Nicholas Restifo, Chief Medical Officer at Medici Therapeutics, shared on LinkedIn about a recent paper by Rigel J. Kishton et al. published on Nature:
“T Cells a Private Line: Rewriting Cell Therapy with IL-9/IL-9R
Instead of shouting at the whole immune system, imagine whispering to only the tumor-killing cells. That’s the idea: a private, non-cross-reactive cytokine signal that boosts the right T cells without collateral chaos. (If you remember “orthogonal” from geometry, think independent here.)
At the forefront are Anusha Kalbasi and Chris Garcia. In two recent papers they move from synthetic orthogonality to native near orthogonality in engineered T cells.
Then – Nature 2022:
A synthetic o9R switch (oIL-2Rβ-ECD + IL-9R-ICD) lets an orthogonal IL-2 variant drive a STAT1/3/5 program. Result: Tscm-like persistence with effector punch and strong tumor control in mice – even without lymphodepletion (preclinical). (We discussed this in a Kishton & Restifo commentary.) https://lnkd.in/epA9E67E
Now – bioRxiv 2025:
Leverage biology’s selectivity: engineer T cells with wild-type IL-9R and dose IL-9. Because IL-9R is scarce in normal tissues, IL-9 acts like a private line to engineered cells.
Versus o9R, IL-9R + IL-9 shows stronger JAK/STAT, adds STAT4 (IL-12-like), deeper infiltration, more stemness, and better tumor control – with repeat IL-9 pulses → repeat expansion peaks, and efficacy at lower cell doses (preclinical, incl. human CAR-T in NSG). They used a mouse-albumin–IL-9 fusion to extend half-life (a human-albumin version is the translational path), though anti-drug antibodies (ADA) remain a watch-item.\
It’s the STAT recipe, not ‘more signal.’
There’s a Goldilocks zone: both attenuation and over-amplification of proximal IL-9R signaling hurt efficacy. STAT1 is the rheostat – low pSTAT1 → proliferative/stem-like; high pSTAT1 → terminal/dysfunctional. Best outcomes sit mid-pSTAT1 with a balanced STAT1/3/4/5 mix.
Why this is important
- A druggable, outpatient-friendly control knob for TIL/NeoPBL/CAR-T that may enable no/low-LD regimens.
- Cleaner, selective expansion of the cells that do the work.
Caveats (the human reality):
- Safety first: IL-9 in humans is unproven; ADA is possible, and IL-9R appears in lung, a tough combo given TIL/IL-2-like capillary-leak risk.
- No-LD reality check: intact immunity can mean poor engraftment, innate clearance, and bystander IL-9R upregulation in inflamed tissue.
- Scale gap: what blooms at 0.5M cells in mice can sputter in a 90-kg adult on steroids with scarred marrow and comorbid lungs.
- Finding Goldilocks isn’t obvious: use step-up IL-9 dosing with hard PD gates (infused-clonotype expansion, ctDNA drop, pSTAT signatures) before escalating.
Bottom line: the field is shifting from more cells to smarter, younger, more controllable cells.
Onward.”
Title: Fine-tuning T cell function through engineered orthogonal chimeric cytokine receptors
Authors: Rigel J. Kishton and Nicholas Restifo
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