CAR-T therapy is incredibly complex and incredibly cool.
One of the reasons CAR-T therapy has been so successful thus far with certain lymphomas and some leukemias is that there is a specific surface protein (CD19) which is expressed in all B-cells (the deranged lineage in the case of lymphoma) and is also not expressed by any other cells in the body. By engineering a patient's T-cells to target CD19, you create a highly sensitive and specific attack that recruits their own immune system to annihilate the entire B lineage population.
One problem we run into when trying this for other cancers (like, that don't come from B-cells) is that it's been really hard to find such a nicely specific surface protein, as well as an entire population of cells you can just annihilate and be survivable for the patient. Most surface proteins are expressed in varying degrees throughout various different organs in the body, so a CAR-T against it would cause a ton of off-target effects. In some early trials for certain cancers they encountered this with unfortunate side effects (including in some cases death). Nevertheless, there is lots and lots of research still ongoing in the field, which is super exciting, from trying out previously unknown targets, to figuring out how to better produce the T-cells, to enhancing the resultant immune response cascade, etc etc.
CAR-T therapy is indeed very cool and very promising against certain lymphomas. My wife had triple-hit DLBPL (rearrangements of the c-MYC, BLC-2 and BCL-6 genes) and received CAR-T therapy. The therapy itself almost killed her due to neurotoxicity and other immune responses. We were initially very optimistic as the CAR-T cells rapidly destroyed the cancer cells and visible signs of the cancer on her body vanished. The cancer is her brain was eliminated, but after a few weeks, the lymphoma in her body came raging back, causing pleural effusion, swelling and horrible pain. Keytruda (pembrolizumab) was started as a salvage therapy but wasn't effective. Time of diagnosis to death was 10 months. CAR-T was administered in the middle of July and Melanie died on the first of October.
For those wondering, she received several rounds of DA-EPOCH-R chemo for the lymphoma, high dose methotrexate for the CNS involvement, had a port installed in her chest and an Ommaya on her skull that allowed drugs to be put into her brain (intrathecal treatment.)
The first rounds of chemo were pretty effective and she had a few good months. The brain involvement eventually damaged some nerves which caused Bell's palsy, which causes eye droop and facial paralysis. It sort of looks like the results of a stroke.
For those curious, the CAR-T therapy itself was $650,000 US. Getting the blood to create the T-cells involved yet another special catheter getting put in to do the draw. The CAR-T infusion was a big deal at the cancer center; lots of staff came by to observe. It was also super stressful for Melanie and everyone as there was a pretty fast reaction to the infusion. She ended up in the ER about six hours later and was in the ICU for about a week.
One thing I do wonder is if some of the drugs used to moderate the CAR-T cell expansion slowed things down enough that some of the cancer was able to avoid the T-cells? Regardless, if things weren't slowed down, she would have died from the infusion.
Wow, I am so sorry. Thank you for sharing part of Melanie's story.
Your thought about the drugs maybe limiting the effect of the CAR-T is an interesting one and the subject of ongoing investigation. One common drug used for CAR-T related cytokine release syndrome, tocilizumab, does not appear to have negative effects on CAR-T proliferation or efficacy. However, it doesn't seem to do as much for neurotoxicity (which seems to be a separate mechanism from the cytokine system), and they often have to resort to steroids for that. Steroids do dampen T-cell activity, but to what degree that impacts CAR-T effectiveness is not clear. However, as you mention, sometimes you are left without much choice.
> Steroids do dampen T-cell activity, but to what degree that impacts CAR-T effectiveness is not clear.
It's an interesting question. Tangential, but in the early days of discussing how to incorporate anti-PD1s into different treatments, there was lots of concern about the negative effects of steroids --let alone chemo-- on T-cell function. Yet a few years later, aPD1 + chemo is well established in lots of settings.
And likewise, despite data from mouse models that steroids and chemo do impair T-cell function, we're now seeing CAR-Ts and also CD3-engaging bispecific Abs combined directly with chemo - again, with good efficacy.
