Delgoffe Lab

We still have space at our Fusion meeting in Lisbon. Amanda, Nik, and I have planned a really great agenda, which we hope will be a view of cancer immunology’s next wave! Register today and join us for what I’m sure will be a really fun few days in Portugal this summer!

Wow! I wonder if they found astrophage...

Funding for medical research grants from the federal government is down 91% this fiscal year. We are entering a new Dark Ages under RFK Jr.

This. NCI has given out exactly one new grant (a P01) since October 1. No R01s at all. Not sure @NIHDirector_Jay has spoken about why in public. Not sure this link will work for long but I searched for non-SBIR+NCI+FY2026+"new grants" on NIH-Reporter. reporter.nih.gov/search/lsggXLO…

Everyone is talking about personalized mRNA cancer vaccines. I want to share two recent Nature papers that cut through the excitement and reveal something the viral posts aren't telling you: the approach works — but only in patients whose immune system actually responds to the vaccine. In the PDAC trial, that was half. Papers: — TNBC-MERIT trial (Nature 2026): nature.com/articles/s4158… — PDAC 3-year follow-up (Nature 2025): nature.com/articles/s4158… Here's the exact number that explains why. The PDAC trial: at 3.2 years median follow-up, vaccine responders had median recurrence-free survival that was never reached. Non-responders: 13.4 months. HR = 0.14. The T cell memory is real — some clones are projected to persist for over a decade. The TNBC trial: 10 of 14 patients remained relapse-free at 5 years. One patient has been in remission for over 6 years, with neoantigen-specific T cells still circulating at ~2% of her CD8 repertoire. So what separates responders from non-responders? Across both trials: only 41 of 251 neoantigens actually triggered a T cell response. That's 16%. Each vaccine encodes up to 20 neoantigens — the algorithm's best guess at which tumor mutations will be immunogenic. Most don't work. Half the PDAC patients didn't respond — not because they couldn't mount an immune response (they responded fine to concurrent COVID vaccines) — but because their selected neoantigens happened to miss. This is the core unsolved problem: predicting, from sequence alone, which mutations will produce peptides that a specific patient's immune system will actually recognize. It sounds like an MHC binding problem. It isn't. Tools like NetMHCpan handle binding affinity reasonably well. What they miss is the full causal chain: 1. Proteasomal processing — will the protein actually be cleaved into this exact peptide? 2. TAP transport — will it reach the ER for MHC loading? 3. HLA-peptide stability — across the patient's specific HLA alleles (10,000+ variants in the population) 4. T cell repertoire availability — has central tolerance already deleted the clones that would recognize it? 5. Tumor clonal architecture — is this mutation in every tumor cell, or just 30%? Targeting subclonal neoantigens leaves most of the tumor untouched. Every step is a filter. Current prediction stops at step one. Compounding everything: average manufacturing time in the TNBC trial was 69 days (range: 34–125) from sample to vaccine release. For pancreatic cancer, where non-responders recur at 13.4 months post-surgery, that's not a footnote. It's a window closing. The good news: the T cell biology is sound. The mRNA platform works. The immunology is spectacular — when it works. The bottleneck is the first step: choosing which 20 neoantigens go in the vaccine. Get that prediction right, and the responder rate moves. This is where AI in cancer immunotherapy has to go next. Not mRNA design. Not LNP formulation. Immunogenicity prediction — integrating mutation calling, HLA typing, T cell repertoire sequencing, and single-cell tumor expression simultaneously, as a causal inference problem, not a binding affinity lookup. We don't have a model that does this well. That's the gap.

@BReinfeld While that video is terrifying I’m glad to know ICI is becoming more widely deployed for the puppers. I think OVs would also be a stellar therapy. Regardless the story going around is just hyped bs from the techbro ai crowd.

@DelgoffeLab jitc.bmj.com/content/jitc/1… WHICH is a thing

Oh. The dog also got checkpoint blockade.

@ratimics_ai @Pragu3704 @addictedtoigno1 The dog also received another form of immunotherapy (immune checkpoint blockade) at the same time. Impossible to tell if it came from the vax or the ICB. Either way, the dog has since progressed.

@Pragu3704 @addictedtoigno1 that's incredible! it shrank the tumor!

This is such a stupid reaction that has caused an enormous amount of confusion. There is a huge difference between "curing" mouse models of cancer and treating any naturally occurring disease in humans or animals.

@Qivshi1 The dog ALSO go adjuvant canine immunotherapy, which probably driving the effect.

Fucking dog cancer story is pissing me off, AI side of of the story is completely overblown, (eg alpha fold part was just him dicking around), all he did was get an mRNA vaccine and got PARTIAL recovery on n = 1 study, but people are gonna think there is a cure toncancer

I agree with this sentiment. It’s an interesting story, but overinflated about the reliance on AI (you wouldn’t use AlphaFold to design an mRNA vaccine). Trials running right now to identify mutations, design bespoke mRNA, and vaccinate a patient, but they are not slam dunks.

Tech confidently commenting on biology (and being wrong) remains unbeaten

A recent study in Nature Communications reveals over 250 metabolic enzymes located directly on chromatin, a discovery that vastly expands the previously known count of only about 20. nature.com/articles/s4146…

@simone_minnie Don’t fight it.. once you acquiesce you’ll wonder why you didn’t join sooner.

My data are dragging me (kicking and screaming) towards a metabolism mechanism and I’d like to unsubscribe 😅

Trump issues new shoes to his top aides.

With researchers and Big Pharma now racing to improve blockbuster GLP-1 weight loss drugs, leptin—discovered by Rockefeller's Jeff Friedman—has resurfaced as a promising candidate. Read more in this piece from @Medscape: medscape.com/viewarticle/ho…

Had a lot of fun with Chenxian in the lab discussing a phenomenal new paper in @CellCellPress reporting how regulatory T cells can utilize ammonia to improve their function.

My own.

This 'senior official' was Vinay Prasad. Disclosing trade secret information without legal authorization is a prohibited act under the FDCA & a criminal violation under the Trade Secrets Act.

Proud to share that Pitt now ranks #2 in the nation for @NIH funding in Microbiology, Immunology, and Virology—up from #3 last year, according to the Blue Ridge Institute for Medical Research. immunology.pitt.edu/news/pitt-immu…

Woah. This is a bleak outlook. Excellent analysis by @Jori_health shows the NIH grants being hit hardest are the very ones designed to bring new scientists into the system - small R, R21s, and K awards. Dismantling the system one generation at a time.