Nicholas P Restifo: From Hand-Crafting TILs to Robotic Manufacturing
Nicholas P Restifo, Chief Medical Officer at Medici Therapeutics, shared a post on LinkedIn:
“From Hand-Crafting TILs to Robotic Manufacturing: Why Patients Should Be Excited
When I made my first tumor-infiltrating lymphocytes (TILs) as a fellow more than 30 years ago, we mixed tumor digests with IL-2 and hoped for the best. My mentor Steve Rosenberg had already shown the “magic”: add IL-2 to a dissociated tumor and TILs expand. The art was spotting the “good” cells.
But manufacturing? Far from magic. Everything was difficult – patient selection, tissue handling, open culture steps, characterization. Yet TILs sometimes worked spectacularly, and that kept us going.
What’s changed – and why I’m optimistic:
· Clinical proof: From the NCI to MD Anderson, Moffitt, Sheba, Copenhagen, Leiden, and beyond – then lifileucel’s FDA approval. The signal is real.
· Scale is real: Centralized facilities and “Gen-2” processes show reproducibility beyond heroic single centers.
· Smarter TILs: Selection of tumor-reactive phenotypes (CD137/4-1BB, PD-1, CD39/CD103) and engineered variants (CISH-KO, PD-1-KO) are now in trials.
· Stemness preserved: Since our work on T memory stem cells (2009–2011), new methods (IL-2-light, IL-15, IL-21, Akt blockade, high potassium) keep cells “younger,” more proliferative, less toxic.
Where the robots come in:
Closed, automated platforms are transforming artisanal culture into standardized, GMP-clean manufacturing.
· Miltenyi CliniMACS Prodigy: direct selection of CD137⁺ TILs, in-system REP, 16-day timeline.
· Lonza Cocoon: cassette-based, parallel scale-out with integrated selection and non-viral workflows.
· Next-gen robotics: systems that sense and adapt to T cell biology, not just automate fixed steps.
Reality check: Not every approach pans out (e.g. EU regulatory hurdles, paused “Selected-TIL” programs). Cost and logistics still bite. But the trajectory is undeniable: closed, standardized, automated, and increasingly engineered.
My takeaway after a lifetime in TILs:
Biology sparked the fire. Manufacturing will determine access. Let’s keep building — better selection, larger closed chambers, gentler regimens, smarter engineering — so more patients can benefit, faster.
Open-access methods and data on automated TIL manufacturing.”
Title: Clinical-scale, modular manufacturing of tumor-reactive TILs using a closed and automated culture system
Authors: Christina Völzke, Lisa Ehrhardt, Laura Fischer, Peter Maul, Carina Wenzel, Arina Riabinska, Elvira Criado-Moronati, Mike Dienstbier, Jessica Hassel, Danmei Zhang, John B. Haanen, Rupert Handgretinger, Ian R. Hardy, Bianca Heemskerk, Andrzej Dzionek.
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