If I knew that my outcome and experience would be identical, I wouldn't have the CAR-T therapy. The chemo (DA-EPOCH and methotrexate) gave Mel a few months of life with decent quality, but then things got very very difficult. The question for me would be, how do you determine when to stop treatment? The therapies keep improving, so that keeps hope alive.
We want to stop the metastatic portion of the disease, as that is what causes death in so many cancers today. There is no cure, yet if we can stop cancers from tumor metastasis, move to a state of being under chronic care for 10+ years, I would consider this a huge step.
Vasculature in and especially around tumors is usually different. Malignant cells consume a vast amount of energy relatively speaking, and often over-express proteins that recruit blood vessels in order to feed this energy demand (VEGF is the one that is discussed the most afaik; this process is called angiogenesis). Inhibiting these proteins is a common chemotherapeutic strategy, see bevacizumab and ranibizumab. Despite this process most solid tumors are hypoxic at their centers and hypoxia-activated prodrugs that are "activated" within hypoxic environments (and toxic after activation) is yet another chemotherapeutic strategy, see evofosfamide or apaziquione.
Solid tumor penetration isn't really related to this though, it has a lot more to do with the fact that it is physically difficult for a molecule to diffuse through the many layers of cells that make up a solid tumor. When you take a drug, it generally ends up in your bloodstream and from there must diffuse through the lipid bilayers that encapsulate cells (whether they be cancer cells or not) in order to reach their target. This diffusion is a big barrier when it comes to designing drugs, because most things won't passively diffuse through lipid bilayers. A successful small-molecule drug will be able to 1) bind to its target effectively enough to stop that target from doing some disease-causing thing, 2) not bind to other things that are important for cellular function, and 3) get into the cell in the first place, without being broken down before it gets there. Balancing all 3 of these requirements is tricky, but rules of thumb have been developed for 3) that help guide the design of small molecules.
Perhaps the most important guideline for 3) is size. Most small molecule drugs (anything that you take in a pill, along with many chemotherapeutics) are designed to be < 500 Dalton. Once you get over 800-1000 Da diffusive cell penetration is rare (there are interesting outliers, cyclosporine cruises through lipid bilayers despite weighing in at ~1200 Da). Immunotherapy generally involves retraining your immune system by introducing antibodies (~150 kDa+) or whole T-cells. These modalities can generally only target things on the outside of cells, because there is no way they're getting inside, and they certainly won't be able to pass through the many layers of cells that make up a solid tumor.
tl;dr is that immunotherapeutic agents won't be able to penetrate solid tumors by diffusion because they (the antibodies and cells involved in immunotherapy) are too big, and there isn't any other mode of entry. I do wonder if a true immune response would need to penetrate at all though, because presumably T-cells would break down a solid tumor layer by layer if the appropriate antigen was present. I'm not sure how correct this line of thinking is though.
If we threw say $100 billion in to computer aided protein design (sorry not sure the technical phrase here), could we make it faster to create antibody therapies? Like not just for cancer, but also for infectious diseases?
This destroys all your B-cells in your body, right? That means the B-cells aren't available for normal operation any more, right? I guess it's better to be immuno compromised than dead...
Gilead just reported a 5 year follow up on their therapy : https://www.gilead.com/news-and-press/press-room/press-relea... . " 92% of Patients Alive at Five Years Have Needed No Additional Cancer Treatments; Data Suggestive of a Potential Cure for These Patients "
Yes. B-cells (normally) make antibodies, so these patients usually receive regular infusions of antibodies by IV (which come from blood donations) to keep their circulating antibody levels up.
There's a related approach that creates in effect an "and" gate on the cells. They attack another cell only if it expresses two specific proteins on its surface. This should enable a wider range of cancer types to be targeted.
