Comment by jseliger | Hacker News Reader

Comment by jseliger | Hacker News Reader

This is obviously good but note that it appears to be covering mesothelioma only, and "The median [overall survival] OS was 15.4 months (95% CI, 11.1-22.6) for UV1 plus ipilimumab and nivolumab (treatment arm) versus 11.1 months (95% CI, 8.8-18.1) for ipilimumab and nivolumab alone." Another headline could be: "Cancer vaccine helps some mesothelioma patients live an extra 4.3 months," which is less exciting than the headline's current phrasing. It's like how people are horrified by "you have a 20% chance of dying" but somewhat reassured by "you have an 80% chance of living."

I'm dying from squamous cell carcinoma and am more excited about the Moderna approach with personalized cancer vaccines, like mRNA-4157. Early data for what I have is promising: https://www.fiercebiotech.com/biotech/moderna-s-keytruda-com...: "The combination treatment shrank tumors in five patients with head and neck cancer (50%), eliminating the tumors in two of those patients, Moderna said in a statement. Another four patients in that group had stable disease, meaning their tumors had stopped growing." Recurrent/metastatic head and neck squamous cell carcinoma is almost always fatal: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155962/, unless the person responds to pembrolizumab/Keytruda (which I do not; about 20 - 30% of patients appear to respond, based on KEYNOTE-048: https://ascopubs.org/doi/full/10.1200/JCO.21.02508). Unfortunately, Moderna won't make mRNA-4157 available under compassionate use or through any other means. :(

Moderna, however, is in a Phase III study of mRNA-4157 in melanoma: https://www.onclive.com/view/adjuvant-mrna-4157-plus-pembrol.... Given the miraculous early data for R/M HNSCC, one hopes they'll launch new trials.

Nivolumab is a PD-1 inhibitor, like pembrolizumab/Keytruda, but I don't know anything more about it.

Nivolumab and ipilimumab are immune checkpoint inhibitors (for PD-1 and CTLA-4), this is meant to increase/maintain the activation of immunized T cells, as ligands of these checkpoint receptors are often expressed by the cancer cells (or more generally the cells in the cancer microenvironment) which attempt to attenuate the immune response directed at them. So this is effectively a fancy cancer vaccine adjuvant.

The vaccine itself targeting telomarase is interesting, but not without limitations. Immunized T cells can only 'see' telomarase (which is inside the cell) if bits of it are presented on the cancer cell surface via MHC molecules (which is what they are for - to provide a 'window' into the cell for the immune system to peek through). Cancer cells predictably shed MHC molecules in an attempt to hide.

Another angle is that telomerase can be transiently activated in rapidly proliferating cells (most notably... lymphocytes). So there may be some on-target off-cancer effects.

Another difficulty is that T cells in general have a hard time getting into solid tumors in sufficient numbers (unless additional measures are taken).

(I am a biologist who works in CAR-T development)

> Unfortunately, Moderna won't make mRNA-4157 available under compassionate use

Sorry to hear. Try contacting Immunocore in Oxford, they have a TCR therapy that targets many tumors, including squamous ones, and they are recruiting or should make it available under compassionate use. Other companies worth looking into are Adaptimmune Therapeutics, also in Oxford, and Evaxion in Copenhagen. They are all going the semi-personalized route. So will look into your tumor type, MHC class I, etc.

Talking about clinical trials, I'm wondering: does one, as a patient, have to go hunting & searching for these clinical trials yourself, or do doctors mention these when things start to look dire?

Asking for a friend that got osteosarcoma earlier this year (in her lower left leg) that has metastasized. She already had retinoblastoma as a child due to a mutation of the RB1 gene, both are probably related.

I don't want to be that friend that thinks they know better than the doctors, but I'm honestly curious.

In my case, we did. But I know the space well, as I work in immunology.

Plus, I was frustrated because our local hospital offerings were far from the state of the art.

In case of a metastasis, even more so, as adverse events are less of a concern.

I'm really sorry for what you're going through. I lost someone very close to me to cancer recently, but it was detected so very late that treatment options were severely limited (immunotherapy was off the table).

Personalised cancer vaccines really seem to be the most promising avenue there is at the moment, as the problem seems to always have been that unless you can kill the tumour right to the last cell whatever is left will just adapt and grow back more resilient than before. I generally scan over tumour shrinkage in these reports (even substantial shrinkage) as palliative in nature (maybe I'm naive but I've trained myself to look at it this way). Elimination of tumours (even in a subset of patients) gives me hope as it at least means something there really is effective and can be revised on later.

I'd say 'differentiated' might be a better description than 'adapt', no?

With targeted therapies (by whatever means), you're killing everything with that marker with high probability.

Unfortunately, tumors typically being heterogenous (tumor cells don't all carry the same markers), after you've killed everything marked... you're still left with everything else.

