Submitted by BousWakebo t3_123ofc9 in Futurology
Comments
etherified t1_jdwb72i wrote
Yeah, for example, it's been well known for years that one of the mechanisms used by evolving cancer cells is to express surface HLA-G, which suppresses or down-regulates the host immune response, giving cancer cells more of the time needed for their nefarious purposes.
(the same HLA-G class is also expressed on embryo cells, helping to suppress the mother's immune response so her body doesn't attack the gestating fetus as a foreign body.)
Crystal-Math-Adept t1_jdwpff9 wrote
I remember hearing about this last century
LimerickExplorer t1_jdx3klk wrote
>last century.
Jesus I'm old.
KevinTheSeaPickle t1_jdxw0td wrote
Me too:( my crows feet have crows feet... When will the crowsfootception end.
BigNorseWolf t1_jdyfryi wrote
technically was also last millenium
Rogermcfarley t1_jdzciym wrote
Jesus: Yeah wait until you have a mission 2000 years from now. I'm still getting ready.
StuartL73 t1_jdylbhb wrote
Now we are in "the roaring twenties " again.
scrangos t1_jdxyicp wrote
There was another super interesting one where one cancer cell hides inside another another cancer cell using it as armor to survive the killer t-cell attacks as those don't penetrate deep enough to kill them both. (the outer one does die tho) Once signs of the killer t-cells are gone then inner ones come out and resume operations.
jjayzx t1_jdxc0eh wrote
I would think they are trying to do this with implants to reduce immunosuppressants or rid them altogether?
starion832000 t1_jdweykt wrote
Everything about cancer is click bait.
MpVpRb t1_jdw46r2 wrote
As usual, good research, misleading headline
A better headline would be .. Scientists learn a bit more about how cancer cells evade immune system
The headline implies the problem is solved
TomTrottel t1_jdznz39 wrote
as long as one can earn so much money with cancer, they will not cure it even if it would be possible :)
BousWakebo OP t1_jdvglq6 wrote
The glycocalyx is developed with high levels of cell-surface mucins, which are thought to help protect the cancer cell from immune cell attack. However, up to now, there has been limited understanding of this barrier particularly as it relates to cell-based cancer immunotherapies.
These types of treatments involve removing immune cells from a patient, modifying them to seek and destroy cancer, and then putting them back into the patient’s body.
“We found that changes in the thickness of the barrier that were as small as 10 nanometers could affect the antitumor activity of our immune cells or the engineered cells used for immunotherapy,” said Sangwoo Park, a graduate student in Matthew Paszek’s Lab at Cornell University in Ithaca, New York.
WoolyLawnsChi t1_jdw392l wrote
>the thickness of cancer cells' glycocalyx is one of the major parameters determining immune cell evasion and engineered immune cells work better if the glycocalyx is thinner.
>
>As a result of these findings the researchers then engineered immune cells with special enzymes on their surface to allow them to attach to and interact with the glycocalyx. They then found that these specialized immune cells were able to overcome the glycocalyx armor of cancer cells,
If I am reading this correctly the discovery isn't some new "drug"
instead it will make existing immunotherapies more effective
Phoenix5869 t1_jdw9fnf wrote
> it will make existing immunotherapies more effective
That’s good to hear, but it’s a far cry from what the title implies
ConversationOk4414 t1_jdzgzfa wrote
They’ve successfully eradicated a form of cancer (I don’t remember which) in their entire study group using this technique.
Solid_Hunter_4188 t1_jdw7gdn wrote
Sounds like a selection/gene therapy done specifically to tcell or NK’s to either increase the number of detectors or improve binding of existing MHC
Brain_Tourismo t1_jdyxij3 wrote
I thought they had engineered enzymes onto the existing NKs, no? Sure it is an extra step but well worth it.
zeek912 t1_je0gj13 wrote
This is pretty old news in the cancer biology field and even older news in the Glycobiology field but I'm happy to see it going more mainstream!
The main mechanism behind mucin/glycocalyx mediated immune evasion is increased levels of sialylation of mucin glycan structures. These densely sialylated proteins interact with a class of immune modulating proteins on immune cells called Siglecs (sialic acid binding immunoglobulin like proteins). These Siglecs bind sialylated structures and tell immune cells to ignore otherwise antigenic cells.
