Abstract
Chronic lymphocytic leukemia (CLL) is a malignancy ideally suited for therapeutic vaccines. CLL B cells, readily available from blood, express surface antigens that can be targeted for immune-recognition. Although usually stealth-like, CLL cells can be stimulated through ligation of CD40 by CD154, to express immune co-stimulatory molecules, such as CD80, CD86, and adhesion molecules (e.g. CD54), allowing them to stimulate T cells against leukemia-associated antigens. A phase I clinical trial with autologous CLL cells transduced to express murine CD154 previously demonstrated tolerability and clinical activity with reduction in leukemia counts and lymph node size associated with increases in leukemia-specific T cell counts (Blood 96:2917Blood 96:2000). In vivo bystander CD40 stimulation of non-transduced CLL cells also was noted following intravenous administration of CD154-transduced CLL cells. The acute decreases in leukemia counts were possibly due to induced expression of death-receptors (e.g. CD95 (Fas) and DR5) and pro-apoptotic proteins such as the BH3- interacting-domain death agonist (Bid), allowing for clearance of leukemia cells by innate immune effector mechanisms. Repeated dosing of transduced cells was initiated; however, some patients developed anti-murine CD154 antibodies, in some cases with neutralizing activity. Therefore, a new replication-defective adenovirus was constructed encoding a humanized, functional, membrane-stable CD154 (ISF35) that efficiently transduces CLL B cells. We are conducting a phase I clinical trial with a single dose of 1x108, 3x108, or 1x109 ISF35-transduced autologous leukemia cells to assess tolerability and activity. To date, 4 patients have had cells collected and transduced. Patient characteristics: Rai I=2, III=1, IV=1; ALC=21−135K/μL; 2 patients had CLL cells with 17p del, and another had CLL cells with trisomy 12 and complex cytogenetic abnormalities; 3 patients had CLL cells with high-level expression of CD38; 2 patients were previously treated and 2 were treatment-naive. Transduction efficiency was 49, 77, 53, and 57%, and viability of transduced cells was 92–95%. The ISF35-transduced CLL cells were induced to express CD95 in all cases. Three patients received their ISF35-transduced cells at the time of abstract submission. There have been no infusion-related toxicities. All 3 patients experienced fever (Grade less than 2) and fatigue (Grade less than 2) lasting 1–4 days following treatment; no dose-limiting toxicities were noted at the 1x108 cell dose. Acute reductions in ALC were 36, 64, and 0%, follow-up is 4, 2, and <1wk and continues. Preliminary data on leukemia cells from blood prior to and 48 hr post-infusion demonstrated induced expression of CD95 and DR5 on CLL cells, including on the leukemia cells in the patient with 17p del. Patient 4 will receive 3x108 ISF35 transduced cells; patients must be treated 2 wks apart; and enrollment and treatment will continue unless DLT is observed.
Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia
