Overcoming Barriers to Cellular Immunotherapy Manufacturing

Today's breakthroughs are ushering in a new era of precision medicine in the fight against cancer — and cellular immunotherapy is one promising pathway.

Researchers have made tremendous headway in lab settings. But despite some wins in the clinic, many questions remain about the process and workflows needed to translate research innovations to viable therapies.

Innovative technologies offer new hope on the frontiers of immunotherapy discovery and manufacturing. Here's what we know — and what's ahead.

The Manufacturing Time Crunch of CAR T

To date, the U.S. Food and Drug Administration has approved three chimeric antigen receptor T cell (CAR T) immunotherapies for B-cell cancers: axicabtagene ciloleucel (Yescarta), for lymphoma, in 2017; tisagenlecleucel (Kymriah), for leukemia and lymphoma, in 2018; and lisocabtagene maraleucel (Breyanzi), for lymphoma, in 2021.

Those approvals mark strides in cancer and immunotherapy research, but there's still a lot to learn, says Alejandro Montoya, M.Sc., a senior product line manager at Corning Life Sciences.

"CAR T cells have opened a new era in cancer immunotherapy," Montoya says. "But we're still in the infancy of this breakthrough technology. CAR Ts are being improved and enhanced to make them more robust, controllable, effective, and accessible — such as the ability to recognize more than one antigen at one time."

Despite the ongoing improvements in CAR T science, barriers in manufacturing and scale create new limitations. The cancer immunotherapy supply chain is delicate. It's reliant on apheresis (the extraction, isolation, and reinfusion of cells) but there's always a time crunch — namely, how fast a cancer is spreading.

"During the time between when a clinician draws a patient's blood and reinfuses it back as treatment, the disease can progress rapidly," says Ben Josey, Ph.D., a field application scientist at Corning Life Sciences. "And in the case of cancer, it can change. The faster you can get these treatments back to the patient, the higher the likelihood that it's going to be effective."

But the workflows are largely manual and time intensive. Lymphocyte isolation, for example, requires adding density gradient media — and it's not fully understood what effects, if any, that process has on cell phenotype. And samples need multiple rounds of centrifuging and washing. These tasks eat up lab resources, and they introduce the risk of human error.

Advances in Cell Processing Automation

New technologies in density gradient media-free automated cell separation may help solve some of these upstream challenges.

Systems such as the Corning® X-SERIES® platform streamline several key steps in cell isolation, separation, and formulation to make the process programmable, remove manual steps, and reduce the risk of human error and contamination.

Semiautomated systems might also prove effective. Corning's X-LAB® System, for example, tracks G-force and cell stratification until cells are separated. From there, valves open and the material moves into separate chambers. In studies, the platform removed 99% of red blood cells, compared to 97% using a manual lysis step (Corning Application Note: CLS-AN-583), Josey said.

"It's a sophisticated yet user-friendly platform," Montoya says. "You can easily add your whole blood samples to a disposable single-use cartridge and have centrifugation automated from there."

The system also transfers additional blood components like platelets into separate compartments as desired.

"It helps minimize the handling required during cell processing, supporting more efficient and reliableupstream manufacturing , since you're able to recover high amounts and highly definedcell populations of these very precious cells," Montoya adds.

Advances in other areas are also helping move CAR T therapies closer to clinical practice. Vector production via adherent culturing, for example, presents challenges of limited surface area. But with fully closed adherent vessel systems like Corning HYPERStack® Cell Culture Vessels, Corning® Automated Manipulator Platform System and Ascent™ Fixed Bed Reactor (FBR) System, researchers can achieve greater scale in a smaller space and with fewer people.

Pushing What's Possible in 3D Cell Culture

Even with new manufacturing tools and technologies, CAR T therapies and applications have yet to break out of blood cancers and into solid masses. Solid tumor cancer environments are often hypoxic, acidic, and immunosuppressive — a difficult environment for T cells.

But promising new opportunities in 3D cell culture could accelerate discoveries and scale-up. Tumor spheroids, which more closely resemble in vivo biology than typical 2D cultures, have shown promise with CAR T cell approaches by helping researchers analyze the effects of reengineered T cells in a high-throughput environment aided by Corning® spheroid microplates. Combined with automated and semiautomated systems, these technologies could help researchers do more screening in less time.

Continued research will advance the cancer care narrative even further, with the hope that someday we could be looking at cancer's end.