A Columbia Group Puts CAR T Cell TNF Upstream of the Macrophages That Drive Cytokine Release Syndrome

An upstream signal the 2018 model had ruled out

In June 2018 the same laboratory published a murine CRS model in Nature Medicine that developed within two to three days of CAR T infusion, proved lethal at high tumor burden, and responded to IL-6 receptor blockade. Its conclusion was that severity was "mediated not by CAR T cell-derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages." Giavridis led that work from Sadelain's laboratory at the Sloan Kettering Institute. The 2026 paper reverses that order: a cytokine made by the engineered cells sits above the macrophage compartment that produces the effectors, which makes the infused product itself a point of intervention rather than only a trigger.

Antitumor activity goes unmentioned in the abstract

The abstract describes TNF as acting before the host cytokines that clinicians measure, promoting macrophage accumulation at the tumor site and inducing IL-6 and IL-1 beta downstream. That places the decisive event inside the first days, at a tissue site rather than in the circulation. Two things the abstract does not report matter for anyone weighing the finding: whether disrupting TNF preserved the antitumor activity of the CAR T cells, and whether any patient samples were examined alongside the mouse work. Neither appears in the summary, and the subscription wall at AAAS blocked the methods and figures.

TNF blockade is absent from the CADTH options

A Canadian rapid review published in May 2024 as CADTH report RC1534 set out the options in use. Tocilizumab, an anti-IL-6 receptor antagonist, carries FDA and Health Canada approval for severe or life-threatening CRS. Corticosteroids play an important role in CRS management and are the mainstay for immune effector cell-associated neurotoxicity syndrome. The anticytokine drugs the review examined were tocilizumab, anakinra and siltuximab. TNF blockade was not among them.

Why This Matters to the APO|APE Reader

Giavridis now lists OverT Bio in New York on the byline, which puts one author of both the 2018 and 2026 papers inside a company whose business is engineered T cells. An upstream cytokine made by the infused product can be blocked with a second antibody at the bedside, or removed from the cell during manufacture, and those two routes answer to different regulators, different release specifications and different reimbursement. A blocking antibody can be withheld from a patient whose disease is responding. A cell engineered to make less TNF cannot be un-engineered after infusion.