Ready-made CAR T Cells

New method could allow scaled-up production of generic cells for cancer immunotherapies

By NANCY FLIESLER | Boston Children’s Research

3 min read

microscope image shows three green-outlined cells surrounding a round blue cell against a dark backdrop
Killer T cells (green and red) surround a cancer cell (blue, center). Image: Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths/National Institutes of Health

CAR T-cell immunotherapy is a powerful approach for treating certain leukemias and lymphomas, but it’s not available for many patients who need it. A new technique developed by researchers at Harvard Medical School and Boston Children’s Hospital could make CAR T-cell therapy more widely accessible.

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Findings are described Aug. 4 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.

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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.

After many years of promise, it seems that iPS cells are finally yielding new therapeutic approaches to the treatment of diseases like cancer.

George Q. Daley

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.

“After many years of promise, it seems that iPS cells are finally yielding new therapeutic approaches to the treatment of 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.

Other authors from HMS and Boston Children’s are Mohamad Najia, Areum Han, Michael Sanborn, Trevor Bingham, Caroline Kubaczka, Deepak Jha, Thorsten Schlaeger, Trista North, and Marcela Maus. Additional authors are affiliated with Massachusetts General Hospital Cancer Center, MIT, the Broad Institute of MIT and Harvard, and Federal University of Santa Catarina in Brazil. A full list can be found in the paper.

The study was supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (U01HL134812, 5U24HL134763 subaward 1701192), the National Institute of Diabetes and Digestive and Kidney Diseases (2U01DK104218), and the Emerson Collective Cancer Research Fund.

Adapted from a Boston Children’s news release.