Driving Ahead with CAR T Cells

Chimeric antigen receptor (CAR) T-cell therapy “is poised for explosive growth,” said Angela Shen, MD, of Novartis in East Hanover, NJ. “However, doing this requires a totally different new model for drug development.”

Shen, global clinical program head for a Novartis-University of Pennsylvania collaboration on the CTL019 CAR T-cell therapy, was among several experts describing challenges and opportunities for CAR therapies at a session during the American Association for Cancer Research Annual Meeting 2013.

Designed to overcome immune tolerance of tumors, CAR T cells are a form of adoptive cell transfer immunotherapy in which a patient's T cells are genetically modified to attack diseased cells by expressing a chimeric protein that couples a targeted antibody-binding domain on the cell surface with stimulatory domains inside the cell that activate its response.

In small early trials, CAR T-cell treatments targeting CD19 recently achieved complete remission in patients with relapsed and aggressive B-cell malignancies. March 2013 saw publication of one study treating 2 children with acute lymphoblastic leukemia (ALL), led by Carl June, MD, of the University of Pennsylvania's Abramson Cancer Center in Philadelphia (New Engl J Med 2013;368:1509–18) and another study treating 5 adults with ALL, led by Michel Sadelain, MD, PhD, of Memorial Sloan–Kettering Cancer Center in New York, NY (Sci Transl Med 2013;5:177ra38).

However, moving forward with these individualized, genetically engineered therapies will differ sharply from normal drug development and approval processes, noted Ke Liu, MD, PhD, director of the Oncology Branch in the Office of Cellular, Tissue, and Gene Therapies at the U.S. Food and Drug Administration's Center for Biologics Evaluation and Research.

Liu pointed to issues in choosing optimal targets, patients, and trial endpoints; monitoring and tracking CAR T cells in vivo; and managing common, severe adverse reactions.

Such issues help to explain why drug companies have been reluctant to buy into the approach. “I can't think of another type of drug that has gone so far into development in a purely academic setting,” June remarked.

Publication of the University of Pennsylvania group's 2011 NEJM paper (N Engl J Med 2011;365:725–33), demonstrating remission in a patient with refractory chronic lymphocytic leukemia, however, represented a turning point for industry involvement, Shen suggested.

The partnership with Novartis began last year, kicking off with CTL019. “Tremendous resources have been committed,” said Shen, including her firm's December purchase of a 173,000-square-foot cell processing plant in New Jersey.

The project has moved quickly, enrolling patients for a phase II trial in January. “There are plans to initiate global trials in B-cell malignancies,” Shen said. “These will be adaptive clinical trials; the product can be improved in real time during development.”

Many research questions are open on CAR T-cell therapy, such as optimal dosages, when (and eventually whether) to move patients on to bone marrow transplants after immunotherapy, and how patient selection will be affected by tumor stage, tumor bulk, and therapeutic history.

Additionally, regulatory requirements for such treatments vary internationally and are rapidly evolving, Shen pointed out.

Perhaps most dauntingly, “the logistics are incredibly complex,” Shen commented. The requirements range from establishing a leukapheresis network to finding or creating vector manufacturing and cell processing sites to handling a “chain of custody” throughout all transfers of the manufactured individualized product to creating a network of trusted sites to manage acute adverse events.

Despite all these obstacles, the case for accelerating work on CAR T-cell therapy seems clear, remarked William Sellers, MD, PhD, vice president and global head of oncology at Novartis Institutes for BioMedical Research in Cambridge, MA. “It has the potential to cure cancer,” Sellers said. “This is pretty rare.”

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