A Phase I/II Study of Xcellerated T Cells^™ after Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma.

Background: Previous studies have demonstrated a correlation between survival and lymphocyte recovery following autologous transplantation in subjects with multiple myeloma and other malignancies (Porrata et al., Blood 2001). We initiated a trial in the transplant setting to evaluate the activity of T cells activated and expanded ex vivo with the Xcellerate™ Process, which uses anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte^™ -Dynabeads®).

Methods: Following induction therapy, patients underwent leukapheresis to collect peripheral blood mononuclear cells for the Xcellerate Process. Patients then underwent stem cell mobilization and collection, followed by high dose melphalan (200 mg/m²). Three days following peripheral blood stem cell infusion, subjects received 50–100 x 10⁹ Xcellerated T Cells.

Results: 36 subjects were treated. The median last f/u visit is 180 days post-transplant (range 90–450). A WaveBioreactor-based Xcellerate III Process, which was instituted in the last 18 subjects, resulted in 249 ± 90 fold (mean ± SD) T cell expansion. There were 93.6 ± 0.8 x 10⁹ cells infused, which were 97.6 ⁺ 4.0% T cells. There were no Grade 3 or 4 acute infusional toxicities. Days of neutropenia and thrombocytopenia were 5 (3–43) and 4.5 (0–128) respectively [median (range)]. There were a median of 2 (range 0–14) units of packed red blood cell transfusions in 18/31 (58%) of subjects and a median of 0 (range 0–22) platelet transfusions in 15/31 (48%) of subjects. There were serious or Grade 3 infections in 5/29 (17%) of subjects, and mucositis in 5/29 (17%) of subjects (all ≤ Grade 2). Median days of hospitalization were 16 (range 10–70). Lymphocyte recovery was rapid, with counts reaching > 500/mm³ generally within 1–2 days following T cell infusion. Historically, lymphocyte recovery to > 500/mm³ usually does not occur for 3 or more weeks post-transplant. The rapid lymphocyte recovery included both CD4⁺ and CD8⁺ T cells. The mean (± SEM) CD4⁺ T cell count at 90 days post-transplant was 1,210 ± 80/mm³, significantly higher than that for historical controls receiving the same treatment regimen without Xcellerated T Cells (198 ± 72). The T cell receptor repertoire measured 25 days after the Xcellerated T Cell infusion demonstrated a normal pattern (n = 4/5). This is in contrast to the severe skewing of T cell receptor diversity observed in myeloma subjects following standard autologous stem cell transplantation (Mariani et al, BJH 2001). In 35 evaluable patients, preliminary results demonstrated 6% CRs, 46% VGPRs, 34% PRs, and 11% with PD, using the M-protein at diagnosis as reference. There have been no reported deaths to date.

Conclusions: In multiple myeloma subjects, administration of Xcellerated T Cells following high-dose chemotherapy and autologous stem cell transplantation leads to rapid lymphocyte recovery and appears to restore a normal T cell receptor repertoire. The majority of subjects achieve clinical responses in the autologous transplant setting.