T Regulatory Lymphocytes (Treg) Depletion for Cancer Treatment Efficacy and Safety Study
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      T regulatory lymphocytes were shown to be partly responsible for immune tolerance to cancer
      cells. In that respect these cells oppose to the mounting of an efficacious immune response
      needed to cure cancer. To treat advanced metastatic colorectal cancer, the investigators
      propose an immunotherapy consisting in autologous lymphocytes infusion depleted from
      T-regulatory cells, associated with a 5-day prior lymphoid-ablative chemotherapy associating
      cyclophosphamide (day 1 & 2) with fludarabine (day 1 to 5). To administer treatment and
      monitor chemotherapy safety, patients will be hospitalized for 3 weeks until complete
      recovery from chemotherapy. Patients will then be followed-up ambulatory for 9 months during
      which time they will be assessed for tumor size with computed tomography (CT) - scan (primary
      criteria).
    

Detailed description: 
      The primary goal of the proposed clinical trial is to eliminate cancer tumor using an
      autologous cell therapy aiming at mounting an efficient immune anti-tumor response by
      selectively depleting regulatory T-cell during a controlled amount of time. This strategy
      will be tested in patients with hepatic metastases from colorectal who are not eligible for
      surgery.

      This is an open-label single cohort phase I-II therapeutic trial. Patients with hepatic
      metastases from primary colorectal cancer, not eligible to surgery and relapsing from
      conventional chemotherapy and/or targeted therapy, will be included.

      Following patient inclusion:

        1. A lymphapheresis will be performed at D-15 which will be subjected to cell sorting
           /purification of regulatory T cells on the one hand and T lymphocytes depleted from
           regulatory T cells (effectors T-cells) on the other, and subsequently frozen and stored
           (The procedures for ex vivo regulatory T cell depletion has been validated in a previous
           study - AFSSAPS- TC 192) ;

        2. A lymphoid-ablative chemotherapy (cyclophosphamide + fludarabine) will be perform from
           D1 to D5,

        3. Autologous effector T-cells administration will be performed at D7. Efficacy will be
           assessed through tumor size change. Change in tumor size will be assessed with CTscans
           (RECIST criteria), MRIs (functional criteria following injection: DCEMRI and diffusion
           MRI to assess change in cellularity and tumor necrosis and morphological criteria
           RECIST), and sonography with contrast injection (to assess vascular microcirculation).
           Assessments will be done prior to lymphoid-ablation and then monthly for 9 months.
           Safety will be systematically assessed daily during in-patient period using the World
           Health Organisation - Common Toxicity Criteria (WHO-CTC).
    

Intervention name(s): Adaptive autologous cell immunotherapy
Intervention type(s): Biological
Intervention description(s): each patient will undergo a blood cytapheresis to collect circulating lymphocytes. Ex-vivo cell sorting procedure will deplete patient's collected lymphocytes from regulatory T cells. Autologous Treg-depleted lymphocytes will be administered to the patient following a 5-day reduced intensity chemo-therapeutic conditioning.
Intervention MeSH terms: Immunomodulating Agents
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Advanced Colorectal Cancer; Hepatic and/or lung metastasis; Adaptive autologous cell immunotherapy; T- regulatory lymphocyte depletion; Neo-adjuvant reduced intensity chemotherapeutic conditioning