Modified T Cells Survive Over Decade

Persistence of chimeric antigen receptor T cells in HIV trials may point toward better immunotherapy for cancer

In chimeric antigen receptor (CAR) T-cell treatment, a form of adoptive cell transfer immunotherapy, 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.

Although clinical trials generally have shown very limited persistence of CAR T cells in patients, such reengineered cells targeting the HIV envelope protein have now been found to survive for more than 10 years. The research highlights the approach's promise for treating cancer and other diseases as well, says Bruce Levine, PhD, associate professor at the University of Pennsylvania (UPenn) in Philadelphia.

Among 43 patients enrolled in studies between 1998 and 2002 who were given the anti-HIV CAR T cells, all remain healthy, says Levine, co-author of an article in Science Translational Medicine. Blood samples demonstrated that the reengineered cell population persists in 41 of the patients, and statistical modeling estimated that more than half of the modified T cells or their descendants will remain alive 16 years after infusion.

Last year, UPenn researchers reported early findings for another CAR T-cell trial, this one treating patients with chronic lymphocytic leukemia (CLL), a B-cell cancer, with a “third-generation” CAR T-cell approach. For this study, CD4⁺ T cells were reengineered to bind to the CD19 protein, which is found on normal B cells and plasma cells. In early results, 2 of 3 patients with CLL achieved complete remission. Analyses revealed that the number of cells expanded more than 1,000-fold and that some of the cells persisted as memory T cells.

Some of these CD19 memory T cells maintain robust function for at least 18 months, said Carl June, MD, UPenn professor and senior author on both papers, at a presentation during the American Association for Cancer Research Annual Meeting 2012 in April.

The HIV and CLL studies indicate that T cells may be particularly promising targets for gene therapy in diseases of the blood because they minimize adverse events, says Levine, who is a longtime collaborator with June. “Unlike hematopoietic stem cells, T cells are terminally differentiated immune cells that have undergone gene rearrangement to produce the diverse repertoire of T-cell receptors,” he notes. Competition among T cells for niches related to specific receptors may maintain this diversity while avoiding genotoxicity.

UPenn scientists also emphasized that in the HIV trials, unlike common practice in other HIV and leukemia therapies, patients did not have their lymphocytes destroyed by chemotherapy or radiation prior to treatment. “We now have reason to believe that lymphodepletion may not always be necessary in cancer, and may depend on disease burden, CAR design, ex vivo culture conditions, or other factors,” Levine says.