Researchers are trying a couple of different ways to address this, one of my favorites involves a chimeric antibody with a sialidase domain attached. I believe that one was the Bertozzi lab (a recent Nobel prize winner) and that one is already well into clinical trials.
Mr_HandSmall t1_jdww2gx wrote
Just a heads up - a well supported, radical breakthrough in cancer biology is very likely going to be published in one of two journals, either Nature or Science. If the scientists performing the work think they have a rigorous, world changing paper, they'll aim to publish in one of these two. Check the link to the original paper when reading these summaries.
spreadlove5683 t1_jdx6cgq wrote
Where does the journal Cell fit into this? Is it not as prestigious? Sincere question as I'm mostly not knowledgeable.
Mr_HandSmall t1_jdxg7xj wrote
Good point, Cell is the very top tier too, maybe just a tiny shade "below". Though I'd still expect the gigantic paradigm shifting breakthroughs to be targeted to the big two. And by the way nothing wrong with research in other journals, it's just not as likely to be seen - at the time of submission - as earth shattering. Of course, looking back in retrospect lots of great research might be published in smaller journals.
ksmizify t1_jdybw82 wrote
Lol you’ve obviously never tried to publish in Nature or Science. There is plenty of excellent science not published in these two journals, and plenty of journals with near or equal impact factors.
Love, a cancer immunotherapy first or senior author on several Nature and Science papers who only goes there if I have a lot of time to spend on revisions…and $11k for the open access fee.
ConversationOk4414 t1_jdzhftz wrote
What is it???? Now you have to tell. You can’t leave me hanging like this.
JackD4wkins t1_jdw120z wrote
If we can genetically change immune cells to fight cancer, why not simply change cancer cells to die instead? CINDELA got it right. Cut out the middle man
OneDayCloserToDeath t1_jdwk23m wrote
They way we do it now is as follows:
- hospital sends blood of the cancer patient to us.
- we filter out all the cells other than the killer T cells
- we inject a virus that contains the genetic material that fights the cancer. The virus infects the killer T-cells and inserts its own genetic material into the T-cells.
- we incubate and grow the T-cells a little over a week until there are enough to meet the required dose.
- we wash out the viruses and cell food juices, freeze the cells, and send them back to the hospital.
- doctor injects the cells back into the patient and they usually become cancer free within two weeks.
I don't see how you would change all the cancer cells in this way. It's more complicated people might think.
JackD4wkins t1_jdwpuwf wrote
Just inject a virus into the cancer directly that contains genetic material designed to disrupt cancer DNA.
Immunotherapy does not work for most people, or even most cancers today...
OneDayCloserToDeath t1_jdwtzoj wrote
And how do you stop the virus from infecting healthy cells and causing more harm than good?
Toranagas1 t1_jebqx8n wrote
The technology they is referring to uses whole genome sequencing to identify InDel mutations in tumor cells then uses Cas9/gRNA specifc for those InDel sequences to induce double stranded DNA breaks, resulting in cell death. Since those sequences don't in theory exist elsewhere in the patient, it may be safe. Looks like a lot of different gRNAs are needed though for good efficacy.
They use lentivirus and AAVs to deliver them in vivo.
The in vivo efficacy data is...fine. The big thing here is the personalized medicine aspect.
PMID: 35217600
JackD4wkins t1_jdxda7b wrote
Because you coded the the virus enzyme to specifically target cancer DNA and not healthy DNA. Even if the virus infects a healthy cell, it will have no effect
OneDayCloserToDeath t1_jdxhmrz wrote
Is this done? Do you have any information on it working?
JackD4wkins t1_jdxjblw wrote
They're working on it in South Korea. Its called the CINDELA program. Not sure what the status is
ecnecn t1_jdzehcr wrote
>CINDELA program
You mean Cancer-Specific InDel Attacker (Cindela) ? I didnt know they use reprogrammed viruses...
