While 50 to 60 percent of patients with diffuse large B-cell lymphoma (DLBCL) are cured with standard combination chemotherapy, others require second-line therapy due to a relapse or primary chemotherapy-refractory disease.
The well-established standard of care for these individuals — high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) when chemotherapy-sensitive remission has been achieved with second-line chemotherapy — leads to cure, at best, in only approximately 50 to 60 percent of cases.
Strategies to Improve HDT-ASCT Outcomes
The need for novel approaches was highlighted recently with the failure of proposed HDT-ASCT interventions to consolidate or maintain remission in chemosensitive patients or improve outcomes compared to controls in two large, randomized, multicenter phase III trials.
In one trial, relapsed and refractory DLBCL patients that proceeded to HDT-ASCT were randomized to maintenance rituximab or observation. Subjects in the former group experienced no improvement in event-free, progression-free, or OS benefit.
Nor were benefits seen in the second study, in which the Bone Marrow Transplant Clinical Trial Network compared two-year progression-free survival of chemosensitive rel/ref DLBCL patients proceeding to HDT-ASCT treated with 131I-tositumomab (Bexxar; GSK)-BEAM to rituximab-BEAM conditioning. At a median follow-up of 25.5 months, no difference was seen in the primary end point of two-year progression-free survival between B-BEAM (48.6%) and R-BEAM (47.9 percent).Back to top
Promising Results with Cellular Immunotherapy
Cellular immunotherapy with allogeneic hematopoietic cell transplantation (allo-SCT) has been utilized to overcome chemoresistance via a graft-versus-lymphoma effect. However, this modality is associated with high rates of treatment-related morbidity and mortality secondary to GVHD and requisite immunosuppression. Additionally, many patients do not have an appropriately HLA-matched donor or are too high risk for allo-SCT secondary to age and/or comorbidities.
Under the guidance of Renier Brentjens, in collaboration with Michel Sadelain and Isabelle Riviere as leaders of the Memorial Sloan Kettering Gene Transfer Facility, our Cellular Therapeutics Center has pioneered the genetic engineering of autologous T lymphocytes through the modification of the patients’ own T lymphocytes to target CD19-expressing B cells (19-28z chimeric antigen receptor T cells or 19-28z CAR-T).
Because B cell lymphomas express this protein on their surface and thus are susceptible to targeted immunotherapeusis by 19-28z CAR cells. This technology has demonstrated a promising clinical efficacy in patients with relapsed and refractory acute B-cell lymphoblastic leukemia (ALL), achieving an early 88 percent complete response rate in phase I. We are now piloting this approach following HDT-ASCT for B-cell lymphoma in a phase I clinical trial.
In this trial, we are targeting high-risk patients that are still eligible for HDT-ASCT as defined by chemosensitive disease who achieve at least a partial remission according to CT, but with FDG avid residual disease on PET or bone marrow involvement by lymphoma following two cycles of chemotherapy. The primary purposes of this phase I study are to assess safety and determine a recommended phase II dose of CAR-T immediately following HDT-ASCT.Back to top