Anti-CD19 CAR T-Cell Therapy After Stem-Cell Transplantation Effective in Advanced Multiple Myeloma
San Diego, CA—Anti-CD19 chimeric antigen receptor (CAR) T-cell administration after autologous stem-cell transplant (ASCT) showed clinical activity in patients with advanced multiple myeloma, according to results of a pilot study presented at the 2016 American Society of Hematology meeting. Substantially longer progression-free survival (PFS) was seen in 2 of 10 patients who received ASCT plus CTL019 than in patients who received first-line ASCT, said Alfred L. Garfall, MD, MS, Assistant Professor of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Although the dominant type of myeloid plasma cells is CD19-negative in nearly all cases of multiple myeloma, minor CD19-positive components of the myeloma clone can be identified in patients, either as CD19-positive subsets of multiple myeloma plasma cells or as clonotypic B lymphocytes, which provided the rationale for using CTL019 in multiple myeloma, explained Dr Garfall.
The clonotypic B-cells may exhibit properties of cancer stem cells and therefore may be a potential therapeutic target in conjunction with therapies that target multiple myeloma plasma cells. Dr Garfall and colleagues hypothesized that CTL019 would prolong the response to standard therapy by depleting the minor CD19-positive population of multiple myeloma cells with cancer stem-cell properties.
“Overall, our results suggest that targeting minor subsets of multiple myeloma cells with enhanced clonogenic potentially may be clinically beneficial,” he said.
In this study, 10 patients with multiple myeloma that progressed after ASCT received high-dose melphalan and ASCT, followed by the administration of 5 × 107 CTL019 cells 12 to 14 days later. Patients had 2 to 10 previous lines of therapy (median, 6), and the majority of patients had high-risk cytogenetic or clinical features. No patient received more intensive maintenance therapy after ASCT than their previous ASCT.
The dominant population of plasma cells in all patients was CD19-negative; however, minor CD19-positive subsets were found in 7 of 9 evaluable patients.
“In general, this was a safe and feasible approach,” said Dr Garfall. “CAR T-cells were successfully manufactured in 10 of 11 patients. There was only 1 episode of cytokine release syndrome that was grade 1 and self-limited,” he added. There was 1 episode of autologous graft-versus-host disease that resolved with prednisone.
“Two patients had substantial prolongation of PFS after transplant with CTL019 compared with previous transplants, but at a lower dose of melphalan,” he said.
One additional patient reached the PFS achieved with previous ASCT. These data compare favorably to a historical cohort of 18 patients who received first-line and salvage ASCT at the Abramson Cancer Center since 2008, where no patients had longer PFS after salvage ASCT, Dr Garfall said.
“The patients who had prolonged PFS, when they went on to progress…they exhibited much more indolent clinical features…slow-growing disease,” he said. Patients with higher peak CTL019 bone marrow frequency had longer time to disease progression, suggesting a link between CTL019 mechanism of action and clinical response.
Antibodies emerged against the stem-cell antigen SOX2, specifically in patients with best clinical outcome. SOX2 is a transcription factor that is required for pluripotency and self-renewal; anti-SOX2 antibodies are generally absent in untreated multiple myeloma and post-ASCT.
A higher dose of CTL019 in this setting may be more beneficial than the dose that was used in this study, said Dr Garfall. The dose used in this study was 10 times lower than is typically used, because of concerns about adverse events after ASCT.