Something I've been thinking/wondering about. I'm clearly not an oncologist, so what i've been thinking about may already be standard - One of the features of cancer cells is that as cell division becomes dysregulated, karyotypes become deranged. There are missing, duplicated, truncated, hybrid chromosomes. If we could find ( or more drastic introduce ) a protein that is always expressed from each chromosome or can be induced to be expressed through a drug in every cell, how could you come up with a treatment that is deactivated by the presence of these proteins. While tumor cells in an individual are heterogeneous, if you had a treatment consisting of a compound that stimulates the production of a certain enzyme, and a drug that is deactivated by a certain enzyme, could you use this to kill all cells that lack the chromosome that code for that enzyme?
Perhaps this is already done in chemotherapy, where a compound induces it's own breakdown in healthy cells, but is this done in a chromosome by chromosome strategy?
Founder CEO of LEAH Labs here. Our pilot studies in dogs with cancer are slated to start in April.
We're first focused on the unmet need for dogs and working to build the first companion animal health company founded on gene editing expertise. That said, our platform is also built with human medicine in mind, as dog and human cancers are quite analogous to one another. We envision using spontaneous cancers in pet dogs as pre-IND or IND-enabling models for novel human cell therapy development. Also, CAR-T in dogs is regulated by the USDA, not the FDA, which helps us do all of this quicker and significantly more cost-effective.
Just talked to somebody yesterday who had one of these vaccines made for their dog. It actually seemed incredibly affordable compared to other treatments, something like 500-2000 for the formation of the vax.
Tumor vaccines are not at all equivalent to CAR-T. CAR-T involves genetically reprogramming T cells with information encoding a specific signal to find cancer, recognize it like a lock and key, and then destroy it.
CAR-T > tumor vaccines in humans for blood malignancies, and we envision the same for dogs.
I know there are groups seeing some successes in solid tumors with tumor vaccines, however.
Not a medical guy but ipilimumab and friends may help do that. They blockade ctla-4 which downregulates cd4 activity. A combination may result in enhanced results.
Rituximab is a monoclonal antibody which targets a B cell surface protein, CD20. Monoclonal antibodies are pretty cool, in that we've figured out how to make a thing that our bodies normally make, and engineer versions that target specific items we want. Antibodies binding to things can alter their function, disable them, and/or cause them to die. In the case of rituximab and CD20, through a variety of antibody-mediated mechanisms, the attached antibodies in effect causes the B cells to die off.
CAR-T cells, on the other hand, is essentially making a fairly small (but kind of insidious) modification to T cells in the lab. These T cells when put back in the body then do their normal T cell thing and proliferate and recruit more of the immune system, but to try to eliminate a target you've chosen for them. The most useful/successful target thus far has been CD19, another B cell surface protein.
T-cell: very effective at killing; not as good at recognizing specific things.
Antibodies: not that effective at killing; excellent at specifically recognizing things.
CAR-T: Let's stick an antibody against X (eg CD19, CD22) to a T-cell surface so it can recognize with the antibody and kill with its innate capacity to kill.
Ta da!
It's fascinating, it is changing hematologic oncology. The bad news is, as always, the price and the manufacturing time (2-8 weeks). This last part seems to be getting better.
It's my understanding that this is no longer _actually_ a $600,000K+ price tag anymore but that drug firms are now in the "profit recouping" phase. Decide for yourself if that's the way it should be but the good news is that it definitely will not be insane forever.
I've had this thought that natural ability to fight of cancer cells was a precision/recall problem for the cells. Good to see that the body has ways to approach this problem. Really cool to see us use antibodies to really improve the recall
every time I see a headline like this I always ask
- which cancers
- for whom
- what's the trial size
- what's the success rate
- what's the cost
the article answers some, to some degree:
- for "leukaemias, lymphomas and myelomas"
- not many; "relatively few US centres are capable of delivering it", "For people with lymphoma, the figure is around 1 in 5" people who could benefit are receiving it [1]
- "tens of thousands"
- "only about 25-35% of CAR-T cell recipients with chronic lymphocytic leukaemia experienced a complete remission"
- as of 2021 per Prime Therapeutics, "Although the wholesale acquisition cost of chimeric antigen receptor (CAR) T-cell therapies to treat B-cell lymphoma is $373,000, a new study by Prime Therapeutics of real-world data found that the total cost averages more than $700,000 and can exceed $1 million in some cases." [2]
I know that "cancer" isn't actually one disease, it is a cacophony of different gene expressions in different tissues.
