Ziopharm Chief Medical Officer Dr. Raffaele Baffa/Photo courtesy of Ziopharm
Chimeric antigen receptor (CAR-T) therapy is one of the biggest cancer therapy breakthroughs of our time, but as with any precise science, there is still some fine-tuning to be done to overcome safety risks, limited payload capacity and the prohibitive cost of manufacturing.
“Virus-free systems can overcome most if not all of these hurdles. However, in order for a virus-free system to be effective, we need to have technology breakthroughs that simultaneously achieve high gene delivery to cells, effective multiple gene integration into the genome, as well as robustly expanding engineered cells to reach clinical-scale in a cost- and time-effective manner,” said Dr. Sareina Wu, Ph.D., founder and chief scientific officer of GenomeFrontier Therapeutics Inc., a Taiwanese cancer immunotherapy innovator.
GenomeFrontier’s response is Quantum Engine™. G-Tailor facilitates multiplex gene design, construction and screening. Quantum Nufect™ is an electroporation buffer system that robustly introduces therapeutic genes into T cells while maintaining high viability. Quantum pBac™, a virus-free vector system, possesses a large payload for highly effective gene integration, and cell expansion platform iCellar™ produces clinical-scale CAR-T cells in rapid fashion.
“Using this virus-free qCART system, we are able to produce one to 3.5 billion CAR-T cells in one liter of culture in just 10 to 12 days,” Wu said.
The first test for the qCART will be GF-CART01, a CD19 and CD20-targeting agent for the treatment of hematological B-cell malignancies including lymphomas and leukemias, a program that is currently in pre-clinical development.
“Even though qCART can better demonstrate its power in developing solid tumor treatment, we chose B cell malignancy as our first indication to clinically validate the qCART system in a timely fashion,” Wu explained.
Coming up behind GF-CART01, GenomeFrontier has programs with dual-targeted agents for multiple myeloma and solid tumors.
CAR-T therapies for solid tumors have been less successful than hematologic cancers for several reasons, including an immunosuppressive tumor microenvironment, its specificity. The mix of antigens on the surface of solid tumor cells are heterogeneous and a specific CAR is likely to miss some of the cancer, leading to a recurrence.
“qCART is expected to transform the field given its power to generate multiplex CAR-T cells that have great fitness, potency and persistence to effectively combat the complex solid tumor microenvironment,” Wu said.
Stateside, Ziopharm Oncology, Inc. is enabling the cancer patient’s own immune system to battle the enemy, both by weaponizing it with controlled IL-12, and by introducing new elements with its T-Cell non-viral cell therapy platform, Sleeping Beauty.
Sleeping Beauty, based on a transposon/transposase system that reprograms T-cell DNA with electroporation and DNA plasmids, uses a CAR to attack CD19, a known antigen on the surface of malignant B cells. It then binds a powerful cytokine called interleukin 15 (IL-15) to the T cell’s membrane to boost its survival time and stave off immune cell exhaustion, allowing the T cell to continue mowing down cancerous invaders. Importantly, a molecular safety switch is inserted into the DNA, so that the modified T cells can be deactivated as needed.
As opposed to the ex vivo T cell expansion required for virus-based CAR-T technologies, the Sleeping Beauty technology enables the rapid personalized manufacturing of genetically modified CARs and T-cell receptors (TCRs) right where the patient is receiving treatment.
Ziopharm Chief Medical Officer Dr. Raffaele Baffa explained exactly how this will benefit patients in real-time.
“Our Rapid Personalized Manufacturing is much shorter, much simpler, so it’s going to allow us to reach a much larger patient population, thereby providing a big potential advantage,” Baffa said. “Existing T-cell therapies require a patient’s T-cells to be isolated, genetically modified with a virus, activated and propagated at a centralized manufacturing location before being shipped back to the patient’s hospital for infusion, which currently takes weeks to complete. Under our Rapid Personalized Manufacturing approach, genetically modified CAR-T cells are very rapidly manufactured onsite in less than two days from gene transfer using the Sleeping Beauty platform."
While the first target for GenomeFrontier is lymphoma and leukemia, Ziopharm’s most advanced programs are in multiple solid tumors, including a personalized TCR-T program sponsored by the National Cancer Institute which is currently in Phase II clinical trials.
“Solid tumors are a completely different beast. Although we put all of them in one basket, each tumor develops a hallmark of mutations, and another issue with solid tumors is that you have metastasis. These metastatic lesions may have a different genetic pedigree than the primary lesion. It’s a little bit more challenging to develop drugs for solid tumors” Baffa said.
After a brief pause, he continued with a smile: “That’s why we’re going after solid tumors. Because we believe that we have the right technology – the Sleeping Beauty Technology – that we are combining with a TCR approach. That allows us to target those specific genetic mutated alterations in solid tumors.”
With increased genetic carrying capacity, the ability to mitigate toxicity, and significant cost-reduction advantages, what do non-viral vectors need to prove their worth?
“The cost is a very important factor. You have to think, when you’re moving patients in clinical, that is going to be a big advantage, because the cost is going to be reflecting the cost of therapy. The flexibility of the way you handle the plasmid is much easier, is safe with the CAR-T,” said Baffa. “The only piece that’s missing compared to the other vectors – especially the viral, of course – is the clinical experience.”