Stem cells combat CAR-T cytokine release in mice

IV drugs
Administering stem cells along with CAR-T cancer treatments may help ameliorate a dangerous side effect, Cynata Therapeutics is reporting. (Getty/bee32)

One of the biggest advances in immuno-oncology over the last year has been the FDA approval of CAR-T personalized cell therapies to treat blood cancer. But these treatments can result in cytokine release syndrome (CRS), a severe immune reaction marked by rashes, fever and neurological symptoms. Now an Australian biotech is reporting promising early results from a mouse trial of mesenchymal stem cells designed to mute severe CRS reactions to CAR-T treatments.

Scientists at the company, Melbourne-based Cynata Therapeutics, use a technology called Cymerus to manufacture mesenchymal stem cells (MSCs) from induced pluripotent stem cells and precursor cells called mesenchymoangioblasts. This allows them to create off-the-shelf MSCs rather than having to rely on donor cells from bone marrow, fat and other tissues. Cynata enlisted researchers at the University of Massachusetts Amherst to test the stem cells in mouse models of human CRS.

They found that the MSCs protected mice from the effects of CRS, producing “consistent and significant decreases in body temperature” and increases in cellular markers of beneficial immune activity, the company announced.

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The researchers tested their cells in eight different treatment settings, comparing the treated mice to animals that received no therapies. They created the mouse model of human CRS by administering an anti-human CD3 antibody by injection. Then they tested the effects of administering the MSCs as soon as 30 minutes after injection and at various time points up to 5 hours later. Some animals received the cells intravenously, while others had them injected into the lining of the abdominal wall.

IV administration produced a more potent effect on cytokine reduction, the company said, though both methods were effective at reducing symptoms of CRS. And 24 hours later, the treated animals showed statistically significant improvements in symptoms with just one dose of MSCs.

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Cynata’s vice president of product development, Kilian Kelly, Ph.D., said in the release that CAR-T treatments are “potentially curative” but that “CRS is a common, unpredictable and potentially fatal complication that may limit treatment uptake.”

Indeed, finding new ways to prevent CRS or limit its severity has been a priority in the field of immuno-oncology ever since the first two CAR-T treatments, Novartis’ Kymriah and Gilead’s Yescarta, were approved for the treatment of some blood cancers. In June, two separate research teams published studies suggesting that the rheumatoid arthritis drug Kineret, originally developed by Amgen, could limit the effects of CRS or stop it altogether. The drug works by inhibiting IL-1, an inflammatory cytokine, and it has the ability to penetrate the brain, which may make it more effective than the IL-6-blocking drug that’s currently approved to treat CRS.

Scientists at the Fred Hutchinson Cancer Research Center have identified biomarkers to predict CRS severity and are working on a variety of tools to make CAR-T treatments safer, including using nanoparticles to remove genes from T cells that would normally prompt them to attack healthy cells.

Cynata’s scientists believe their MSCs may be able to be administered along with CAR-T treatments or shortly afterward to limit the effects of CRS. It is currently seeking partnerships with other companies that are developing immunotherapies “to explore the benefits of our MSCs in humans,” Kelly said.