Immunotherapies like this IMO show the real issue with "curing" the disease: there won't be a one-size-fits-all pill to pop that will work.
Instead we may need individualized/highly customized medicine. Alas this might not be in the "profit profile" of a typical pharma company. So it might cost 250,000$ to cure cancer, but it is a CURE, genetically specific to your cancer and genetics. Not a perpetual therapy like the phama execs like.
That may take an army of lab workers, or some pretty interesting lab equipment.
But the payoff is great. FORTY PERCENT of Americans will be diagnosed with cancer in their lifetimes.
For those interested in some of the history of immunotherapy, and cancer treatments more generally, I recommend Dr Peter Attia's excellent interview[1] with Dr Steven Rosenberg. Dr Rosenberg is Chief of Surgery at the National Cancer Institute, and was on the ground floor and helped pioneer the use of immunotherapy in fighting cancer[2].
Just an fyi - while car-t is very promising in many ways, it has not been effective against solid tumors.
Last time I looked into this (while my father was still alive and battling cancer, 2020), attempts to get car-t to be more effective against solid tumors have failed pretty consistently. This is why you only see car-t mentioned with leukemias, lymphomas, etc.
Side note: If you're reading this because you're desperately looking for cancer treatment for a loved one, keep looking! I can share my personal anecdote if folks are interested, but the tldr is that my own searching ended up being fruitful and resulting in treatment that extended my father's life (pain and side effect free!). And without my insistence, the doctors treating him would have simply followed the conventional treatment (the dreaded FOLFIRINOX).
My father was diagnosed with Ampulla of vater carcinoma. It's a pretty rare cancer, most similar to pancreatic cancer. After the curative options had been exhausted (read: cancer returned after surgery), the oncologist started a regimen of abraxane and one other chemo agent (I'm blanking on the name right now). These of course come with their share of side effects, as they are "classic" chemo. Not to mention their efficacy is pretty terrible. But really at this point we needed more data. They had never sequenced the tumor. Many, many emails and calls later, the doctor finally agreed to order the sequencing. Till this day I don't know why there was so much resistance to this (also keep in mind, this wasn't some rural hospital, this was at Johns Hopkins). Some time goes by and we finally get the results. The results showed a brca mutation. This was of course excellent news, as the brca mutations are very widely studied due to their connection with breast cancer. After some research, it turned out parp inhibitors were the latest most effective treatment at the time, specifically Lynparza. Again, many emails and calls, until the oncologist agreed to prescribe it. And unlike the conventional chemo agents, this was taken orally and had few if any side effects. Months go by and the ct results come in - the tumors are shrinking! All in all my father remained in remission under the parp inhibitors for a little over a year, side effect and pain free (I can't stress that last part enough). Lynparza eventually stopped being effective (this is believed to occur due to the cancer mutating). We subsequently tried a clinical trial but in the end the battle was lost, and my father passed.
While the parp inhibitor wasn't a cure, my father, my family, and I, would not give up that extra year for the world. So the tldr is: don't just listen to the oncologist, get a second opinion, don't be afraid to read hundreds of medical papers, and definitely badger the oncologist if you have salient information.
Just to add one note, really the biggest issue I have with the oncologist's actions is that they seemed to mindlessly follow a playbook. If x fails, apply y. With very little information gathering, and very little researching on newest therapies. And being a terribly rare cancer, it's likely this was the first time in their career they were even encountering it. But they just went with "approximate to cancer I know, now follow outdated pancreatic cancer playbook".
I'm not a medical doctor, but I wonder if this can be explained as liability-avoiding behavior. If a doctor follows a "best practice", it's more defensible in court than trying something new or uncommon.
although too late to help your father, anyone facing acquired resistance to PARP inhibitors should look into novobiocin [0].
novobiocin is an antibiotic developed decades ago but recently "rediscovered" as offering anti-carcinogenic against some cancers which resist PARP inhibitors. in short, it targets an enzyme (polymerase theta) critical to these cancers.
thanks for sharing this story.
i'm so sorry for your loss, but it is amazing how such persistence and critical thinking offered your father and family another treasured year of life. he must have been unbelievably proud.
