CAR T-cell immunotherapy is a powerful approach for treating certain leukemias and lymphomas, but it’s unavailable for many patients who need it. A new technique developed by Harvard Medical School and Boston Children’s Hospital researchers could make CAR T-cell therapy more widely accessible.
Killer T cells (green and red) surround a cancer cell (blue, center). Image credit: Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths/National Institutes of Health
Findings are described in Cell Stem Cell.
In CAR T-cell therapy, T cells from a patient’s own blood are engineered to carry so-called chimeric antigen receptors, or CARs, that enhance the T cells’ ability to attack and kill tumor cells.
It can be difficult to gather enough functional T cells from patients’ blood, and manufacturing CAR T cells for each individual patient is expensive and takes time—time patients may not have on their side.
The new technique—developed by the lab of George Q. Daley, a member of the Boston Children’s Stem Cell Program and the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, and colleagues—uses induced pluripotent stem cells (iPS cells) to make generic CAR T cells that could be produced at scale for use in multiple patients.
“We show that generic iPS cells can be converted to CAR T cells not only more efficiently, but more effectively—creating an enhanced CAR T cell that more faithfully resembles the gold-standard clinical-grade cells we currently use,” said senior author Daley, who is also the Caroline Shields Walker Professor of Medicine in the Blavatnik Institute at HMS, dean of HMS, and professor of pediatrics at Boston Children’s. “Our strategy could enable ‘off-the-shelf’ CAR-T therapies and help more patients access these treatments.”
Enhanced antitumor activity
While iPS cells are, in theory, a limitless source of different cell types, Daley, first author Ran Jing, research fellow in pediatrics at Boston Children’s, and 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 clear cancer cells in live mice compared to T cells made with prior iPS-cell methods.
“After many years of promise, it seems that iPS cells are finally yielding new therapeutic approaches to treating diseases like cancer,” said Daley.
Disclosures, funding, and authorship
Boston Children’s and ElevateBio, a technology-driven company focused on cell and gene therapy development, are forming a new company (not yet named) around the technology.
Source: HMS