Jonathan D. Grinstein, PhD, the North American Editor of Inside Precision Medicine, hosts a new series called Behind the Breakthroughs that features profiles of the people shaping human healthcare. With each episode, Jonathan gives listeners access to their motivational tales and visions for this emerging, game-changing field.
While immunotherapies have been successful in treating cancer, their low response rates and risk of relapse limit the immunoncology approach. Then CAR Ts, the poster child of cell and gene therapy, ushered in a new era for cancer and, more recently, autoimmunity treatment.
However, cell and gene therapies, including CAR Ts, are still far from reaching their full potential due to many factors, including high cost, severely limiting the accessibility and industrialization of these potentially revolutionary therapeutic modalities. After all, what is the point of precision medicine if it only benefits a few people?
In this episode of Behind the Breakthroughs, Helen Sabzevari, PhD, president and CEO of Precigen, discusses the barriers to implementing cell and gene therapies that impede the accessibility and implementation of precision medicine. Sabzevari also explains how key cell and gene therapy platform tools can provide safety measures, such as guardrails to cellular toxicity, and address cost by offering “off-the-shelf” efficient gene delivery vectors that can be used on-site, cutting out centralized manufacturing.
This interview has been edited for length and clarity.
IPM: What led you to work on cell and gene therapy?
Sabzevari: Cell and gene therapies are, in my opinion, the future of precision medicine. There would be nothing else in the future. I believe that all of the issues that we are currently dealing with in terms of toxicities, incremental progress in treatments or the percentage of patients who benefit from them, and the high cost associated with our healthcare.
But the medicines we have only address a small portion of the population and provide no benefit to the majority. Meanwhile, health organizations must bear all of the costs associated with this because you are hoping that 20% of the patients will respond, but you do not know which 20% is generous. As a result, everyone receives this [treatment], and unfortunately, 80% of them do not respond and have extremely negative side effects, while the remaining 20% have adverse side effects but may benefit. This scenario cannot be continued.
That is why I truly believe that cell therapy is the way to go in the future. Simply put, precision medicine is at its best, developed for a patient and with that patient’s benefit in mind. It reduces, in my opinion, the rate of response as well as the toxicities and cost.
IPM: What technologies has Precigen developed to advance cell and gene therapies?
Sabzevari: When we started Precigen, we had two platforms. One of them was a gorilla adenovector platform. Humans don’t have pre-immunity to these viruses, which we’ve tested in thousands of healthy volunteers. They can be used for repeat dosing and have large capacities (up to 12 kb).
We decided that an ideal scenario for using the gorilla adenovector would be any indication that starts with an infection like HPV, which is continually present in the body. In order to clear it, you have to have a strong agent that really enhances the T cell numbers. We went with recurrent respiratory papillomatosis (RRP), a disease resulting from HPV.
Patients start developing benign tumors in the trachea and vocal cords, and there’s no real treatment except surgery. But that’s just like mowing a lawn—you cut it, and it pops back up. Some patients have had hundreds of surgeries in their lifetime. We designed a therapeutic vaccine to elicit immune responses directed against cells infected with HPV 6 or HPV 11
IPM: What is Precigen’s approach to CAR Ts?
Sabzevari: We didn’t want to go after the typical CAR T scenarios because there’s no way a company like Precigen can compete with pharma companies like Novartis and Gilead. The major issues with CAR T come down to manufacturing because you’re training your immune army outside the body to go in and find a specific cancer. However, the manufacturing is centralized, and there’s toxicity and high cost—$500,000 per shot is not sustainable. As a researcher and a drug developer, what bothers me the most is when a treatment can only be used to help a specific group that others don’t have access to. That’s now how medicine should be run.
IPM: How is Precigen making CAR Ts more cost-effective?
Sabzevari: We developed a cost-effective CAR T platform that has safety switches to eliminate the cells if anything goes wrong and can “manufacture” CAR Ts inside the body. When you need centralized manufacturing, you need four to six weeks. We developed a device that can electroporate four billion T cells of patients in under 15 minutes, and you can do this at the hospital.
When a patient walks into a hospital or cancer center and the oncologist diagnoses the patient with, let’s say, mesothelioma of the lung, the oncologist writes up a prescription for a CAR T. After apheresis, the technicians pull out one of these plasmids in the clean room and take the patient’s T cells into their system for electroporation. The cells get collected, put in the incubator, and left overnight, and the next day, the cells are infused in the patient with their own CAR Ts. If, for some reason, there is a relapse and a mutational change in the tumor, the process can be repeated with a different CAR T.