Phoenix5869 t1_jdw9452 wrote
That‘s called programmed apoptosis and we’ve been trying to figure it out for decades
JackD4wkins t1_jdwhfop wrote
With crispr you can just attack the cancer DNA itself and shred it. No fancy reprogramming needed
r0b0c0p316 t1_jdwq1gi wrote
We have lots of things that will destroy cancerous cells. The main problem is making sure they specifically target the cancer and not any normal tissue.
JackD4wkins t1_jdwq9d8 wrote
Doesn't seem to be a concern when we're using chemo and radiation as the current standard of care lol. Today, ~10% of all new cancers are linked to prior cancer treatments
r0b0c0p316 t1_jdwrms7 wrote
Many chemotherapy drugs are designed to inhibit or kill rapidly dividing cells which allow us to hit cancers with some specificity but other cell populations are also hit as a side effect. This is the reason why many people on chemo lose their hair; hair follicle cells are susceptible to the same chemo drugs.
Radiation is targeted by aiming a beam at the tumor. By using multiple beams that converge at the tumor site, we can ensure that surrounding tissue receives a lower more tolerable dose.
JackD4wkins t1_jdwsofu wrote
Chemo is so toxic that the people administering it cannot even touch it.... and don't get me started on radiation.
These treatments are brutal, carcinogenic in their own rights, and are not even necessarily curative. Crispr enzymes coded specifically to attack cancer DNA has been proven to not affect ANY healthy cells, while selectively annihilating cancer cells in vivo.
r0b0c0p316 t1_jdx3zwm wrote
I agree that chemo and radiation are not great options for fighting cancer. The fact that they have off-target effects is a problem, and that's my point; that it's difficult to only target the cancer.
How do you get CRISPR delivered to tumorigenic cells without targeting normal healthy tissue? Targeting anything to specifically hit cancer is tough because cancer presents so similarly to healthy tissue. If you have any papers that discuss this cancer-specific CRISPR targeting I would love to read them because I haven't seen anything about it that's unique to the CRISPR system.
JackD4wkins t1_jdxdxlh wrote
You can easily code crispr to target specific strings of DNA. Just take a sample of a patients cancer, analyze which parts of DNA are driving that specific cancer, code your crispr enzyme accordingly, pack it into a virus, and away you go... its really not complicated. Even if the virus infects a healthy cell, the crispr enzyme is specific to cancer DNA and has no effect on healthy dna. The amount of off-target effect is negligible compared to current treatments i.e. chemo and radiation.
The system combines crispr with cancer bioinformatic analysis. Check out CINDELA in sourth korea
r0b0c0p316 t1_jdxjxyc wrote
I found this PNAS paper on CINDELA which is a pretty cool proof of concept but it's still far from being an effective treatment (just like the results of the research from the OP). Their mouse experiments were compelling but a lack of comparison between tumor cells vs healthy cells from the same mouse or patient, plus the short time-frame where they administer their sgRNAs means that we can't know for sure what any off-target effects there might be. Also, since it can take as few as 6 driver mutations to generate a cancerous cell, it may not be possible to find 20+ unique indels specific to the cancer but not found in healthy cells.
It could be a promising treatment in combination with other therapies, but there's still a lot more work to be done before its ready for human trials.
JackD4wkins t1_jdxkg2x wrote
Once a cell becomes cancerous, the rapid division facilitates further mutation, providing more targets.
Crispr has been shown to have very few off-target indels when coded correctly.
Nevermind other treatments - if we can get this scaled, this may be the silver bullet we stopped believing in
r0b0c0p316 t1_jdxmclb wrote
> Once a cell becomes cancerous, the rapid division facilitates further mutation, providing more targets.
That's a fair point, but this also means that tumors have significant heterogeneity, so it can be difficult to find sufficient indels to target. I like your enthusiasm, but this research is still a long ways off from being a 'silver bullet'. Even the paper's authors discuss using it in combination with other treatments.
I'm not saying it won't work; I'm just saying it'll take a lot more funding and research to find out and it's not as simple as you might think.
