PI3K Inhibitors Increased T-Cell Expansion Ahead of CAR-T Cell Therapy – Cancer Therapy Advisor

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 apatients own lymphocytes, which are genetically modified in a lab to express asynthetic antigen receptor that targets them to that patients own cancercells.

In order for CAR-T cells to be given topatients, they must expand in a lab for a period of 1 to 2 weeks, explainedstudy author Edmund K. Waller, MD, PhD, FACP, of Winship Cancer Institute,Atlanta, Georgia. In some patients who have had extensive prior chemotherapyexposure, their T cells do not grow to a satisfactory extent to allow them toreceive CAR-T.

Dr Waller worked with Christopher R.Funk, BS, a medical student at Emory, to define laboratory conditions thatcould enhance the expansion of T cells and generate more effective T cells foruse in CAR-T manufacturing.

Specifically, they explored the effect ofsmall-molecule inhibitors of the PI3 kinase to modify the behavior of T cellsduring laboratory expansion. This line of research was prompted by theclinical observation that patients treated with PI3 kinase inhibitors developedautoimmune disease as a side effect of drug therapy, Dr. Waller said. Wereasoned that PI3 kinase inhibitors might augment T-cell expansion when addedto cells in the laboratory.

The team showed that expansion of T cellscan be increased significantly when PI3K inhibitors idelalisib, a PI3K deltainhibitor, or duvelisib, a dual PI3K delta and gamma inhibitor, were added tothe culture.

In addition, they successfully expanded Tcells from lymphoma patients who were heavily pretreated with prior rounds ofchemotherapy and whose T cells would have ordinarily failed the manufacturingstep in CAR-T, Dr Waller said.

In these patients, PI3K inhibitorsincreased frequencies of CD8 cells and costimulatory molecule-expressing cells.The addition of idelalisib also resulted in a dose-dependent decrease in immunecheckpoint molecules LAG3, Tim-3, and PD-1.

Looking at the T-cell differentiationstate, the PI3K inhibitors increased the frequency of early, memory, andeffector memory cells. Finally, PI3K inhibitors also significantly increasedmitochondrial mass within total CD3 and CD8 subsets.

The end result is that we are able tomanufacture, in a shorter time, more potent T cells from patients who havereceived prior chemotherapy treatment, thus, facilitating CAR-T manufacturing,Dr Waller said.

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PI3K Inhibitors Increased T-Cell Expansion Ahead of CAR-T Cell Therapy - Cancer Therapy Advisor