It's really the cancerous tissue that has to be sampled. Part of what makes cancer so hard to fight is its ability to mutate quickly. Someone with enough means would likely have a tumor sampled multiple times (for instance, sample again after the treatment stops working).
As a absolute non-expert, the cancer deaths I have heard about seem to often include surgically removing the solid tumor but perishing due to metastasis - so in that regard, wouldn't a combination of surgery followed up by car-t be a reasonably reliable way of ensuring that the cancer gets actually eliminated?
For solid tumors, what comes to mind is injecting the chemo drugs directly into the center of the tumor. Stronger chemo drugs could be used, that would be degraded before they "broke out" of the solid tumor.
Jimmy Carter hasn't received CAR-T therapy afaik, but he's gotten other recently developed immuno modulatory anticancer therapy --pd1 inhibitors-- and I suspect that's a big reason for him still being alive.
I can say the same for a family friend who probably had 6 months to live w advanced prostate cancer (this was about ten yrs ago). Shortly after his prognosis a new prostate cancer drug--xtandi-- was approved and he lived another 5 years.
Many anticancer drugs have incremental benefit, but some recent advancements have been revolutionary.
I don't understand why they can't do it again if a person relapses. Why is it a one time only event? Or, to put it another way, when the efficacy wears off, why does it persist?
There's a couple of reasons for why a person may relapse after CAR-T therapy, and much is still under investigation.
One large category is that the attack on the CD19 target has selected for B-cells which have a mutated CD19 or do not express CD19. This part kind of makes sense, and is somewhat understandable.
The other category is roughly that the CAR-T cells fucked up, and this is where things are a little murky. Sometimes the CAR-T cells kind of disappeared really quickly after infusion. Sometimes they're there but there's no significant immune response. Remember the therapy uses the patient's own T-cells which get "armed" outside the body and then re-infused. What if the patient's own T-cells are kind of uh, wimpy? Or their immune system overall is? (We know, for example, that T-cell immunity in general declines over age, which probably partly explains better results in younger patients than older).
Anyways, for various reasons, you can see why just "doing it again" may not work due to some issue with the targeting and the immune reaction.
Oh and also CAR-T therapy is not benign. You can get intense cytokine release syndrome where the (intended) activation of your immune system causes a ton of systemic effects (sometimes resulting in organ failure, seizures, death).
Nevertheless, sometimes they do try it again. I've had patients they've attempted CAR-T two or three times on. As you may guess, it was not effective.
Choosing another target is a good idea! But, as you can imagine, we've been trying a lot of targets and they don't seem to work as well. One issue is that CD19 is the only known target that is a) expressed throughout the entirety of the B-cell lifespan, b) fairly preserved under immunological pressure, and c) is not expressed on other cells. Other targets do not maintain those characteristics and as such either won't catch all the tumor cells or will catch too many other cells. (CD21, for example, is also expressed on T-cells.)
That being said, there are studies ongoing for some of these targets in like "last last resort" capacity, as well as certain dual-target CAR-Ts looking at CD19 + another (CD22 or CD123, for example), to try to widen the net while tolerating a degree of on-target but non-tumor effects.
One could also imagine a way to more rapidly alter a patient's CAR-Ts such that you could quickly switch targets, or update them if their malignant CD19 was mutating. Currently the manufacture and production of CAR-T cells is very slow and expensive process, but I do have some friends working on improving that. Some are also working on the idea of a sort of "blank slate" CAR-T cell line which could be used in anybody, rather than being harvested from the particular patient in question.
re: CRS. It is still a significant risk, but our understanding has definitely dramatically improved over the past 10 years. We're getting better and better at anticipating, appropriately triaging, and providing necessary diagnostics & supportive care. That being said, severe outcomes and death do still occur. I don't know the numbers, to be honest.
re: the wimpy response. I am less well-versed in the immunological complexities but there are just so many steps which could contribute. Part of the CAR-T cell success requires them to continue to clonally expand after infusion into the body, and sometimes after infusion they just... don't. Or only a tiny subpopulation of them does. Why? We're not sure. Sometimes they fail to recruit the body's immune response. Why? Also not sure. Maybe it has to do with the health of the T-cells when they were harvested? Maybe something went wrong with the CAR engineering? Maybe with the host immune system?
