Universal cancer vaccine trial shows significant improvement in overall survival | Hacker News Reader

Universal cancer vaccine trial shows significant improvement in overall survival

ultimovacs.com

235 pointsespenwa50 comments

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.

"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.

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.

> 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 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.

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)

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)

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.

“UV1 is a therapeutic cancer vaccine used to generate an immune response against the enzyme human telomerase (hTERT). The enzyme is essential for the ability of cancer cells to proliferate. Telomerase is present in 85-90% of all cancers, across the stages of the disease.”

It’s a protein epitope vaccine against a normal human protein. Not stated here, but it may also target normal stem cells needed for repair and renewal processes. This risk may be reduced by the cessation of checkpoint blockades, but, the immune system can’t forget a target, and autoimmunity is an unsolved problem. HLA binding is also not perfectly specific, and any immune response is likely to generate more immunity from the target cell. This universal targeting of normal peptides may be an acceptable last-line defense, but I would be more comfortable targeting a somatic mutation with some significant differentiation from anything in the human exome.

> the immune system can’t forget a target

Doesn't catching measles reset the immune system's "memory"?

I don’t know much about this, but I’m not sure “reset” is the right term here. It seems more like “overwhelm” than “reset” to what a newborn might have. Measles can cause autoimmunity, and I’m not sure it’s been shown to abate it.

k. I was going by stuff like this:

https://www.bbc.com/future/article/20211112-the-people-with-...

> the immune system can’t forget a target

This recent study has developed an “inverse vaccine” for multiple sclerosis that apparently can make the immune system forget stuff:

https://news.ycombinator.com/item?id=37528816

I have a friend doing her PhD in cancer research. She tells me to take every Phase I trial with a huge grain of salt, because they rarely make it to market. [1]

1: https://i.postimg.cc/L4G0FdWf/cancer-study.jpg

These are Phase II trials.

There’s a lot of approved cancer treatment protocols that increase median survival by a mere few weeks. This drug also seems to be heading that way.

Is this image from something with stats? The numbers seem kind of round.

Not that specific stats would help me that much.

It's part of the huge, finger in the air balancing act of developing drugs. How much money do you put into early phase 1 and before stuff that may or may not make it. And what's the market if it does make it. Because the ones that do make it have to cover the cost of all the ones that don't, who's learning it took to get to this point.

Note that this is for a very hard cancer to treat, and no one was expecting the great results seen here. Upcoming studies will focus on other cancer types where we expect results to be even better.

Disclaimer: I'm an investor in Ultimovacs and run a community for Ultimovacs investors at tekinvestor.no (in Norwegian, but google translate can help :))

"Ultimovacs is evaluating the universal cancer vaccine UV1 in a broad clinical development program across various cancer indications with different biologies and disease stages, in combination with different checkpoint inhibitors. The topline data from NIPU are the first results among the five randomized trials in the UV1 Phase II clinical program. In addition to malignant mesothelioma, Phase II studies are ongoing in patients with malignant melanoma, head and neck cancer, ovarian cancer, and non-small cell lung cancer. The topline data from the malignant melanoma and head and neck cancer trials are expected during the first and second half of 2024. UV1 is a patented, proprietary technology owned by Ultimovacs."

27% doesn’t seem all that significant considering a vaccine

>A 2021 study showed that among adults hospitalized with flu, vaccinated patients had a 26% lower risk of intensive care unit (ICU) admission and a 31% lower risk of death from flu compared with those who were unvaccinated.

Yet you should still be getting the flu vaccine

Numbers like that are highly misleading, because it's a conditional. If your chances of dying from something are 1 in 10 million, and a treatment changes that to 1 in a billion, then that treatment would mean you're 99% less likely to die of whatever. But the risk of death is so extremely low to begin with, that that 99% figure is largely just noise.

