Previous studies in multiple myeloma have demonstrated a significant association between survival and lymphocyte recovery following autologous transplantation (Porrata et al., Blood 2001). Furthermore, in a murine model of myeloma, adoptive transfer of activated T cells following bone marrow transplantation has demonstrated a marked anti-tumor effect in vivo (Hou Fowler, BBMT 2003). We have initiated a clinical trial in patients with multiple myeloma to evaluate the activity of T cells activated and expanded ex vivo with the Xcellerate™ Process, which uses anti-CD3 and anti-CD28 antibodies covalently linked to magnetic beads (Xcyte™ Dynabeads®). Following induction therapy, patients undergo a leukapheresis to collect peripheral blood mononuclear cells for the Xcellerate Process. Patients then undergo stem cell mobilization and collection, followed by high dose chemotherapy with melphalan (200 mg/m2). Three days following peripheral blood stem cell infusion, patients receive an infusion of 5–10 × 1010 autologous Xcellerated T Cells. Thirty-one of the planned 35 patients have been treated to date. T cells have been successfully activated and expanded in all patients. In the first 18 patients, T cells expanded 166 ± 44 fold (mean ± SD), with the final product being >99.0 ± 0.1% CD3+. A bioreactor process was subsequently instituted, and T Cells expanded 253 ± 86 fold, with final product 98.0 ± 3.2% CD3+ (n = 10). Xcellerated T Cell infusions have been well-tolerated, with no Grade 3 or 4 acute infusional toxicities. Lymphocyte recovery has been rapid, with counts reaching > 500/mm3 generally within 1–2 days following T cell infusion (Day 4–5 post transplant). Historically, lymphocyte recovery to >500/mm3 usually does not occur for 3 or more weeks post-transplant in myeloma patients treated with this regimen, but without Xcellerated T Cells. The T cell receptor repertoire of leukapheresis samples as measured by Vβ spectratyping demonstrates marked skewing. Following the Xcellerate Process, the repertoire returns to a more normal pattern (n = 5; p = 0.01). In addition, the T cell repertoire measured 25 days following T cell infusion (Day 28 posttransplant) demonstrates a more normal pattern than prior to T cell infusion (n = 5). This is in marked contrast to the severe skewing of T cell receptor diversity normally seen in myeloma patients following autologous stem cell transplantation (Mariani et al, BJH 2001). Data on clinical outcomes will be presented.
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Martin et al. (2004) studied this question.