How to design a cancer vaccine (and vastly improve them): Alex Rubinsteyn & Ben Vincent

Описание: Back in early May, I flew to North Carolina to interview Alex Rubinsteyn (left) and Benjamin Vincent (right). Together, they run the Personalized Immunotherapy Research Lab (PIRL) at UNC-Chapel Hill. It would be difficult for me to emphasize the degree to which Alex and Benjamin are in a league of their own amongst almost any other researcher I have ever met, demonstrating a degree of translational ambition, scientific insight, clarity of thought, and just genuine kindness that one rarely sees. And each time I stumble across a person like this, I try my best to get them in front of a camera. This is the first interview I’ve ever done where I traveled specifically for a guest(s), and I’m very, very glad I did it.

We’re in an interesting moment with cancer vaccines. Between Sid Sijbrandij’s ‘founder mode’ journey on his cancer (which involved cancer vaccines), and the dog cancer vaccine story, a lot of eyes are being directed here. As luck would have it, Alex and Benjamin have spent a fairly high fraction of their career in this exact field, and have contributed to some of the most foundation work in it: MHCflurry 2.0, OpenVax, LENS, and plenty of other work. In fact, Alex actually helped run a neoantigen cancer vaccine trial a few years back! So obviously, they’d make for great conversation here. We talked for three hours about this area, eventually stretching beyond cancer vaccines and discussing the grander field of personalized immunotherapy. This is comfortably the longest episode I’ve ever recorded, and I suspect we could have gone for an hour longer.

Finally: this is a complicated subject, and we really get into the details. Because of it, it may be worth skimming a companion cancer vaccine essay I released a month back. Many subjects from the article are discussed + expanded upon in the podcast. Here is the essay: https://www.owlposting.com/p/how-to-b...

Spotify: https://open.spotify.com/episode/5xk4...

Apple Podcasts: https://podcasts.apple.com/us/podcast...

Youtube:    • How to design a cancer vaccine (and vastly...  

Transcript: https://www.owlposting.com/p/how-to-d...

Timestamps:
0:00 Introduction
1:26 What cancer vaccines are, and the "easy living drug" dream
4:34 TAAs vs neoantigens — and why the field switched
8:18 MHC, HLA, and neoantigens, defined
12:57 The 100,000 MHCs per cell and the information-theoretic problem
15:28 Why a cancer can't just drop its MHC
20:18 Immunopeptidomics: why predicting antigens isn't knowing them
28:57 How many targets you actually need, and the HLA-loss problem
30:22 Can a tumor mutate its own MHC?
31:34 What are tumor-associated antigens and cancer-testis antigens?
34:09 The thymus, AIRE, and why T cells were never trained against CTAs
37:35 Why "normal" proteins is still an unfinished reference problem
41:05 The short list of T-cell killing success stories
43:20 Did the old vaccine literature just need Keytruda?
47:31 Why not cut out the middleman and engineer the T cells?
50:09 Autologous vs affinity-enhanced TCRs, and a database-matched middle path
54:23 Can we TCR-T and CAR-T in-vivo?
1:02:08 Why whole-tumor and lysate vaccines never worked
1:04:46 Immunodominance, or why a great vaccine can still do nothing
1:10:38 Can you predict immunogenicity with ML?
1:12:24 What you tell the FDA for hyper-personalized drugs
1:14:14 How secret is the computational pipeline?
1:17:40 Why the field desperately needs real benchmarking
1:21:57 Moderna and BioNTech: are the success stories real?
1:30:04 Tumor mutational burden, and scraping the bottom for glioblastoma
1:36:46 If cancer is so heterogeneous, why does any of this work?
1:38:40 The hyper-optimistic case: metastatic disease and antigen spreading
1:43:00 Antigenic drift, driver variants, and the 2030s adaptive vaccine
1:48:02 Why cell therapy at all, instead of antibodies?
1:52:43 Neoantigen vaccines as a categorical departure for the FDA
2:00:03 The antigen-selection safety logic, and why it's flawed
2:04:42 Running investigator-initiated trials (which exist in the US!)
2:19:40 The tragedy of the commons in cancer vaccine trials
2:22:38 How Ben and Alex met (on Twitter!)
2:27:49 Founder-mode oncology and the rise of concierge cancer care
2:31:50 How good is concierge oncology, really? The Sid index case
2:40:03 Why old precision oncology was useless, and why now is different
2:43:07 LLMs, and patients advocating for their own testing
2:47:30 The molecular-testing trial that should exist
2:48:50 Single-cell long-read as the one true assay
2:49:56 What would you do with $100M equity-free?
2:53:27 The automated box: tumor in, RNA therapeutic out
2:55:58 Why identifying targets is the easy part