It seems following up with CD22 is a useful practice:
"Another Single-Targeted CAR T-Cell
Loss of CD19 is a common mechanism of relapse after treatment with CD19-targeted CAR T-cells. Similar to CD19, CD22 is also diffusely expressed in B cells in patients with B-ALL (92–96), and CD22 expression can be detected in a number of patients with CD19-negative relapses (14). Single-targeted CD22 CAR T-cell therapy is also a common therapeutic tactic for CD19-negative relapse. A phase I dose-escalation trial of a novel CD22-CAR with a 4-1BB domain was conducted (97), which enrolled 21 children and adults with R/R B-ALL, involving 17 children who did not receive CD19-directed immunotherapy. A CR rate of 73% was observed in patients receiving CD22-CAR T-cells, involving 5 patients with dim or without expression of CD19 in leukemia cells."
Although I am confused because the next section, while touting the benefits of CD19/CD22 cocktail doesn't present much better statistics:
"Sequential Infusion of Two Groups of Single-Targeted CAR T-Cells
Clinical studies (98) have shown that sequential infusion of third-generation CD19 and CD22 CAR T-cells, which is called cocktail therapy, is feasible and safe for patients with R/R B-ALL (Figure 4A). In a clinical trial, cocktail therapy was used to treat 27 patients with R/R B-ALL. As a consequence, the trial yielded a 6-month OS rate of 79% and an event-free survival rate of 72% with sustained remission, in which 24/27 (88.9%) patients received CR or CRi, and 13/27 (48.1%) patients attained MRD-negative CR. The center subsequently enrolled more candidates (99), among whom 81 patients received CAR22 T-cells following the infusion of CD19 CARs, while 8 patients received CD19 CARs following the infusion of CD22 CARs. The median follow-up time was 7.6 months. Among 50 evaluable patients, 48 (96.0%) achieved CR/CRi by day 30, 94% of whom were MRD-negative. The PFS of B-ALL patients was 12.0 months, and the median OS was not reached. In total, 23 patients experienced a relapse, with no CD19 or CD22 antigen loss observed. Drawing on the finding that a high MRD-negative rate in R/R ALL patients was achieved by sequential infusion of third-generation CD22 and CD19 CAR T-cells, demonstrating this method has great feasibility for the treatment of CD19-negative relapse ALL."
It's at least better than most chemos. If CAR-T introduced a decent remission (1-3 years) and didn't invoke CRS, you can at least consider trying it again, unlike doxyrubicin etc.
This may be an oversimplification, and I could be wrong, but the way I understand it is this:
Relapse events are often triggered by an alternative mutation in the cancer. So let's say your skin cell becomes cancerous because gene 1111 mutates. You have, let's say, a million other genes that dictate your skin cell, and maybe like a few dozen mutations that could be cancerous (some mutations are harmless). So the T cell targets that gene 1111 mutation, but as a response, either that same mutated cell mutates again, or a healthy cell mutates. Now it's gene 1232 that mutates, but your T cells are modified to only recognize that gene 1111 mutation, so the new gene 1232 mutation sneaks by without being killed by the T cell.
There are a lot of intuitions I have about why you can't just do it again, and ultimately I think it depends. Maybe gene 1232 doesn't change a protein that T cells can target without killing your other cells. Maybe your skin cell has dozens of mutations but 99% of them aren't cancerous, and we don't yet have the right signal/noise reduction in sequencing / the right AI to determine the mutation that is causing the cancer. Here we need to keep in mind that these proteins are very small and very hard to determine the structure of. Cancer cells can be very hard to differentiate from normal cells in a way that you can target them, so a new mutation is a whole new puzzle to solve.
