A Phase I/II Trial of Xcellerated T Cells™ in Patients with Chronic Lymphocytic Leukemia.

Background: T cells from CLL subjects can be activated and expanded ex vivo using the Xcellerate^TM Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte^TM-Dynabeads®). With this process, anergic T cells from CLL subjects can be activated, leading to upregulation of important immune molecules on leukemic B cells and leukemic cell apoptosis (Bonyhadi et al., ASH 2002). This trial was initiated to evaluate the safety and efficacy of autologous Xcellerated T Cells in CLL subjects.

Methods: Subjects had high risk or symptomatic/progressive intermediate-risk disease and ECOG PS 0–2. PBMC were collected by leukapheresis for the Xcellerate Process, and subjects subsequently received an infusion of Xcellerated T Cells. Cohorts of 3 subjects each were treated with increasing cell doses: 10 x 10⁹, 30 x 10⁹ and 60–100 x 10⁹. Additional subjects were treated at the highest dose level.

Results: 17 subjects have been treated to date. Data are available for 14 subjects, with a median follow-up of 12 weeks (range 8–12). Baseline characteristics [median (range)] were: age=57 (39–68), years from diagnosis=3.9 (1.8–8.7), WBC =56 x 10³/mm³ (6–274). Prior treatments included chemotherapy ± monoclonal antibody treatment (n=8), investigational vaccine (n=3), and no prior therapy (n=3). After the first cohort, a WaveBioreactor-based Xcellerate III Process (Hami et al., Bioprocessing Journal 2003) was instituted, which yielded 137 ± 35 x 10⁹ cells with 98.4 ± 1.1% T cell purity (n= 13; mean ± SD). To date there has been one serious adverse event of atrial fibrillation, which was unlikely related to Xcellerated T Cells. Following treatment, T cell counts increased in a dose dependent manner and were sustained over the 12 week f/u period, with peak mean increase of 118% in the highest dose cohort. Increases in neutrophil, platelet, hemoglobin and NK counts were observed, with peak mean increases of 118%, 26%, 9% and 66%, respectively. A ≥ 50% reduction in lymph node area was observed in 11 of 14 evaluable subjects. Median (range) spleen measurement in cm below left costal margin decreased from 3 (0–10) prior to treatment to <1 (0–4), a 50% or greater decrease in 10 of 12 subjects with enlarged spleens. Treatment effects were observed at all dose levels of Xcellerated T Cells administered. Decreases in peripheral leukemic cell counts have not been observed to date. Six subjects have received a second infusion of Xcellerated T Cells (median dose 77.1 x 10⁹; range 68.7–96.4 x 10⁹) a median of 10.3 months (range 5.8–11.0) following the first infusion. The second infusions were well-tolerated, with no serious adverse events reported; clinical efficacy data are pending.

Conclusions: Xcellerated T Cells were reproducibly manufactured for CLL subjects and were well tolerated in doses of up to 100 x 10⁹ cells. Treatment led to significant increases in T cell counts, increases in neutrophil, platelet and hemoglobin counts, and significant decreases in lymphadenopathy and splenomegaly. Data on subjects receiving a second treatment will be reported. Clinical trials of Xcellerated T Cells following cytoreductive therapy are planned.