Better, ready-made CAR T cells for cancer immunotherapy

A technique developed by the lab of George Q. Daley, MD, Ph.D., in the Boston Children's Hospital Stem Cell Program, could make CAR T-cell therapy more widely accessible.

It can be difficult to gather enough functional T cells from a patient's blood, and manufacturing CAR T cells for each individual patient is expensive and takes time — time patients may not have on their side. Using induced pluripotent stem cells (iPS cells), Daley and his colleagues developed a method to make generic CAR T cells that could be produced at scale for use in multiple patients.

While iPS cells are, in theory, a limitless source of different cell types, Daley, first author Ran Jing, Ph.D., and their colleagues had to overcome the challenge of deriving mature, fully functioning T cells from which CAR T cells could be made. In the past, researchers have struggled with this because of the tendency for iPS cells to produce immature, embryonic cells in the Petri dish.

Looking at epigenetic factors involved in blood development, the team zeroed in on the enzyme EZH1, which restricts the differentiation of mature lymphoid cells. Suppressing EZH1, they found, gave iPS cells the ability to make mature T cells. The team also developed a culture system that avoids co-culture with mouse-derived cells, which is cumbersome and yields T cells that aren't sufficiently mature.

When the iPS-cell-derived T cells were further transformed into CAR T cells, they showed anti-tumor activity comparable to that of CAR T cells derived by methods currently used for clinical therapies. These new cells had an enhanced ability to kill cancer cells in the lab and to clear cancer cells in live mice when compared to T cells made with prior iPS-cell methods.

Ref:

Ran Jing, George Q. Daley et. al, EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity, Cell Stem Cell, 4-Aug-2022, DOI: 10.1016/j.stem.2022.06.014,