Lymphocytic B-Leukemia (B-CLL) w/Human IL-2 Gene Modified & Human CD40 Ligand-Expressing Autologous Tumor Cells

Study Overview
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Brief Summary
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In the laboratory, we will put a special gene into cancer cells that have been taken from the subject. This gene will make the cells produce interleukin 2 (IL-2), which may help the patient's immune system kill cancer cells. Also, we will use CD40 ligand (CD40L) with the IL-2. Studies of cancers in animals and in cancer cells that are grown in laboratories have suggested adding the CD40L helps the IL-2 work better. Some of these new cells will then be given back to the subject as a vaccine shot. We believe that a part of the subject's immune system (cells called T-reg cells) might try to kill off these special cells. If the T-reg cells do that, the vaccine would not work as well or last as long. To try to avoid this, before the special cells are put back into the subject's body, we will give them an intravenous (IV) dose of IL-2 immunotoxin (called denileuk diftitox or ONTAK). ONTAK should get rid of some of the T-reg cells in the subject's body which should help the special cells work better and longer. The purpose of this study is to learn the safety and cancer-fighting effects of using IL-2 with the vaccine.

Detailed Description
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This is a phase I trial to assess the safety of depleting regulatory T (Treg) cells using 1-3 doses of an interleukin-2 immunotoxin directed to the CD25 antigen (denileukin diftitox, ONTAK) in chronic lymphocytic leukemia (B-CLL) patients, followed by six subcutaneous (SC) injections of autologous leukemic cells modified ex vivo to secrete human interleukin-2 (hIL-2) and to express human CD40 ligand (hCD40L). Patients will receive a fixed dose (2 x 10e7) of IL-2 secreting B-cells together with 2 x 10e7 hCD40L expressing B-cells, representing a safe, well tolerated and immunogenic dose in our previous dose escalation study. All eligible patients will be treated with six injections. Any patient whose disease regresses after the administration of 6 injections may be offered further injections of tumor vaccine if sufficient vaccine is available. There will be no use of placebo or control subjects.

Official Title
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Treatment of Chronic Lymphocytic B-Leukemia (B-CLL) With Human IL-2 Gene Modified and Human CD40 Ligand-Expressing Autologous Tumor Cells After Depletion of Regulatory T Cells

Conditions
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CHRONIC LYMPHOCYTIC B-LEUKEMIA

Intervention / Treatment
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* Biological: IL-2 secreting and hCL4OL-expressing autologous B-CLL cells
* Biological: IL-2
* Biological: CD40L
* Drug: ONTAK
* Biological: immunotoxin dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre Inclusion Eligibility Criteria: Proof of B-CLL diagnosis not in Richter's transformation Eligibility Criteria: Manipulated B-CLL cells available (at least 6 injections) B-CLL with measurable disease, not in Richter's transformation Life expectancy greater than or equal to 10 weeks ECOG 0-2 (see Section 4.3 of the full protocol for details) Recovered from the toxic effects of all prior chemotherapy Absolute neutrophil count (ANC) greater than or equal to 500/mL Absolute lymphocyte count (ALC) greater than or equal to 200/mL Hemoglobin greater than or equal to 8 g/dL Platelet count greater than or equal to 50,000/mL Total bilirubin less than or equal to 1.5mg/dL -SGOT less than or equal to 2 x Normal Normal PTT -Creatinine less than 3 x Normal (age-related) or Creatinine clearance > 80mg/min/1.73m2 Serum albumin level greater than or equal to 3 g/dl Must not have received treatment with other investigational agents within the last 4 weeks Practicing appropriate birth control during the study and for 3 months after the study is concluded. Exclusion Criteria: Congestive heart failure Significant arrythmia or history of myocardial infarction Active CNS disease or a history of seizure Active infection / receiving antibiotics (other than prophylactic trimethoprim sulfamethoxazole Seropositive for HIV Pregnancy or lactation / will not use birth control methods Autoimmune disease (GvHD, immune thrombocytopenia-ITP or autoimmune hemolytic anemia-AIHA) Receiving immunosuppressive drugs Hypersensitivity to denileukin diftitox or any of its components: diphteria toxin, interleukin-2, or excipients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: IL-2 secreting and hCL4OL-expressing autologous B-CLL cells|Patients will be treated with six subcutaneous injections of their IL-2-secreting and hCD40L-expressing autologous B-CLL cells, separated by one to two weeks in an immunological treatment window|
|Biological: IL-2|subcutaneous (SC) injections of autologous leukemic cells modified ex vivo to secrete human interleukin-2 (hIL-2) and to express human CD40 ligand (hCD40L).|
|Biological: CD40L|subcutaneous (SC) injections of autologous leukemic cells modified ex vivo to secrete human interleukin-2 (hIL-2) and to express human CD40 ligand (hCD40L).|
|Drug: ONTAK|an interleukin-2 immunotoxin directed to the CD25 antigen (denileukin diftitox, ONTAK|
|Biological: immunotoxin dose|Days 0, 2, and 4 (18 ug/kg) i.v|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of (Treg) cells using interleukin-2 immunotoxin directed to the CD25 antigen in(B-CLL) patients, then six (SC) injections of autologous leukemic cells modified to secrete (hIL-2) and to express (hCD40L). |  | 15 years | 
| To obtain preliminary data on the anti-tumor effects of this treatment regimen. |  | 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| determine whether MHC-restricted or unrestricted anti-tumor immune responses are induced and sustained by the combination of Treg cell depletion and SC injections of B-CLL cells, which have been modified ex vivo to secrete hIL-2 and to express hCD40L |  | 15 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LYMPHOCYTIC, B-LEUKEMIA, B-CLL