If I am wrong please correct me - my degree is in chemistry / applied math and not genetics/biology and this info comes from domain knowledge I pick up at my job (SDE for a cancer company) + books I've read.
So let's say you're targetting cd19 (the protein). You're saying that the target might stop emitting cd19. Okay, but then why not target cd21 or another target that the cancer is emitting, and run CAR-T again?
Sometimes the cancer doesn't emit any marker proteins, or maybe the ones it does are difficult to detect/create antibodies to bind to.
(I'm in the same situation as 2 above, I'm a software engineer with domain knowledge from working in a cancer research lab at a university; I may be entirely wrong.)
You need to choose a marker that you can "afford" to use for destruction - which either doesn't exist at all in healthy cells, or, more likely, it exists but losing all your healthy cells with the same marker won't kill you (but is still likely to harm you, just in ways that can be treated). Such markers are scarce, and not guaranteed to exist; if we find one for this cancer (like CD19) that works, but if it fails, then it's exceedingly likely that targeting "cd21 or another target" will simply kill you because it will also destroy some vital cells in your liver or veins or brain.
Short, incomplete answer: Cancer evolves. After a therapy has failed, you've effectively selected the proportion of the cancer most resistant to that therapy.
It all comes down to what surface receptors the cancer is presenting on whether you can get T cells to attack it.
If the B-specific receptors are gone on your B-cell lymphoma, there may not be a great target left that isn't also on a bunch of cells you need.
Each thing you do that targets "weird" characteristics of cancer (or bacterial infection, or pests) selects for cancer (or bacteria, or pests) that is presenting as less weird relative to everything else around.
One reason would be that CD4 and CD8 populations undergo major changes with age. There’s a shift towards exhausted phenotype. Immune system produces fewer and fewer naive T cells in the bone marrow, thymus is less efficient in adulthood as well. I’d imagine CAR-Ts are less efficient in older adults. So getting in relapse after a decade would put a patient in a different position.
Other good answers are here about additional mutations occurring, making the cells no longer receptive. Another reason is that receiving CAR-T itself is quite risky. Almost everyone experiences some level of neurotoxicity, decreased cognition and more. It is my hope that these negative effects caused by the treatment will vanish, as CAR-T itself is pretty amazing.
In addition to what others have written (mainly, loss of tumor antigen target CD19) the antigen receptor (part of the CAR) can be recognized as foreign (FMC63 on human CD19 targeting CARs is mouse origin) and the body will generate an antibody response to it. Thus, the second time CAR-T is infused, they are quickly rejected.
'In the beginning, only about 25-35% of CAR-T cell recipients with chronic lymphocytic leukaemia experienced a complete remission of their cancer, says Porter.'
I'm not very familiar with pharma success rates, but isn't complete remission for 30% of virtually dead patients already an incredibly good result?
If anybody is interested, there was a phenomenal documentary made a few years back, about the early clinical trials of CAR-T therapy for Leukaemia students.
One of the reasons CAR-T therapy has been so successful thus far with certain lymphomas and some leukemias is that there is a specific surface protein (CD19) which is expressed in all B-cells (the deranged lineage in the case of lymphoma) and is also not expressed by any other cells in the body. By engineering a patient's T-cells to target CD19, you create a highly sensitive and specific attack that recruits their own immune system to annihilate the entire B lineage population.
One problem we run into when trying this for other cancers (like, that don't come from B-cells) is that it's been really hard to find such a nicely specific surface protein, as well as an entire population of cells you can just annihilate and be survivable for the patient. Most surface proteins are expressed in varying degrees throughout various different organs in the body, so a CAR-T against it would cause a ton of off-target effects. In some early trials for certain cancers they encountered this with unfortunate side effects (including in some cases death). Nevertheless, there is lots and lots of research still ongoing in the field, which is super exciting, from trying out previously unknown targets, to figuring out how to better produce the T-cells, to enhancing the resultant immune response cascade, etc etc.