A Phase I Extension Trial of Repeated Infusions of ISF35

The study is a Phase Ib extension trial that will assess the toxicity, tolerability, and safety of up to two repeated administrations of 1x10\^8, 3x10\^8, or 1x10\^9 autologous Ad-ISF35-transduced CLL B cells given intravenously to patients with CLL who tolerated ISF35 in the prior Phase I infusion trial at M.D. Anderson.

In a previous Phase I clinical trial at M.D. Anderson, patients with CLL received an intravenous infusion of autologous leukemia cells transduced ex vivo with an adenovirus encoding the wild-type murine CD154. This treatment was well tolerated and without dose-limiting toxicity. Patients each experienced acute reductions in the leukemia-cell blood count and in the size of enlarged lymph nodes and spleen.

The infusion induced changes in circulating bystander, non-infected CLL cells and both acute and long-term clinical responses. The changes in bystander CLL cells were similar to those observed in CLL cells following ligation of CD40, which included enhanced or de novo expression of CD54, CD80, and CD86, allowing the modified CLL cells to function more effectively in presenting antigens to autologous T cells. Following CD40 ligation, CLL cells are induced to express CD95 and DR5 and to undergo changes in expression of pro- and anti-apoptotic proteins, ultimately favoring apoptosis in the CLL cells.

To build upon these results, an extension to this trial will be completed in order to assess the tolerability of repeated infusions of ISF35 and to test whether additional administrations will enhance the anti-leukemic activity exhibited in the previous Phase I trial.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must have been enrolled and tolerated the single dose ISF35 in MDACC Protocol 2004-0914.
2. Subjects must have adequate Ad-ISF35 transduced CLL B cells to allow for at least one additional treatment.
3. Women of childbearing potential (not postmenopausal for at least one year or not surgically incapable of bearing children) must agree not to become pregnant for the duration of the study. Both men and women participants must agree to use contraception for the duration of the study.
4. Subjects must have Zubrod performance status of ≤ 2.
5. Subjects must have adequate hematologic, renal, hepatic, and coagulation function:

   * Adequate hematologic function:

     * Platelet count ≥ 50,000/μl; AND
     * Hemoglobin ≥ 10 g/dl (may be supported by erythropoietin or transfusion).
   * Adequate renal function:

     * Serum creatinine ≤ 1.5 times upper limit of normal; OR
     * Measured creatinine clearance ≥ 40 mL/min/1.73 m\^2.
   * Adequate hepatic function:

     * Total bilirubin ≤ 2.5 times upper limit of normal; AND
     * ALT ≤ 2.5 times upper limit of normal; AND
   * Adequate coagulation tests:

     * Prothrombin time international normalized ratio (INR) ≤ 2; AND
     * Partial thromboplastin time ≤ 1.66 times upper limit of normal
6. Subjects must give written informed consent for the Phase 1B extension trial.

Exclusion Criteria:

1. Unresolved toxicity (Grade ≥ 2) from single administration of Add-ISF35 transduced autologous CLL B cells.
2. Presence of more than 55% prolymphocytes.
3. Chemotherapy (e.g., purine analogues, alkylating agents, or corticosteroids), antibody therapy, immunotherapy, radiation therapy, or participation in any investigational drug treatment within 4 weeks of enrollment into protocol or at any time during the study.
4. Ongoing toxicity from prior anti-neoplastic therapy.
5. Prior gene therapy (EXCEPT Ad-ISF35) or allogeneic stem cell transplantation.
6. Untreated autoimmune hemolytic anemia or immune thrombocytopenia.
7. Active infection requiring parenteral antibiotics.
8. HIV/HBV/HCV seropositivity.
9. Uncompensated hypothyroidism (defined as TSH greater than 4x upper limit of normal not treated with replacement hormone).