JackD4wkins t1_jdxt1rw wrote
A man can dream haha. I'm partial to multiple rounds of treatment personally. We ID the mutations to target, rip up those cancer cells, then target the remaining ones with different mutations. No chemo/ radiation side effects. It will not be a one-and-done. Will require multiple rounds to take down all of them. The goal is to avoid other treatment modalities completely to avoid their horrific side effects
king5327 t1_jdyslcs wrote
Healthy and cancerous cells have almost exactly the same DNA. Minus a few mutations. CRISPR can target them, but might not necessarily be able to do anything useful at those locations.
CRISPR can't tell the difference between cells, it only targets specific sequences. Cancer can be caused by many different mutations, some of which won't cause it on its own. A bad target could lead to complications.
CRISPR has to work on all of the cells, otherwise the stragglers will start a new tumor.
Altogether, for CRISPR to work needs a safe target where the change will be effective and it has to wipe the floor with all of the cancer. Which means the patient needs to be lucky for it to even be a possibility, even if the success rate is high once administered.
(Source: mostly things I've read over the past decade and a half, I may be out of date)
JackD4wkins t1_jdyyu13 wrote
Crispr has been demonstrates to act at cancer causing mutation locations. Target selection is vital to success and require targeting multiple different mutations simultaneously.
Bad targeting has been rare and inconsequential in the context of current treatment side effects i.e. chemo and radiation.
Crispr can by used more than once to mop ip stragglers.
Kinexity t1_jdwmi96 wrote
Why do we have to complicate the process to meet some arbitrary goal which doesn't make our cure better but rather makes it harder to deploy?
JackD4wkins t1_jdwq341 wrote
Exactly, redesigning immune cells is much harder than just vandalizing cancer DNA with the exact same tool...
Kinexity t1_jdwrahf wrote
No. It's the opposite. We don't have a reliable methods to attack DNA of cancer cells. Using immune system to do the job for us has been proven to work safely and reliably.
JackD4wkins t1_jdws2qf wrote
We do have reliable methods of attacking cancer DNA. Its called CINDELA. The South Koreans beat you to it.
Using the immune system does not work reliably except in a very small subset of cases in a small subset of cancers...
Kinexity t1_jdwx3uf wrote
If it works and they pass the trials then more power to them. The paper I saw about it was from last year so it shouldn't be surprising that it did not take off yet and should also be a proof that if it took so much longer to develop than immunotherapy then it was indeed harder to get it to work.
IllustriousLP t1_jdz3gy0 wrote
The immunotherapy keytruda destroyed my cancer . I have a rare kind called sarcoma . I believe my diet of cutting carbs and vitamin c iv played a big part in how effective this drug worked for me. More studies need to be done with patients to see how important diet and vitamin c iv really is for effectiveness.
ConversationOk4414 t1_jdzh9fq wrote
I saw an article about this, not a paper, but it seems promising.
Toranagas1 t1_jeb4pwy wrote
I looked at that PNAS paper and it's pretty good, but isn't necessarily a substitute for cancer immunotherapy. The killing here is subject to transduction efficiency from lentivirus, which won't be 100%. You can see it in their data, that therapy doesn't clear the tumor.
Can potentially be very useful when used with cancer immunotherapy as a memory response is what is most likely to full cure the cancer.
JackD4wkins t1_jebbuwn wrote
Immunotherapies are very limited in their applicability. They only work for specific variations of specific cancers...
Transduction efficiency does not need to be 100% on the first attempt. Multiple treatments of even just 50% efficacy result in cure with just 7-8 treatments, without the devastation of chemo or radiation. Nobody requires 100% efficacy from one dose for other treatments, why people place such a high standard on transduction is a mystery to me. "If you can't cure it with one shot, then its not worth doing" is the logic of madness
Toranagas1 t1_jebh1oa wrote
Aggressive cancers, such as those that are targeted by therapies like CAR-T cells or immune checkpoint inhibitors grow quite fast. I'm not arguing against multiple treatments, and probably it would improve responses, but are also likely to be insufficient to "cure" it, as the cancer cells not destroyed will continue to grow (at worst at a log phase) and you may never quite reach zero. Only a small number of cells need survive to continue growth of the tumor.
Moreover, one notable advantage for CAR-T cell or TIL therapies is that when patients respond very rapidly, there is little time for the tumors to develop escape mechanisms. After clearance there is also often immunological memory that can maintain clearance or control of subsequent growth.
