As senior cancer executive at Bristol Myers Squibb, Kristen Hege oversaw the development of the cell therapy that will become Abecma is the first FDA-approved treatment for multiple myeloma made from a patient’s own T cellsThe drug comes after regulators approved Breyanzi, another BMS CAR T therapy. These drugs are made in the same way as other drugs: a patient’s T cells are collected, engineered and multiplied in the laboratory, and then infused into the patient. It’s been a long and expensive process, and one that Hege is working to improve.
Manufacturing a CAR T therapy can take up to two weeks. But the entire process, from collecting the T cells to infusing the engineered cells back into the patient — what the industry calls the vein-to-venous time — can take as long as a week on either end. That’s because engineering work is often done in labs at different locations, often in different states. Like any custom item shipped over long distances, shipping and handling can add to the time it takes to get the finished product to its destination.
BMS is trying to improve CAR T in a program called “NEX-T,” Hege explained in an interview with MedCity News World Medical Innovation Forum in Boston. While BMS is committed to improving the way it manufactures autologous cell therapies — therapies 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 still early days for approved autologous CAR Ts,” said Hege, senior vice president of early clinical development, hematology/oncology and cell therapy at BMS. “First-generation autologous CAR T manufacturing may not be ours. the best state for the future.”
Hege was first exposed to CAR T research in the mid-1990s. As an oncologist at UCSF, she helped launch the first CAR T clinical trial in solid tumors. Now at BMS, she oversees the early clinical development of a range of cancer treatments including cell therapy. The company describes NEX-T as a transformational change in manufacturing, driven by the translational insights it gleaned from treating thousands of patients with CAR T therapy. In addition to faster turnaround times, the strategy also aims to reduce costs throughout the process.
As a field, cell therapy is finding new ways to improve the way autologous therapies are made. Some of these innovations came from the University of Pennsylvania, which originally developed the first approved CAR T therapy, Novartis’ Kymriah. Penn Medicine recently launched a Shorten the manufacturing process Generate functional CAR T cells within 24 hours.That study is post February in Nature Biomedical Engineering.
BMS’ NEX-T study has shortened CAR T manufacturing to less than a week, Hege said. The company has found efficiencies in the way cells are collected and processed, reducing overall cell therapy manufacturing time. BMS also made some improvements to the cells to make more powerful CAR T products, she said. The result is cell therapy that is more durable, more powerful, and able to last longer. The hope is that these properties translate into longer-lasting efficacy, Hege said.
Data from more than 1,800 patients treated with the company’s first-generation CAR T drugs Breyanzi and Abecma informed the faster process. In addition to optimizing the functionality of the final product, a BMS has the goal of increasing the speed and efficiency of the manufacturing process, reducing costs while increasing throughput.
“We can begin to understand what are the phenotypic and functional properties of the starting material and the final CAR T process associated with favorable patient outcomes,” Hege said. “Now we’re applying it to optimization engineering, essentially the biology of next-generation products.”
In the longer term, BMS is pursuing allogeneic cell therapies made from engineered cells from healthy donors. These cells are not necessarily T cells. They may be gamma delta T cells or natural killer cells. BMS has sought out partners for this research. last fall, BMS commits $150 million to launch alliance with Century Therapeutics, a biotechnology for therapy by engineering induced pluripotent stem cells (iPSCs) into natural killer cells or T cells. These cells are engineered to be less likely to trigger an immune response or be rejected. They are also designed to have properties that make them more effective treatments.
One of the main goals of next-generation cell therapy is the treatment of solid tumors. CAR T therapies approved for blood cancers hit targets that are abundantly found in tumors, but less so in healthy cells. But for solid tumors, many of the good targets on the tumor are also present in healthy tissue. This means that for cell therapy to work against solid tumors, it needs to address a new target. The solid nature of solid tumors presents the challenge of “trafficking” – allowing therapy to penetrate the tumor to work. Cancer cells have the function of preventing immune cells from entering, Hege said. After penetrating cells, cell therapy must contend with the tumor microenvironment, which is an ecosystem of cancer cells brimming with immunosuppressive mechanisms.
Instead of tracking targets on the surface of cancer cells, as CAR T therapy does, another approach is to target intracellular antigens within cells. The approach is promising because solid tumors have more of these targets, Hege said. need to be able to do this, BMS has turned to Immatics’ technology to engineer T cell receptors (TCR) can hit these antigens. In addition to cell therapy for solid tumors, Hege said further engineering could be done to counteract the immunosuppressive forces of the tumor microenvironment.
Another strategy for BMS is to track both targets with monotherapy, thereby reducing the risk of tumors escaping treatment. Breyanzi, BMS CAR T therapy approved for diffuse large B-cell lymphoma, targeting the cancer protein CD19. The company’s other approved CAR T drug, Abecma, targets B-cell maturation antigens. In clinical trials, escapes from these therapies are rare, but tracking two targets with cell therapy may still be better than just one, Hege said. She added that BMS is pursuing a dual-target approach for both cancer proteins, but the company has not disclosed what those additional cancer targets are.
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