Thanks Sander!

FLC work led by @markyarchoan.bsky.social and TIRTL by @pogorely.bsky.social w/ Marina Baretti Allison Kirk,
Jeremy Crawford, Samir Adhikari, @nick-clark-bioinfo.bsky.social, Anastasia Minervina, David Brice, Stefan Schattgen, Zeal Kamdar, & Balaji Sundararaman, Support Fibrolamellar Cancer Found.

If you'd like to try TIRTL, we've got two detailed protocols online, one for the 384-well format (which requires some small volume liquid handlers) and one for a 96-well format which can be done in any lab. protocols.io/view/tirtl-s... and www.protocols.io/view/tirtl-s...

Together, these studies lay groundwork for rational design of epitope-targeted immunotherapies and demonstrate how high-resolution immunomonitoring can guide next-generation T cell therapies, including public motif-driven adoptive cell transfer.

Combining vaccine-induced epitope-specific functional data with TIRTL-Seq repertoire analytics produced a powerful stratification model for clinical response, surpassing standard immune monitoring.

Applying TIRTL-Seq in our FLC vaccine cohort revealed expansive, polyclonal tumor-reactive T cell responses, many shared across patients with common HLA types. This approach exposed public TCR motifs rarely seen in tumor immunity, and mapped the functional landscape of response.

A major challenge is that tumor- and pathogen-specific T cells circulate at extremely low frequencies, often below 1 in 100,000 or even 1 in a million, making them essentially invisible to standard single-cell approaches.

To truly interrogate immune responses at the clonal level, we needed unprecedented resolution. Enter TIRTL-Seq: an affordable, scalable platform generating millions of paired TCRαβ clones per experiment, enabling thorough quantification and tracking of T cell dynamics.

In a first-of-its-kind trial, we combined the FLC vaccine with immune checkpoint blockade. Among patients with advanced disease, 75% mounted strong fusion-specific T cell responses, with 25% experiencing partial responses and durable progression-free survival.

FLC is a rare, aggressive liver cancer lacking effective systemic therapies. Our vaccine targets the recurrent DNAJB1::PRKACA fusion, offering a universal neoantigen to drive anti-tumor immunity. www.nature.com/articles/s41...

Thank you!

Thanks!

Thank you!

Haha yes, thanks!

Thanks Kilian!

Thank you Stacey!! They have all kinds of different birds out here, you need to visit.

This was a collaborative effort between led by Phil Bradley (not on the socials) and @sschattgen, with Kasi Vegesana, @Asya_Minervina, @villanilab, the MGH COVID-19 team, @s_valkiers and many others!