Allogenic Immunotherapy Based on Natural Killer (NK) Cell Adoptive Transfer in Metastatic Gastrointestinal Carcinoma Treated With Cetuximab
Condition: Gastrointestinal Metastatic Cancer
MeSH terms: Neoplasm Metastasis
Study type: Interventional
Phase: Phase 1

Summary: 
      Gastrointestinal (GI) cancers account for the most common cancers. Despite recent advances in
      GI cancer treatments, the 5-year overall survival rate for these patients remain
      unacceptable, except for patients who are candidates for metastasis surgical resection.
      Strategies leading to a decrease of metastatic number and size will contribute to improve the
      probability to undergo a curative surgical procedure.

      Haploidentical Natural Killer (NK) cells can persist and expand in vivo following adoptive
      transfer and may have a role in the treatment of selected malignancies, since the failure to
      recognize the appropriate KIR ligand on a mismatched tumor cell can trigger NK cell
      elimination of that target cell. NK also express an activating Fc receptor that mediates
      antibody-dependent cellular cytotoxicity (ADCC) and production of immune modulatory cytokines
      in response to antibody-coated targets. Cetuximab, an IgG1 chimeric monoclonal antibody
      against colorectal cancers that expressed EGFR (epidermal growth factor receptor), improves
      overall survival and progression-free survival and preserves quality-of-life measures in
      patients with colorectal cancer in whom other treatments have failed.

      In an attempt to improve the outcome in GI cancers, we will conduct a phase I/II clinical
      trial assessing NK cell based immunotherapy. Patients with liver metastases related to a
      EGFR+ GI cancer, previously treated by a standard chemotherapy that did not achieve a
      complete response or a curative resection of residual metastases will be included in this
      phase I/II trial supported by the French National Institute of Cancer (INCA, PHRC 2005). This
      phase I/II study will involve 22 patients. The main objective of this study will be to
      demonstrate the safety of NK hepatic intraarterial infusion in association with cetuximab.
      Secondary objectives will include the assessment of the clinical efficacity of this strategy.
    

Detailed description: 
      Patients will be treated with a conditioning chemotherapy including 60 mg/kg intravenous
      cyclophosphamide, 25 mg/m2 intravenous fludarabine for 5 consecutive days and cetuximab. A
      lymphapheresis from an haploidentical related donor will be performed and T cells will be
      depleted . Allogenic NK cells will then be adoptively transferred by hepatic intraarterial
      infusion according to a dose escalation protocol (three doses with at least three patients
      per cohort)to define the dose-limiting toxicity (DLT). Then 10 more patients will receive the
      recommended NK cell dose.

      Dose escalation protocol : 3.10^6 ; 8.10^6 and 12.10^6 cells/kg of recipient body weight.
    

Intervention name(s): allogenic immunotherapy based on Natural Killer cells adoptive transfer; cetuximab; Cyclophosphamide; fludarabine; interleukin-2
Intervention type(s): Biological; Biological; Drug; Drug; Drug
Intervention description(s): day -1 : donor NK cell purification ; day 0 : adoptive transfer (according to a dose escalation) ; Dose escalation protocol : 3.10^6 ; 8.10^6 and 12.10^6 cells/kg of recipient body weight; day -8 : cetuximab 400 mg/m2 ; day -1 and every week (for 7 weeks) : cetuximab 250 mg/m2; day -6 : cyclophosphamide 60 mg/Kg; day -6 to day -2 : fludarabine 25 mg/m2; day -1 : addition of 1000 UI/ml of interleukin 2 to NK cells and overnight culture at 37°C, 5%CO2 ; day 0, hour +12 : 10 MUI of interleukin 2 injection, 2 times a week during 3 weeks.
Intervention MeSH terms: Cyclophosphamide; Fludarabine; Cetuximab; Interleukin-2
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: natural killer cells; adoptive transfer; allogenic immunotherapy; gastrointestinal cancer EGFR+