On August 4, 2016 ZIOPHARM Oncology, Inc. (Nasdaq:ZIOP), a biopharmaceutical company focused on new immunotherapies, reported the publication of data highlighting the benefits of using the non-viral Sleeping Beauty (SB) system to genetically modify T-cells to express a chimeric antigen receptor (CAR) for use against leukemias and lymphomas (Press release, Ziopharm, AUG 4, 2016, View Source [SID:1234514282]). The article, titled "Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells," was published in the Journal of Clinical Investigation (doi:10.1172/JCI86721), and is available online here.

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In the paper, 26 patients with multiply relapsed B-lineage acute lymphoblastic leukemia (ALL, n=17) or B-cell non-Hodgkin lymphoma, (NHL, n=9) were enrolled in two investigator-initiated clinical trials at the University of Texas MD Anderson Cancer Center infusing SB-modified T cells after autologous (n=7) or allogeneic (n=19) hematopoietic stem-cell transplantation (HSCT).

Autologous CAR-T: Seven patients with advanced NHL were treated with autologous HSCT followed by administration of patient-derived CAR T cells. Six of the seven patients remain in complete remission (CR) and the 30-month progression-free survival (PFS) and overall survival (OS) rates were 83.3% and 100%, respectively.
Allogeneic CAR-T: Nineteen patients (ALL n=17, NHL n=2) received donor-derived CAR T cells. The patients had advanced disease at the time of HSCT and CAR T cells were administered without additional lymphodepletion. Eleven of 19 patients remain in remission with 1-year PFS and OS rates of 53% and 63%, respectively.
HLA partially-matched allogeneic CAR-T: When the subset of allogeneic recipients of HSCT receiving haplo-identical CAR T cells were examined, eight patients had 1-year PFS and OS rates of 75% and 100%, respectively.
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 and 51 days, respectively. No unexpected acute infusion or delayed toxicities were noted in the autologous or allogeneic recipients. Mild elevations in cytokines were observed without cytokine storm.

Francois Lebel, M.D., Executive Vice President, Research and Development, Chief Medical Officer at ZIOPHARM, states: "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. 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."

Supported by results from two Phase I clinical studies conducted by investigators at MD Anderson Cancer Center, the publication describes how the use of the SB transposon/transposase platform could reduce the costs and complexity associated with recombinant viral vector-based immunotherapy. Additionally, by infusing a CD19-specific CAR T cells to target minimal residual disease after autologous and allogeneic HSCT, the SB system may improve tolerability by avoiding cytokine storm.

"The use of the non-viral Sleeping Beauty platform provides us with leverage to both decrease the cost of modifying T cells and reduce the T-cell manufacturing steps requiring GMP," said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of ZIOPHARM. "As we continue to advance Sleeping Beauty engineered designs, ZIOPHARM benefits from both viral and non-viral approaches within CAR-T, while focusing efforts on non-viral gene delivery for TCR given its unique ability to enable personalized therapies for patients with solid tumors."