Keep in mind that the method proposed here relies on the ability for the lentivirus to enter the cell of interest. In the same way that tumors that are refractory to treatment often unregulate immunosuppressive molecules to escape the immune system so is this therapy subject to escape by preventing entry.
There is also some stuff about safety of widely infecting cells with lentiviral vectors containing a myriad of gRNAs and hoping there will be no serious off target events, but considering we are already comparing it to another pretty dangerous therapy I will leave that one out. I assume you are primarily referring to CAR-T or TIL when you say immunotherapy.
To be frank, the results from that PNAS paper are really interesting but the degree of killing isn't the most impressive. Very worthwhile studying though. The personalized medicine aspect here is really fascinating.
JackD4wkins t1_jec6avt wrote
Reducing the number of cancer cells that survive the first round depends on how we encode the CRISPR enzyme. As long as we can identify a majority of oncogenic mutations - ideally 50+ - then the only limiting factor becomes dose size. With subsequent doses to catch the remaining cancer cells.
And yes theoretically a cancer could evolve to prevent lentivirus mediated transduction... luckily nature provides an near infinite number of viral vectors from which to choose, and we are already using directed evolution to breed specialized cancer-hunting viruses in massive quantities.
Edit: I appreciate you taking the time to point out limitations in the CINDELA method. It helps further improve.
Toranagas1 t1_jeca51a wrote
Possibly those things could help, I guess it remains to be experimentally determined. Anyway it's a decent proof of concept paper, although the in vivo data is a little weak.
Btw, they are giving a lot of doses already, every day at lower viral titers, and every 3rd day at high titers up to two weeks. Then they cut the experiments two weeks after that so we don't really get a good sense of how things would fare longitudinally but I can tell you from having read a lot of these papers that all of those mice will die pretty close to the controls, probably delayed by only a few days or a week.
I dont mean to be negative, as I can sense you are excited by the possibilities this strategy brings up, just trying to inject some realistic perspective into the data they show.
Iamdrw85 t1_jdwrxaq wrote
If you collected white blood cells and modified them to seek out sugar cells that are waxy by nature, could you potentially have a way to literally feed off of cancer cells as an immunotherapy?
EminentBean t1_jdxaqf4 wrote
That’s so fucking cool and holy shit let’s speed this research along
bateka2 t1_je03bwi wrote
As a cancer patient without treatment... "They're too small, we'll wait and see."...(but big enough to metastasize) ....I fast 75hrs every other week to increase killer cells. We are left to do whatever we can to fight our battle. I wonder if taking large amounts of guifenesin would interrupt mucin production enough to impact cancer cells?
FuturologyBot t1_jdvl6bs wrote
The following submission statement was provided by /u/BousWakebo:
The glycocalyx is developed with high levels of cell-surface mucins, which are thought to help protect the cancer cell from immune cell attack. However, up to now, there has been limited understanding of this barrier particularly as it relates to cell-based cancer immunotherapies.
These types of treatments involve removing immune cells from a patient, modifying them to seek and destroy cancer, and then putting them back into the patient’s body.
“We found that changes in the thickness of the barrier that were as small as 10 nanometers could affect the antitumor activity of our immune cells or the engineered cells used for immunotherapy,” said Sangwoo Park, a graduate student in Matthew Paszek’s Lab at Cornell University in Ithaca, New York.
Please reply to OP's comment here: https://old.reddit.com/r/Futurology/comments/123ofc9/scientists_discover_how_cancer_cells_evade_immune/jdvglq6/
[deleted] t1_jdwhgcr wrote
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[deleted] t1_jdwkc13 wrote
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ConversationOk4414 t1_jdzgv6b wrote
I know it’s been successful in treating one kind of cancer; have there been further developments with other types?
OCorinna t1_je02r0c wrote
Let me guess, they've been studying how health insurers evade payments? Or maybe it's the other way around, who knows...
aisle36 t1_jdwz1wu wrote
relax guys, Biden said himself that he would “cure cancer”
thejewdude22 t1_jdvuzgh wrote
Scientists discover another way how cancer cells evade immune system. Would be less clickbaity