An improved stem cell-based CAR-T was able to give rise to more memory T cells, which could make the therapy more effective against tumors, researchers found. (luismmolina/iStock/Getty Images Plus).
Just over a year after ElevateBio and Boston Children’s Hospital joined forces to develop new cell and gene therapies, the two are back with a new spin-off company and new data showing the promise of standard CAR-T treatment.
Research produced in his laboratory found that scientists were able to develop a specific kind of stem cell-based allogeneic CAR-T with enhanced anti-tumor activities.
Chimeric Antigen Receptor T cells (CAR-T) are engineered T cells adapted to attack a patient’s cancer cells. Typically, a patient’s own immune cells are used to produce CAR-T, and then these modified cells are re-injected. These are autologous CAR-Ts: They can be effective, but they are also expensive and the manufacturing process is time-consuming.
These drawbacks have prompted the development of “conventional” CAR-Ts, which are derived from donor cells and can be manufactured in advance.
But the new paper notes that current T cells derived from stem cells are not mature enough to work as well as they could. To change this, the researchers knocked out EZH1, a gene that helps maintain the flexibility of stem cells to become a range of different cell types. The researchers wanted to prioritize maturation over flexibility.
With the gene knockout, stem cell T cells more closely resembled innate T cells and had better tumor-killing activity than non-knockout stem cells, according to the paper, which was lead by Ran Jing,
To verify this, the team used a mouse model to see how well the stem cells without EZH1 stacked. Immunodeficient mice were injected with diffuse large B-cell lymphoma (DLBCL) cells and then given three types of CAR-T. While CAR-Ts derived from EZH1-knockout stem cells could not completely eradicate tumor cells in any animal after seven weeks, stem cells lacking EZH1 function “induced complete remission in the majority of animals.”
Additionally, once activated, the modified CAR-Ts gave rise to more memory T-cell signature genes and low levels of cytotoxicity genes, the paper reported. These changes are valuable, the researchers said; earlier evidence suggests that the increase in memory T cells correlates with “superior” T-cell persistence. The authors suggest that this may be why the therapy worked better in mice.
“Therefore, the presence of a memory-like T cell subset may contribute to the enhanced persistence and antitumor activity of EZ-T cells in the DLBCL model,” they wrote.
Looking ahead, ElevateBio says the named company will have access to its technology, cell lines and manufacturing technology to produce the therapy. Daley will also remain an associate with the company moving forward.