EBAG9 Silencing Boosts Adoptive T Cell Therapy

Researchers in Berlin who previously showed that shutting down a certain gene in mice led to sustained immune response to cancer following immunotherapy have gone on to demonstrate the strategy’s viability in human cells. The latest findings, published recently in the journal Molecular Therapy, could inform treatments that achieve longer-lasting therapeutic success or even a “real chance of a cure.”

As the guards of our immune system, T cells are on permanent patrol in our blood vessels and tissues, where they hunt down foreign structures. Equipped with chimeric antigen receptor (CAR), T cells can also detect very specific surface structures on cancer cells. For patients with lymphoma, multiple myeloma, or certain types of leukemia, CAR T treatment is sometimes the last chance of overcoming the cancer. The treatment involves taking T cells from the patient’s blood and adding artificial CARs receptors to them in the lab.  Once the CAR T cells are returned to the patient by infusion, they circulate in the body as a kind of living drug that can bind to very specific tumor cells and destroy them. The engineered immune cells remain in the body permanently and multiply. If the cancer flares up again, they’ll go back into action. 

In practice, however, many patients still relapse. This is because the tumor cells can outwit the CAR T cells by producing more of the protein EBAG9 and by causing the T cells to produce more of it, too. In T cells, EBAG9 inhibits the release of cytotoxic enzymes, which slows the desired immune response.

A month earlier, a team led by authors Dr. Armin Rehm and Dr. Uta Höpken from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) showed in the journal JCI Insight that shutting down the EBAG9 gene in mice led to a sustained increase in the immune response to cancer. The mice also developed more T memory cells, which allows our immune system to respond better to a cancer antigen after encountering it previously.

Now the researchers have also demonstrated these findings in vitro, in human CAR T cells. The team says that this is the decisive step on the road to therapeutic use. “Shutting down EBAG9 allows the body to eradicate tumor cells earlier and more radically,” according to the authors.

The MDC team had also found in 2009 that mice without the EBAG9 gene dealt with bacterial and viral infections much better than mice with the gene, and that they formed more T memory cells, which are of particular interest in tumor biology. In 2015, lead author Dr. Anthea Wirges succeeded in curbing synthesis of the EBAG9 protein using microRNA. For the latest study, she used microRNA to cultivate “EBAG9-silenced” CAR T cells with different human leukemia or lymphoma cells. Just like in the mouse model, the silencing reduced tumor growth much more. Relapses also only developed much later.

“Releasing the EBAG9 brake allows the genetically engineered T cells to release more cytotoxic substances. However, they don’t cause the strong cytokine storm that is typically a side effect of CAR therapy,” says Wirges. In fact, the risk is minimized because fewer cells are used. “Switching off the immune brake works across the board. We can do it with every CAR T cell that we produce—regardless of which type of blood cancer it targets.”

However, the first-line therapy for blood cancer will remain chemotherapy combined with conventional antibody therapy, as many patients respond very well to this. “CAR therapy only comes into play if the cancer returns. It’s very expensive because it’s an individual cellular product for a single person,” says Höpken. However, this single treatment can save a life.

Thanks to their findings from animal models and the in vitro experiments using human cells, the team now knows that releasing the EBAG9 brake is highly effective and doesn’t cause any more side effects than conventional CAR T therapy. “We now need bold clinicians and a partner for financing the clinical studies,” says Rehm.

The researchers will also present their concept to the Paul Ehrlich Institute, Germany’s biologics approval agency, in November.

If everything goes well, the therapy using EBAG9-silenced CAR T cells could be available to patients in as little as two years’ time.