I mean noise in both the colloquial sense, as well as the statistical one. It's difficult to measure the effectiveness of treatments when what you're treating is so relatively harmless. An experimental study, outside of an absurd size, would show 0 deaths. So you only have observational studies left, which tend to be deeply flawed and highly susceptible to number juking.

In any case, if somebody dies from the flu they were likely quite elderly, or had severe preexisting conditions. And so it's this group of people that taking things like a flus hot can make the most sense. But if you take e.g. a younger to mid aged person of good health, his chance of dying from the flu are practically zero. If they want to get it, more power to them. But saying all people should get a flu shot, does not seem to make much sense.

The flu vaccine reduces severity and likelihood of catching it as well (which can serve to protect vulnerable populations). Your own personal chance of death is not all that matters.

Getting it yearly may also reduce the risk of other related conditions e.g. https://www.uth.edu/news/story/uthealth-houston-study-flu-va...

It's nearly risk free and it's definitely worth it even if all it did was decrease the severity of flu if you catch it (and it does more than that).

The flu shot does not prevent one from getting the flu and spreading it to others. Like the past 3 years have shown, you're just not going to get herd immunity with these short term low efficacy shots, even when paired alongside monumental, wide scale, and completely unsustainable efforts.

Also, the risk of something needs to be put in context of the risk of what you're protecting against. If something only has a severe negative side effect 1 in a million times, then it absolutely should be considered extremely low risk. But you're risk of whatever it's protecting against only has a severe outcome 1 in 2 million times? Well not only should it also then be considered extremely low risk, but getting the treatment would be quite illogical. These risks also needs to be multiplied repeatedly for low efficacy treatments which entail annual use.

Both of your comments have described concepts that are very important to understand when discussing medical interventions, especially at the population level. Your reasoning is correct, I just wanted to add the terminology we use:

Absolute risk reduction (ARR), relative risk reduction (RRR), number needed to treat (NNT), number needed to harm (NNH).

Reading about these is a good starting point for anyone wanting to understand more about the decision making process.

> The flu shot does not prevent one from getting the flu and spreading it to others

It does both of those things. Maybe read: https://www.cdc.gov/flu/vaccines-work/vaccineeffect.htm

> Also, the risk of something needs to be put in context of the risk of what you're protecting against

True. And one thing we're protecting against is getting the flu. That has a probability much much higher than 1 in 2 million.

> The flu vaccine reduces severity and likelihood of catching it as well (which can serve to protect vulnerable populations). Your own personal chance of death is not all that matters.

This is an insane perspective, eventually leading to totalitarianism. Thinking this to the end, everyone should get forced to be vaccinated for everything, because it might save someone who might die from it.

"Protect the weak and innocent" is a great excuse for reducing the freedoms of people.

Absolutely insane.

It’s a question of values. I’m happy to pay taxes because my vision for how the world should work includes people who are thriving (like me) helping those who aren’t. Same reason I’m happy to get vaccines even if they don’t help me much (though most, maybe all, are worth it even if I only care about myself).

I guess I forgot to directly respond - point I was trying to make is that I don’t find this insane.

I never said anything about forcing people to get vaccinated. I was simply arguing that getting vaccinated is wise and considerate.

"Your own personal chance of death is not all that matters" is just a fact. There are outcomes other than your death that should influence your decisions.

Pretty good numbers, actually, considering the other conventional treatments for mesothelioma (surgery, aggressive chemo) is similar:

>> The median survival for patients in the chemotherapy arms was 8.5 months compared to 7.6 months for BSC (best supportive care), which was not statistically different.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307510/

Why are some metrics using an 80% confidence interval while others use 95%?

2035:

"How are you feeling?"

"Oh, a touch of cancer last week but I popped a couple of pills and all good now".

“the study did not meet the primary endpoint”

This is officially the king of all clickbait

Indeed. It failed its primary endpoint, and yet someone posted this press release.

Sounds like another money maker for the pharmaceutical industry that does nothing for the patient.

Reply on news.ycombinator.com