Image by NIAID
Researchers have reported “favorable” long-term results from a pair of phase 1 trials in which they used the non-viral Sleeping Beauty (SB) transposon/transposase system to create CD19-specific chimeric antigen receptor (CAR) T cells.
These CAR T cells appeared to be safe, and results suggested they can provide additional control of leukemia and lymphoma when given after autologous or allogeneic hematopoietic stem cell transplant (HSCT).
In addition, the researchers said use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy.
The team described their results with the SB system in The Journal of Clinical Investigation. Results from these trials were previously reported at the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
The trials were sponsored by MD Anderson Cancer Center in collaboration with the National Cancer Institute, National Center for Research Resources, Intrexon Corporation, and Ziopharm Oncology.
The trials included 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma (NHL, n=9).
The patients received SB-modified T cells after autologous (n=7) or allogeneic (n=19) HSCT.
The researchers said SB-mediated gene transfer and stimulation resulted in large ex vivo expansion of T cells while retaining CAR expression and without integration hotspots.
Autologous and allogeneic T cells survived after infusion an average of 201 days and 51 days, respectively.
Safety
The researchers said there were no unexpected acute infusion or delayed toxicities. Mild elevations in cytokines were observed but not cytokine storm.
Three allogeneic HSCT recipients developed graft-vs-host disease (GVHD). One patient developed grade 1 acute skin GVHD that resolved with topical steroids, and 1 developed chronic skin GVHD that responded to systemic steroids.
The third patient, who had a history of drug-induced liver toxicity, developed recurrent liver toxicity with a component of liver GVHD 1 month after T-cell infusion. This patient died of liver failure.
There were 5 other deaths, all of them due to disease relapse.
Efficacy: Autologous HSCT
Seven patients with advanced NHL were treated with autologous HSCT, followed by the administration of patient-derived CAR T cells.
Six of the 7 patients were in complete remission (CR) at a median follow-up of 25.5 months (range, 6.4 to 32.7 months).
The 30-month progression-free survival (PFS) rate was 83%, and the overall survival (OS) rate was 100%.
Efficacy: Allogeneic HSCT
Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells after allogeneic HSCT. The patients had advanced disease at the time of HSCT, and CAR T cells were administered without additional lymphodepletion.
Eleven of 19 patients were still in CR at a median follow-up of 7.5 months (range, 2.7 to 17.9 months). The 1-year PFS rate was 53%, and the OS rate was 63%.
The researchers also looked at the subset of allogeneic HSCT recipients who received haplo-identical CAR T cells. These 8 patients had a 1-year PFS rate of 75% and an OS rate of 100%.
“By following these patients over an extended duration, as we do in these studies, we can better understand the added benefit of CAR-T over HSCT alone,” said Francois Lebel, MD, of Ziopharm Oncology.
“Although the primary objective of these trials was not to establish efficacy, the recipients’ outcomes are encouraging, with apparent doubling of survivals compared to historical controls. We are encouraged by these clinical data and look forward to results from our phase 1 study infusing our next-generation CD19-specific CAR T cells in patients with advanced lymphoid malignancies.”
