Six of eight patients with advanced, progressive B-cell lymphoma or chronic lymphocytic leukemia responded to molecularly reprogrammed targeted autologous T cells.
Dramatic progress has been made recently in generating and deploying redirected T cells for patients with refractory B-cell malignancies (JW Oncol Hematol Sep 13 2011). Now, investigators have transduced autologous T cells with a retroviral vector encoding a chimeric antigen receptor that targets the B-cell surface antigen CD19 and the T-cell activating molecule CD28. The modified T cells were expanded ex vivo and reinfused in eight patients with relapsed or refractory B-cell lymphoma or chronic lymphocytic leukemia (CLL) after a short course of chemotherapy (fludarabine plus cyclophosphamide). Patients received interleukin (IL)-2 after T-cell infusion to enhance in vivo expansion.
Of four patients with CLL, one achieved complete remission, two achieved partial remission (PR), and one achieved stable disease. Of four patients with follicular lymphoma, three achieved PR, and one died of influenza before evaluation for response. One patient with marginal zone lymphoma achieved PR. Of all eight patients, four experienced long-term depletion of normal B cells, consistent with known CD19 expression on circulating B cells and with persistence of the transduced T cells; serum immunoglobulin levels fell in these patients, necessitating regular prophylactic infusions of intravenous immunoglobulin. Four patients experienced severe toxicity in the first week after T-cell infusion, attributed to the release of inflammatory cytokines by the activated T cells, including tumor necrosis factor and interferon gamma. Because the exogenously administered IL-2 might have contributed to this toxicity, the investigators dropped IL-2 from the ongoing protocol.
Comment: These results extend the earlier promising reports of cellular immunotherapy with redirected autologous T cells for refractory B-cell malignancy. Further refinement of the methodology for generating therapeutic T-cell doses, better understanding and management of toxicities, and new insights into longer-term safety and efficacy should lead to the development of larger-scale clinical trials.