Drs. Verneris and Fry will also be a part of bringing those new treatments, including CD19, from academic supercenters like Children's Colorado to the patients who need them, wherever they are. Working within a consortium funded by the National Institutes of Health and the Clinical & Translational Science Institute, they're working to help smaller centers get CAR therapies online.
"Right now it's largely hub and spoke," Dr. Verneris says. "This work will help set up smaller pediatric hospitals that just don't have the staff at the moment to deal with the massive amount of regulation."
A collaboration to bring CAR-T cell biomanufacturing to the Anschutz Medical Campus
Brian M. Freed, PhD, drops a heavy binder on his desk. Its contents: about 800 pages of standard operating procedures for cell handling at ClinImmune, a transplant immunology lab just across the Anschutz Medical Campus from Children's Colorado.
As a facility that collects, processes, stores and matches stem cells used in bone marrow transplant for institutions all over the world, ClinImmune has infused cell products into thousands of patients. As its Executive Director, Dr. Freed is well familiar with the kind of paperwork that requires.
"This is one of three volumes," he remarks.
Infusing cell products into humans, on a procedural level, is incredibly complex. It requires a rigorous precision of equipment and expertise. That's particularly true for the manufacture of CARs.
"It's a patient-specific drug, there's HIV-based vectors and it involves genetic engineering," says Dr. Fry. "These are the components that make people nervous."
Located next door to ClinImmune, the Gates Center for Regenerative Medicine has been a leading stem cell research lab for more than a decade. Given that experience, the Gates Biomanufacturing Facility had good bones for Good Manufacturing Practice, or GMP, as it's known. They had the right equipment and facilities, and they had many of the right people.
What they lacked was the regulatory infrastructure, which involves paperwork — and people with the training to do it — on a mind-boggling scale. For that, they collaborated with ClinImmune, a lab intimate with cell-infusion's many regulatory demands.
The regulatory demands of cell therapy
"Batch records run 500 pages. There's a 400-page document just about training staff," says Dr. Fry. "It's thousands and thousands of pages.
"To be clear," he adds, "that's a good thing."
"If we infuse one of these products into a patient and 30 days later there's some adverse event, we want to know why," notes Tim Gardner, Gates Center's Chief Financial and Operations Officer. "Then we can look at the documentation and know everything there is to know about how it was manufactured: the humidity level in the room, the particle count, the people, the practices, the equipment, when it was last maintained and how. We have one person documenting for every person doing."
With five cell therapy suites, each of which can run different products, the Gates Center has capacity to do a lot. They'll produce cells for innumerable novel CAR therapies. Some of them — novel CARs targeting CD19 and CD22, another for CD33 and another for TSLPR — will come online in trials just this year.
"Our job is to set up a platform to allow efficient transfer from research to clinic," says Ryan Crisman, PhD, Gates's Director. In collaboration with Dr. Fry, Gates is positioned to manufacture cells for a wide array of future trials.
This year, they'll make CD19 for a trial that seeks to expand access to commercial therapy. As it stands, patients must have competed their first chemotherapy regimen, relapsed, and undergone and failed yet another round of "salvage" chemotherapy before they're eligible. Dr. Fry wants to see CD19 move up to the first relapse — maybe even, eventually, up front.
The happy accidents that push medicine forward
"We took all the time we needed to get this facility to the point where they could support multiple human trials," says Dr. Fry.