be controlled by
      increasing the number of circulating regulatory T cells (Treg) (4). The production of large
      numbers of autologous Treg is possible by isolation of CD25+ cells from the whole blood of a
      patient and subsequent ex vivo expansion in the presence of the immunomodulatory drug
      rapamycin, Interleukin-2 (IL-2) and CD3/CD28 expander beads (5).

      ER-TREG 01 is a single-center, open-label, fast-track phase I dose-escalation study designed
      to assess the safety profile and maximal tolerated dose (MTD) of a single infusion of ex vivo
      expanded autologous Treg in patients with active ulcerative colitis.
    

Detailed description: 
      While the primary cause of inflammatory bowel disease (IBD) development remains unknown, it
      is widely accepted that the initial events culminate in persistent immune responses with
      infiltration of immune cells and tissue destruction in the gut. Immune cell populations
      present within the inflamed bowel wall of IBD patients have been extensively characterized
      and studied (1;6). Studies focusing on T cells have demonstrated that the mucosa of Crohn's
      disease (CD) patients is dominated by Th1 cells, while in patients with ulcerative colitis
      (UC) T helper cells with an atypical Th2 profile, which excessively produce IL-5 and IL-13
      but not IL-4, are abundant (7). Furthermore, Th17 cells can be identified in the inflamed
      lamina propria and these cells are thought to play an important role in the pathophysiology
      of IBD, although the pathogenic mechanisms of these cells are not yet fully understood (8;9).
      Treg are also present within the lamina propria and these cells control the effector T cell
      populations mentioned above. They can be generated through the interaction of local T cells
      with CD103 expressing dendritic cells and intestinal epithelial cells, respectively (10;11).
      Moreover, the expression of integrins on the Treg surface (e.g. α4β7) facilitates mucosal
      migration through their interaction with specific ligands (e.g. MAdCAM1). As such, homing and
      local expansion of Treg cells create a local Treg pool that is essential for self-tolerance
      and the support of gut homeostasis (12). In addition, Treg cells are shown to suppress
      proinflammatory intestinal immune responses in colitis and colitis-associated cancer (13-16)
      and they are thought to augment intestinal Th17 responses (17). As previous studies have
      demonstrated insufficient expansion of mucosal Treg cells in IBD patients in comparison to
      the massive local expansion of effector T cells, it is likely that the relatively low number
      of Treg cells in IBD patients explains why these cells fail to control excessive immune
      responses (18).

      Experimental colitis studies in mice have demonstrated that colitogenic immune responses can
      be controlled by increasing the number of mucosal Treg cells and highlight the potential of
      Treg-based cell therapy in IBD (19). Specifically, co-transfer of naïve CD4+ T cells with
      Treg both prevents chronic colitis and ameliorates established colitis in severe combined
      immunodeficiency (SCID) mice (20). Moreover, CD4+ T cells expanded ex vivo in the presence of
      rapamycin prevent the development of colitis in a naïve CD4+ T cell model in SCID mice.
      Importantly, the systemic administration of rapamycin alone only partially prevented the
      development of colonic Inflammation (20). In addition, the adoptive transfer of nTreg cells
      as well as the adoptive transfer of ex vivo transforming growth factor (TGF)-β-induced Treg
      (iTreg) suppressed colitis activity in vivo in mouse models (13;15;21). Collectively, these
      data suggest that Treg cells could be used for therapy of intestinal inflammation in IBD
      (22).

      To allow an adoptive transfer of large numbers of Treg, CD25+ Treg cells are isolated from an
      autologous leukapheresis product and in vitro expanded during 21 days in the presence of the
      additives Interleukin-2 (IL-2), rapamycin and anti-CD3/anti-CD28 expander beads. After 21
      days of expansion, anti-CD3/anti-CD28 expander beads are removed from the Treg drug product.
      Next, Treg are frozen in aliquots of 10 Million Treg/mL until further use (5).

      Twelve patients, including 10% patient loss, resulting in at least ten treated and fully
      evaluable patients, will be enrolled in this single-center, open-label, fast-track
      dose-escalation study. Autologous ex vivo expanded CD4+CD25+CD127-/lo Treg cells will be
      adoptively transferred in patients with ulcerative colitis with active disease or stable
      disease under the allowed concomintant therapy at the time of enrollment. The maximal
      tolerated dose (MTD) is defined as the dose that does not produce more than one dose-limiting
      toxicity (DLT) among a total of four treated patients at the particular dose level.

      The first enrolled patient will receive the initial starting dose of 0.5 x10e6 Treg/kg
      bodyweight. Adoptive transfer is escalated to the next dose level (1 x 10e6 Treg/kg, 2 x 10e6
      Treg/kg, 5 x 10e6/Treg/kg and 10 x 10e6 Treg/kg bodyweight), in a next patient, if no DLT
      occurs. Consecutive patients will be treated at least four weeks apart to monitor acute
      severe adverse advents. If a DLT is noted, three additional patients will receive the same
      dose level. Dose-escalation continues until at least two patients among a cohort of four
      patients experience a DLT. If two patients among a cohort of four patients experience a DLT,
      dose de-escalation to the highest previously tolerated dose-level will follow. Three
      additional patients will receive the highest previously tolerated dose. If a DLT is noted in
      at least two patients at the tested dose-level, dose de-escalation will continue until less
      than two patients have experienced a DLT. After successful enrollment at the highest
      dose-level, five additional patients will be enrolled at the highest dose level to extend
      safety assessment. If no DLTs or less than two DLTs are experienced at all dose-levels
      tested, the MTD is not reached. In this case, a maximal administered dose (MAD) is defined.
    

Intervention name(s): Regulatory T cells
Intervention type(s): Biological
Intervention description(s): Autologous, ex vivo expanded, regulatory T cells
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Ulcerative colitis; Regulatory T cells; Adoptive cell therapy