Which I believe is why most targeted therapies use simultaneous adjuvant general therapies that help with the remainder?

(Family member going through BRAF targeted therapy with some adjuvant cocktail for metastatic colon cancer)

If you are truly dying of metastatic cancer, and as you seem extremely well-informed and competent to make your own decisions, I feel obligated to share. Not medical advice, entertainment purposes only:

Checkpoint blockades are great if you are providing a lot of the epitopes to target, but not so great if your immune system isn’t already killing cells to provide that. One way of providing substrate is personalized mRNA. Another much simpler way is tumor ablation. I have done this on myself and my animals with mixed results, mostly positive. I use ascorbic acid to ablate skin tumors, and ethyl-cellulose injection for larger masses.

"Phase II studies are ongoing in patients with malignant melanoma, head and neck cancer, ovarian cancer, and non-small cell lung cancer."

Thank you! I missed that sentence. Embarrassing. Will be interested to see how it performs.

Weren’t you able to get into the study at UCSD? How is that going? Are you allowed to talk about it?

I was! I've now been infused twice with 1100mg of petosemtamab / MCLA-158 (https://beta.clinicaltrials.gov/study/NCT03526835), on Sept. 27 and then Oct. 12. The next is Oct. 25. For the first week I had no apparent reactions, and then a rash erupted on my face, chest, and back. That's pretty normal for EGFR drugs, and the rash was (and is) itchy and annoying but not unbearable. To treat it, I inject an antibiotic called doxycycline (which is used against acne bacteria) into my peg tube and use a a topical steroid. At the bottom of this post: https://jakeseliger.com/2023/10/16/how-do-you-say-goodbye/ there's a photo showing some of what's happening to my face.

So, overall it's going pretty well, and I feel physically better than I did on chemo and Keytruda—a low bar, but I'll take whatever improvements I can get. The next CT scans are scheduled for Nov. 21, but unless I'm responding to petosemtamab in a pretty major way, they'll probably be ambiguous. The median time to respond is 1.8 months, so it'd be surprising to see big changes between the Sept. 5 CT baseline CT scans and the Nov. 21 scans. Two tumors are physically protruding from my neck, which is disconcerting, but they aren't painful.

The FDA apparently wants to see how the 1100mg and 1500mg petosemtamab doses differ, and I got randomized to the lower dose. That isn't necessarily bad: more of a drug can be deleterious relative to right dose.

I wasn't NDA'ed, so I'm assuming I can talk about what's going on. I'm a bit surprised by the lack of an NDA; I've signed NDAs for three-person startups who want grant writing services for a Dept. of Energy Small Business Innovation and Research (SBIR) proposal, but nothing WRT this.

Thanks for the update and I hope this works out.

Thank you for sharing and I hope the science evolves alongside your recovery.

You're an excellent writer! Some scenes feel poignantly vivid. As in, my thinking "That is the those way those things go, both in moments of happiness and others."

Hope your late November CT brings good news.

I'm sorry to hear that. I have zero knowledge about your specific condition and I hope the best for you. Given that, I want to recommend you to read Being Mortal by Atul Gawande. It's rough, anti status-quo, and yet very compelling.

Do you have an opinion on https://www.science.org/content/blog-post/new-mode-cancer-tr...?

Nope. Nothing other than "I hope it works!" Interestingly, AOH1996 is supposed to be given at Honor Health Research Institute: https://beta.clinicaltrials.gov/study/NCT05227326, which is down the street from me, but the trial isn't listed as recruiting yet. Not sure why: if I weren't in the trial I'm in (https://news.ycombinator.com/item?id=37924671), AOH1996 would likely be on the list. It's a first-in-human trial with only 8 participants, and most drugs, even super promising-seeming ones, don't make it even to phase 2.

But https://www.clinicaltrials.gov/study/NCT04787042 is also a promising phase 1 trial for an interleukin-18 attack, and it's also at Honor Health.

Not who you asked but that’s a promising molecule. Unfortunately until we see phase 1/2 results we can’t be sure if it ends up actually being effective. It’s sad that we can’t predict efficacy any better without injecting actual people with the drug but that’s reality. Cancer is too complex to model any other way in a complete fashion. If a drug is blockbuster effective you’d notice in phase 1 itself, as was the case for ibrutinib. Fingers crossed.

In my air-chair opinion, the future of cancer treatments will not be one "cure-all" drug, but many, all depending on a cancer's characteristics and an individual's response to treatments. Cancer can also mutate or become metastatic when under duress, so the characteristics change then as well.

So the more treatments we can create, the better.

That's been the last 15 years of oncology, afaik.

Old: type cancer on location and characteristics, give treatment statistically effective against that combination

New: sequence cancer, feed into software, study treatment options and plan from that

It's been a huge change.

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