As a top cancer executive at Bristol Myers Squibb, Kristen Hege oversaw development of the cell therapy that would become Abecma, the first FDA- approved treatment for multiple myeloma that’s made from a patient’s own T cells. That drug followed the regulatory nod for another another BMS CAR T therapy, Breyanzi. Those drugs and others in this class are made the same way: a patient’s T cells are collected, engineered and multiplied in a lab, and then reinfused into the patient. It’s a lengthy and expensive process, and it’s one that Hege is trying to improve.
Manufacturing CAR T therapies can take up to two weeks. But the entire process, from when T cells are collected to the infusion of the engineered cells back into the patient—what the industry calls vein to vein time—can add up to a week on either end. That’s because the engineering work is typically done in a lab that’s at a different site, often in a different state. Just like any bespoke good transported across a distance, shipping and handling adds to the time it takes to get a finished product to its destination.
BMS is trying to improve CAR T in an initiative it calls “NEX-T,” Hege explained to MedCity News in an interview at the World Medical Innovation Forum in Boston. While BMS pursues this effort to improve the way it manufactures autologous cell therapies—treatments made from a patient’s own immune cells—Hege said the company is also developing a new generation of off-the-shelf therapies.
“It’s important to point out that it’s early days for approved autologous CAR T,” said Hege, BMS’s senior vice president of early clinical development, hematology/oncology & cell therapy. “This first generation of autologous CAR T manufacturing is probably not what we would consider a future optimal state.”
Hege first encountered CAR T research in the mid-1990s. As an oncologist at the University of California, San Francisco, she helped launch the first CAR T clinical trial for solid tumors. Now at BMS, she oversees early clinical development of a range of cancer treatments, including cell therapies. The company has described NEX-T as changes to manufacturing driven by the translational insights it has gleaned from treating thousands of patients with its CAR T therapies. In addition to a faster turnaround time, the strategy is intended to reduce the costs of the overall process.
As a field, cell therapy is moving finding new ways to improve the way autologous therapies are manufactured. Some of that innovation is coming from the University of Pennsylvania, where the first approved CAR T treatment, the Novartis therapy Kymriah, was initially developed. Penn Medicine recently unveiled a shortened manufacturing process that yields functional CAR T cells in 24 hours. That research was published in February in Nature Biomedical Engineering.
The NEX-T research of BMS has shortened CAR T manufacturing to less than one week, Hege said. The company found efficiencies in how cells are collected and processed, shortening the overall cell therapy manufacturing time. BMS has also made some enhancements to the cells in order to produce a more functional CAR T product, she said. The result is a cell therapy that is more durable, more functional, and has the ability to last longer. Hopefully, these properties translate to more durable efficacy, Hege said.
The speedier process is informed by data from more than 1,800 patients treated with the company’s first-generation CAR T drugs, Breyanzi and Abecma. In addition to optimizing the function of the end product, BMS also has a goal of improving the speed and efficiency of the manufacturing process, which increases the capacity while also lowering cost.
“We can begin to understand what are the phenotypic and functional properties of the starting material and the final CAR T process that are associated with favorable patient outcomes,” Hege said. “Now we apply that to optimize the engineering, and in essence, the biology of next-generation products.”
Longer term, BMS is pursuing allogeneic cell therapies made by engineering cells from healthy donors. The cells don’t have to be T cells. They could be gamma delta T cells or natural killer cells. BMS has turned to partners for this research. Last fall, BMS committed $150 million to kick off an alliance with Century Therapeutics, a biotech that makes its therapies by engineering induced pluripotent stem cells (iPSCs) into natural killer cells or T cells. Those cells are engineered so that they are less likely to prompt an immune response or be rejected. They’re also engineered to have properties that make them more effective therapies.
One of the key goals for the next-generation of cell therapies is treating solid tumors. CAR T therapies approved for blood cancers hit targets that are found in abundance on tumors but less so in healthy cells. But for solid tumors, many of the good targets on tumors are also found in healthy tissue. That means that for a cell therapy to work on a solid tumor, it needs to address a novel target. The solid nature of solid tumors poses a “trafficking” challenge—getting the therapy to penetrate into the tumor to do its work. Cancer cells have features that keep immune cells out, Hege said. After penetrating a cell, a cell therapy must then contend with the tumor microenvironment, the ecosystem of a cancer cell that is filled with immunosuppressive mechanisms.
Rather than going after a target on the cancer cell’s surface the way CAR T therapies do, an alternative approach is to target intracellular antigens within a cell. This approach is promising because there are many more of these targets for solid tumors, Hege said. To do that, BMS has turned to the technology of Immatics, which is engineering T cell receptors (TCRs) that can hit those antigens. Beyond getting a cell therapy into a solid tumor, Hege said that further engineering can be done to counteract the immunosuppressive forces of the tumor microenvironment.
Another strategy that BMS is going after two targets with a single therapy, reducing the risk that a tumor escapes from the therapy. Breyanzi, the BMS CAR T therapy approved for diffuse large B cell lymphoma, targets the cancer protein CD19. The company’s other approved CAR T drug, Abecma, targets B-cell maturation antigen. Hege said that the frequency of escape from those therapies was low in clinical trials, but it’s still possible that going after two targets with a cell therapy is better than just one. She added that BMS is pursuing dual target approaches for both cancer proteins, but the company has not disclosed what those additional cancer targets are.
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