Paul Thomas

Great culture can save lives. Literally.

Amazing letter in today’s @thetimes.com about Tom Stoppard

TIRTL-seq: deep, quantitative and affordable paired TCR repertoire sequencing - Nature Methods TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

Excited to see our TIRTL-seq method published in Nature Methods www.nature.com/articles/s41...! Some updates after the revision: (1/4)

Thanks Sander!

A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma @naturemedicine.bsky.social @markyarchoan.bsky.social @hopkinspress.bsky.social @pgtimmune.bsky.social @fredhutch.org @stjude.bsky.social
www.nature.com/articles/s41...

@natmethods.nature.com TIRTL-seq: deep, quantitative and affordable paired TCR repertoire sequencing
www.nature.com/articles/s41...
@pogorely.bsky.social @fredhutch.org @stjude.bsky.social @pgtimmune.bsky.social

We are hiring! We have a postdoc position opened @fredhutch.org to join our team to design next gen cellular therapies for cancer. Heavy focus on T cell signaling and understanding how synthetic receptors instruct T cells to fight cancer.

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.

A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial - Nature Medicine In this phase 1 trial, treatment of patients with fibrolamellar hepatocellular carcinoma with a therapeutic peptide vaccine targeting the fusion kinase DNAJB1–PRKACA, which is the driver of the diseas...

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...

TIRTL-seq: deep, quantitative and affordable paired TCR repertoire sequencing - Nature Methods TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

Two complementary studies from our group out today: a therapeutic peptide vaccine trial for fibrolamellar carcinoma (FLC) & TIRTL-Seq, our robust method for deep quantitative paired TCR sequencing a🧵w/ @markyarchoan.bsky.social & @pogorely.bsky.social www.nature.com/articles/s41...

Thank you!

Thanks!

Thank you!

Haha yes, thanks!

Thanks Kilian!

excited that this paper is finally out in @pnas.org :
www.pnas.org/doi/10.1073/...

Led by Gian Marco Visani (effort initiated by Michael Pun), fantastic collaboration with @pgtimmune.bsky.social @asya-minervina.bsky.social and Phil Bradley.

Viral immunologist taps ‘incredible potential’ of immune system New Fred Hutch Cancer Center viral immunologist Dr. Paul Thomas is working to turn the "incredible potential" of the immune system into real-life diagnostic and therapeutic applications. He studies ho...

After many rewarding years at @StJudeResearch surrounded by exceptional colleagues & groundbreaking science, I’m delighted to join @fredhutch to push boundaries in viral & cancer immunology. Grateful to St. Jude and looking forward to what’s next at FH! More here: www.fredhutch.org/en/news/cent...

Viral immunologist taps ‘incredible potential’ of immune system New Fred Hutch Cancer Center viral immunologist Dr. Paul Thomas is working to turn the "incredible potential" of the immune system into real-life diagnostic and therapeutic applications. He studies ho...

Viral immunologist @pgtimmune.bsky.social, who recently joined Fred Hutch's Vaccine and Infectious Diseases Division, aims to harness the "incredible potential" of the immune system to advance diagnostics, vaccines and cancer therapies. bit.ly/3WJVpos

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!

GitHub - phbradley/metaconga: Scripts and files for meta-analysis with conga Scripts and files for meta-analysis with conga. Contribute to phbradley/metaconga development by creating an account on GitHub.

In short, you can think of MetaCoNGA as our first draft of the human TCR repertoire. Beta code for matching your T cell populations to those from metaCoNGA is available on Github (github.com/phbradley/me...).

Alternatively, maybe you’ve matched TCRs and GEX to a newly curated regulatory unconventional population (previously difficult to match w/TCR sequence). These vary substantially across donors & conditions & may be highly predictive of immune states relevant to health and disease.

Maybe you’ve identified a novel condition-associated population and you want to see where it falls–is it a conventional epitope specific response? If so, we might be able to tell you the pathogen, the epitope, or the HLA-restriction (or all 3)?

Finally, can we put these two analyses together to make a useful tool for the field? We introduce a mapping tool that allows you to take a new data set and match it to the classifications we’ve defined in MetaCoNGA. This has many uses-