Non-viral CAR-T therapy
Ziopharm is advancing Sleeping Beauty, one of the most clinically advanced non-viral cell therapy technologies, to develop therapeutics for both solid tumors and blood cancers. For B-cell malignancies like leukemias and lymphomas, our therapies are designed to target known antigens, or surface markers that distinguish cancer cells from healthy cells.
Sleeping Beauty genetic modification
Sleeping Beauty is based on a transposon/transposase system that uses electroporation and DNA plasmids to reprogram T-cell DNA. Ziopharm’s bioengineering approach has three components:
- First, using a CAR we program T cells to attack CD19, a known antigen on the surface of malignant B cells.
- Second, we tether interleukin 15 to the T-cells’ membranes, and this membrane-bound IL-15 or mbIL-15 is designed to give the T-cells a survival advantage and stave off immune cell exhaustion so the T cells can kill and continue to kill cancer cells.
- Third, we insert a molecular safety switch into the DNA, letting us deactivate the modified T cells as needed.
“Membrane-bound IL-15… what it means is we’ve taken a very powerful cytokine, called interleukin 15, and we’ve sewn it to the surface of your T cells.”
The process reduces time and complexity
Our Sleeping Beauty system greatly reduces the time between genetic modification and infusion, making it possible to manufacture T cells on site where patients are receiving their care in less than two days. Existing T cell therapies require a patient’s T cells to be isolated, genetically modified with a virus, activated and propagated at a centralized bio-manufacturing center before being shipped back to the patient’s hospital for infusion. This process currently takes weeks.
Under our Point-of-Care approach, genetically modified CAR T cells are very rapidly manufactured onsite in less than two days using Sleeping Beauty.
“We call the process Point-of-Care because we’re taking the patients’ cells and we’re genetically modifying them in a rapid manufacturing process that allows us to get those cells back into the patient in a manner of a few days.”
Ziopharm, in collaboration with our partners, is developing Sleeping Beauty to target B-cell malignancies with CAR+ T cells produced with very rapid manufacturing. In our first and second generation clinical trials, we have treated more than 30 patients with Sleeping Beauty-modified T cells, and clinical data has demonstrated safety, tolerability, disease response, long-term survival, and persistence of infused CD19-specific CAR+ T cells. See our publication, “Phase 1 trials using Sleeping Beauty to generate CD19-specific CAR T cells” in The Journal of Clinical Investigation
In our third-generation clinical trials, we expect our Sleeping Beauty platform will manufacture modified T-cells in two days. In addition, preclinical studies showed that – in less than two days – we can manufacture CAR+ T cells co-expressing membrane-bound interleukin-15 (mbIL15) and a kill switch without ex vivo activation or propagation. The cells achieved anti-tumor effects and prolonged T cell survival in mice models.. See our publication, “Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells,” in the Proceedings of the National Academy of Sciences (PNAS)