CliniMACs Prodigy system in the Frederick National Laboratory's CAR T cell therapy production suite.
Closeup of a Miltenyi CliniMACs Prodigy system. The chamber at the lower left is where the patient's original T cells are washed and then transduced with a viral vector that carries the gene for the CAR, and where the resulting CAR T cells are cultivated to produce millions more. The yellow pump in the center drives liquid flow through the system. The numbered knobs are valves that direct liquids and gases through the tubing. Valve 22 controls the tubing connected to the “harvest bag,” which collects the CAR T cells when they are ready. The yellow box to the right holds a magnet and column that separate T cells from other immune cells.

The Biopharmaceutical Development Program (BDP) at Frederick National Laboratory is engineering cells into cancer-killers that are being used to treat children and young adults participating in early-phase pediatric cancer trials. 

The treatment is called chimeric antigen receptor (CAR) T cell therapy. CAR T cells are a type of white blood cell that has been removed from the patient in a process called apheresis and genetically altered to recognize a specific protein on the surface of the patient’s cancer cells. They’re multiplied and then infused back into the patient, where they seek out the tumor cells, bind to them using their CAR, and destroy them.  

BDP’s CAR T-cell therapy production program, now in its third year, is focusing on designs to treat two types of cancer: CD33 CAR T cells for pediatric acute myeloid leukemia and GD2 CAR T cells for pediatric osteosarcoma and neuroblastoma. 

BDP’s support to these clinical trials makes a difference in the speed at which the two therapies can be assessed for safety and appropriate dosing; approved for further trials; and, with positive results, licensed by the FDA, said George Mitra, Ph.D., BDP director. 

There are many clinical trials, worldwide, testing CAR T-cell therapies in small numbers of patients with specific cancers at a single medical facility. For these, a hospital clinician collaborates with a head scientist in a laboratory. 

However, for a CAR T-cell therapy product to become licensed, it needs broad results. “You need to look at a lot of different patient populations, and usually that is not feasible with single-center studies,” said Mitra. 

The CD33 CAR T and GD2 CAR T trials began at single clinical sites but, with BDP’s support, expanded to others: the Children’s Hospital of Philadelphia, the National Cancer Institute, Dana-Farber Cancer Institute, Seattle Children's Hospital/Fred Hutchinson Cancer Research Center, Children's Hospital Los Angeles, and Children's Hospital Colorado. 

Jason Yovandich, Ph.D., chief of the Biological Resources Branch in the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis, the group that funds and coordinates BDP’s participation in these and other early-phase trials, sad that as of early November 2022, BDP had produced 21 CD33 CAR T doses and that 16 patients had received their infusions. BDP had also produced three GD2 CAR T doses, two of which had been administered to their patients.

‘Getting things right the first time’ 

Four people in safety gear working the Frederick National Laboratory's CAR T cell therapy production suite.
BDP uses Miltenyi CliniMACs Prodigy systems in their CAR T-cell therapy production suites. BDP staff to the left are monitoring a Prodigy system during CAR T-cell cultivation. BDP staff to the right are scanning a barcode to load a tubing set onto a Prodigy system, preparing to start a CAR T-cell production run

The young people participating in these trials have cancers that either relapsed or didn’t respond to traditional treatments in the first place. They’re in a vulnerable state of health and may be able to give only one apheresis sample for BDP to work with. 

Julie Blake, BDP manufacturing manager, said that means BDP focuses on “getting things right the first time” throughout the CAR T-cell production process.  

The program maintains a carefully documented chain of custody and identity for the sample and resulting therapy. 

The sample arrives at BDP, deep-frozen at −150 °C, in a specialized shipping vessel equipped with GPS tracking software. Later, the finished CAR T therapy dose returns to the clinic in the same vessel. At least two staff from production and quality assurance (QA) witness and record each sample’s arrival to ensure that it’s properly documented. 

“Since this is an autologous product, it’s important that we're checking and verifying the details” at every step, said Marie Elena Fraley, BDP QA manager. (An autologous product is made from the patient who’s receiving it.) 

Production and QA staff also record and witness every key point in the engineering process. “We don't do anything without two people,” said Blake. “You always have somebody performing and somebody verifying.” 

Quality control (QC) performs the assays to guarantee each production run is right. “The objective is to be sure that everything is safe and to characterize what we've actually produced,” said Brian Bowser, Ph.D., BDP QC manager. “We have to get the right answer, but we have to get it quickly.” 

With a patient waiting back at the clinic, time is certainly of the essence. BDP aims to produce and return the CAR T-cell therapy dose to the trial site within 14 days of receiving the patient’s sample. 

Democratizing CAR T cell therapy development 

Despite growing interest in CAR T-cell therapy for cancer, developing and producing one is quite expensive. A single dose of some FDA-approved treatments costs nearly half a million dollars, a considerable obstacle to the development of new therapies. 

However, “NCI seeks to democratize the process for bringing new CAR T cell therapies to cancer patients,” said Mitra. Thanks to special NCI programs, researchers and physicians who have established proof of concept can gain access to resources like the BDP to test their novel CAR T-cell therapies in multicenter trial settings. 

BDP then develops the production processes for the new CAR T-cell therapies and shepherds them through the process to obtain FDA approval for clinical trials. 

BDP’s production schedule is busy, and it’s expected to get busier. BDP has initiated and secured approval for projects involving CAR T-cell therapies to treat prostate cancer and mesothelioma, and staff anticipate more new projects soon. 

Story revised 12/19/22 to reflect updated CAR T cell therapy production and infusion numbers.

Media Inquiries

Mary Ellen Hackett
Manager, Communications Office