Expansion of T cells collected for use with chimeric antigen receptor T-cell (CAR-T) therapy can be significantly increased when phosphoinositide 3-kinase (PI3K) inhibitors are added to the culture, according to data presented recently at the 34th Annual Meeting & Preconference Programs of the Society for Immunotherapy of Cancer, or SITC 2019.1
CAR-T cells are generated from a patient’s own lymphocytes, which are genetically modified in a lab to express a synthetic antigen receptor that targets them to that patient’s own cancer cells.
“In order for CAR-T cells to be given to patients, they must expand in a lab for a period of 1 to 2 weeks,” explained study author Edmund K. Waller, MD, PhD, FACP, of Winship Cancer Institute, Atlanta, Georgia. “In some patients who have had extensive prior chemotherapy exposure, their T cells do not grow to a satisfactory extent to allow them to receive CAR-T.”
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Dr Waller worked with Christopher R. Funk, BS, a medical student at Emory, to define laboratory conditions that could enhance the expansion of T cells and generate more effective T cells for use in CAR-T manufacturing.
Specifically, they explored the effect of small-molecule inhibitors of the PI3 kinase to modify the behavior of T cells during laboratory expansion. “This line of research was prompted by the clinical observation that patients treated with PI3 kinase inhibitors developed autoimmune disease as a side effect of drug therapy,” Dr. Waller said. “We reasoned that PI3 kinase inhibitors might augment T-cell expansion when added to cells in the laboratory.”
The team showed that expansion of T cells can be increased significantly when PI3K inhibitors idelalisib, a PI3K delta inhibitor, or duvelisib, a dual PI3K delta and gamma inhibitor, were added to the culture.
In addition, they successfully expanded T cells from lymphoma patients who were heavily pretreated with prior rounds of chemotherapy and whose T cells would have ordinarily failed the manufacturing step in CAR-T, Dr Waller said.
In these patients, PI3K inhibitors increased frequencies of CD8 cells and costimulatory molecule-expressing cells. The addition of idelalisib also resulted in a dose-dependent decrease in immune checkpoint molecules LAG3, Tim-3, and PD-1.
Looking at the T-cell differentiation state, the PI3K inhibitors increased the frequency of early, memory, and effector memory cells. Finally, PI3K inhibitors also significantly increased mitochondrial mass within total CD3 and CD8 subsets.
“The end result is that we are able to manufacture, in a shorter time, more potent T cells from patients who have received prior chemotherapy treatment, thus, facilitating CAR-T manufacturing,” Dr Waller said.
