Allogeneic Cytokine-induced Killer Immunotherapy for Relapse After Allogeneic Marrow Transplant for Haematological Malignancies
Condition: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Chronic Myeloid Leukemia; Non Hodgkin's Lymphoma; Hodgkin's Disease; Myelodysplastic Syndrome; Multiple Myeloma
MeSH terms: Leukemia; Leukemia, Myeloid; Multiple Myeloma; Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Hodgkin Disease; Hematologic Neoplasms; Myelodysplastic Syndromes
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Cytokine-induced killer ( CIK ) cells have been shown by our lab to be cytolytic against both
      autologous and allogeneic acute myeloid leukemia ( AML ) cells. Large scale expansion of CIK
      cells has also been shown to be feasible in healthy allogeneic stem cell donors as well as in
      patients undergoing mobilization for autologous transplant.

      Donor lymphocyte infusion (DLI) has been shown to be active against some haematological
      malignancies including CML, AML, MDS,NHL and Hodgkin's disease. These donor lymphocytes can
      be further activated in vitro to become CIK cells. At least 2 other centers in the world have
      given allogeneic CIK cells for patients relapsing post allogeneic transplant for a variety of
      haematological malignancies. These early reports have demonstrated feasibility, absence of
      increased GVHD and possible efficacy in some cases.

      We are proposing a Phase I /II study on the feasibility / efficacy of immunotherapy with
      allogeneic CIK cells for patients who relapse after allogeneic marrow transplant for their
      haematological malignancies. These patients have to be either refractory to conventional
      donor lymphocyte infusion, or need a larger number of donor lymphocyte than could be provided
      by unmanipulated donor lymphocytes. Donor lymphocytes will be collected and cultured in GMP
      facilities to maturity, then infused into patients. This will be given in graded doses at 4
      weekly intervals and continued on in the absence of GVHD till remission is achieved or
      disease progression occurs. Patients may receive various forms of chemotherapy appropriate to
      the clinical condition in each case before the allogeneic CIK infusion.

      Efficacy will be assessed by comparing the response to allogeneic CIK infusion vs that to due
      to conventional DLI, ie response to the two different treatment using DLI response as the
      comparator. We expect about 10 such cases to be done over the next 3 years. Significant
      statistics is unlikely to be generated but observation and description of the response can
      generate useful information for presence or not of the efficacy of such a treatment.

      If clinical efficacy and superiority over conventional DLI is demonstrated, then future
      allogeneic CIK may take the place of DLI in this group of poor prognosis patients who relapse
      after allogeneic transplant .
    

Detailed description: 
      1. Patient inclusion criteria This trial includes only patients who have relapsed after an
           allogeneic transplant, who have either 1.1 No response to conventional DLI given for at
           least one dose, or 1.2 No possibility of access to large number of donor lymphocyte for
           repeated doses of DLI, This applies to cases of unrelated transplant or cord blood
           transplant

           1,3 Patients who developed significant GVHD to conventional DLI, but had no other
           therapeutic option. In such cases the rationale is based on mice studies of mismatched
           CIK producing much less GVHD than mismatched unmanipulated splenocytes.

        2. Collection of peripheral blood stem cells ( PBSC ) Sibling allogeneic donors will
           routinely have their PBSC harvested for the purpose of infusion into the recipients.
           Currently our practice involves one additional day of collection to freeze as backup to
           be used for DLI in the event of relapse. This collection is frozen in a few aliquots,
           and is available for CIK culture when need arises

           For cord blood transplant, one issue is that DLI is not available. There is one report
           on growing CIK from residual cells in the bags of cord blood after infusion, then stored
           frozen for use in future if need arises. This does not in anyway compromise the cord
           blood infusion. Similarly this can be done in the case of unrelated donor transplant.
           This will serve as a backup in the event that donor is not available for repeat
           collection of lymphocyte.

        3. Culture of CIK cells

      For culture from frozen product, this is rapidly thawed and culture started in gas permeable
      bags in complete medium and cytokine as detailed in SOP attached ( appendix 1 ). Culture
      medium and cytokine are added periodically till maturation of CIK at between 21-28 days.

      For culture from residual cells in the thawed cord blood infusion bags, cells may need to
      undergo ficoll to remove rbc, then start culture in the similar way

      3. Harvesting of CIK cells

      At maturity between D21-D28, all bags of CIK cells are pooled and washed using COBE 2991 cell
      harvester. This will ensure removal of >99.9% of the original culture medium. Cells are then
      frozen and aliquots sent for quality control to ensure compliance to GMP standard. This
      includes bacteriological and fungal culture, mycoplasma and endotoxin testing.

      4. Infusion of CIK cells Patients may undergo cytoreductive chemotherapy or oral
      immunosuppressive therapy as deemed fit in each individual case by the attending physician.
      At the nadir of lymphopenia , CIK cells are rapidly thawed at bedside and infused.

      Dose and schedule of CIK cells follows the following principle 4.1 First dose for patients
      who have already received DLI and showed resistance : at double or triple the last DLI dose (
      expressed as CD3/kg ).

      4.2 First dose for patients who have not received any DLI : this will follow the conventional
      practice of DLI where the first dose will be 10 million CD3/kg.

      4.3 Subsequent doses will be given at 4-weekly intervals allowing time to observe for
      development of GVHD and response.

      4.3.1 If no response was observed, dose will be doubled or tripled ( depending on the size of
      the available aliquot ). If there is good response, dose will remain the same as the previous
      infusion.

      4.3.2 In the presence of GVHD, infusion will be withheld till resolution of GVHD, then
      resumed at half or one-third of the previous dose ( depending on the size of the available
      aliquot).

      4.4 Duration of CIK infusion will depending on the response status 4.4.1 In responding
      patients, 4-weekly CIK infusion will continue till a complete remission is achieved and then
      another 2-3 infusions beyond.

      4.4.2 In patients who achieve a stable partial response, CIK infusion will continue in a
      4-weekly interval, provided no adverse effect and CIK cells are available. This will continue
      on and stop if disease breaks through.

      4.4.3 In patients where disease continues to progress after 2-3 cycles of CIK infusion, no
      further infusion will be given
    

Intervention name(s): infusion of allogeneic CIK cells
Intervention type(s): Biological
Intervention description(s): infusion of allogeneic CIK cells at graded doses
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: allogeneic transplant; haematological malignancies; allogeneic CIK cells