[HN Gopher] Last-resort cancer therapy holds back disease for mo...
___________________________________________________________________
Last-resort cancer therapy holds back disease for more than a
decade
Author : pseudolus
Score : 236 points
Date : 2022-02-03 13:39 UTC (9 hours ago)
(HTM) web link (www.nature.com)
(TXT) w3m dump (www.nature.com)
| trynewideas wrote:
| 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]
|
| [1] https://www.nature.com/articles/d41586-020-02675-w
|
| [2] https://www.pharmacytimes.com/view/study-finds-total-cost-
| of...
| mft_ wrote:
| > - "only about 25-35% of CAR-T cell recipients with chronic
| lymphocytic leukaemia experienced a complete remission"
|
| Not sure why you picked CLL, which is but one of several
| diseases that CAR-Ts have been tested against, and which is so
| far unapproved.
|
| Response rates do vary, but are higher than you quote in B-ALL
| and DLBCL (the diseases that CAR-Ts were first approved for)
|
| 83% in B-ALL: https://www.nature.com/articles/nrd.2017.196 82%
| in ref DLBCL:
| https://www.nejm.org/doi/full/10.1056/nejmoa1707447 64% in
| DLBCL, 71% in FL:
| https://www.nejm.org/doi/full/10.1056/NEJMoa1708566
| robbiep wrote:
| I think they were just summarising the article, but also as
| you would know it was first used in CLL patients
| omarhaneef wrote:
| 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?
| diskzero wrote:
| 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.
| f6v wrote:
| 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.
| polski-g wrote:
| Luckily you can still go with a bone marrow transplant.
| justsocrateasin wrote:
| 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.
| omarhaneef wrote:
| 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?
| arjvik wrote:
| 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.)
| s1artibartfast wrote:
| My understanding is a little different:
|
| All skin cells have gene 1111, and you CAR-T goes after cells
| expressing gene 1111, killing all your skin.
|
| Some of the cancerous skin cells mutate to not express gene
| 1111, evading the CAR-T efficacy.
| mlyle wrote:
| Short, incomplete answer: Cancer evolves. After a therapy has
| failed, you've effectively selected the proportion of the
| cancer most resistant to that therapy.
| inter_netuser wrote:
| can't it be sequenced again and again and custom treatment
| prepared every time?
|
| cancer in general an umbrella term for 100s of different
| diseases.
| mlyle wrote:
| 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.
| doctoring wrote:
| 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.
| omarhaneef wrote:
| It seems it would be effective if the B-cells were still
| emitting CD-21 or some other target.
|
| I thought that they manage the CRS pretty well these days. Is
| it still a major risk?
|
| I would be very curious to know more about this wimpy or no
| response. I am doubly surprised that it doesn't help to just
| do more.
| doctoring wrote:
| 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?
|
| Here's a decent overview of some mechanisms of relapse
| after CAR-T which might be a good jumping off point:
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863137/
| omarhaneef wrote:
| Great article. thank you.
|
| 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."
| dna4cy wrote:
| 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.
| mmettler wrote:
| ELI5: will this work on other types of cancers? For example,
| breast cancer, non small-cell lung cancers, etc.?
| busyant wrote:
| 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.
| sam537 wrote:
| Simplify it like this:
|
| 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.
| aledalgrande wrote:
| Thank you, this is a very good TLDR.
| elromulous wrote:
| 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).
| aantix wrote:
| Would love to hear your story and the specifics of his
| alternate treatment.
|
| Thank-you for sharing your story.
| elromulous wrote:
| This is a much abbreviated version of the story.
|
| 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.
|
| Edit: typos
| fallingknife wrote:
| Par for the course with doctors. I really don't understand
| why they are always so against doing any kind of
| investigation.
| choeger wrote:
| Your father had all the reason to be proud of you.
| elromulous wrote:
| Thank you.
| elromulous wrote:
| 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".
| glial wrote:
| 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.
| faeyanpiraat wrote:
| Also the sheer volume of patients does not give you any
| room for getting bogged down on researching the best
| treatment for one patient.
| bobduke wrote:
| If you are willing to share the details, please do!
| voiprodrigo wrote:
| Definitely interested. Thanks for sharing.
| Agingcoder wrote:
| '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?
| doctoring wrote:
| 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.
| est31 wrote:
| 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...
| drocer88 wrote:
| Yes ( well, maybe not "all" ). For example, Yescarta(r) is an
| FDA approved CAR T-cell therapy for patients with refractory
| b-cell lymphoma. From https://www.gilead.com/-/media/files/pd
| fs/medicines/other/ye... : "Before you get YESCARTA, you will
| get 3 days of chemotherapy to prepare your body". This
| chemotherapay is "lymphodepleting" (
| https://www.yescartahcp.com/large-b-cell-lymphoma ). This
| chemotherapy decreases the number of T cells.
|
| 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 "
| inter_netuser wrote:
| They are regenerated in 2-3 months.
| mft_ wrote:
| CAR-Ts can persist ("engraft") and cause long-term
| supression of the normal B-cells, and happily the malignant
| B-cells also.
| doctoring wrote:
| 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.
| netizen-936824 wrote:
| That's likely the reason its referred to as "last resort"
|
| Having a working immune system won't do you any good if
| you're dead
| mft_ wrote:
| They aren't - that's just journalistic hyperbole, relating
| to the very first patients.
|
| CAR-Ts are now being tested in much earlier lines of
| therapy.
| kick_in_the_dor wrote:
| Very interesting! Any idea why this only works for a decade? Or
| has it only been a therapy for that long?
| sulam wrote:
| This is how long it's worked so far, the title is a bit
| misleading.
| pfdietz wrote:
| 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.
|
| https://www.science.org/content/blog-post/two-steps-activati...
| monkeycantype wrote:
| 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?
| waffle_maniac wrote:
| Leah Labs, a YC company, is using CAR-T therapy for B-cell
| lymphoma cancer in dogs. They're currently raising if anyone is
| interested.
| dna4cy wrote:
| 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.
|
| Happy to discuss what we're up to :)
| mmaunder wrote:
| That's awesome! Best of luck!!
| realce wrote:
| 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.
| dna4cy wrote:
| 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.
| realce wrote:
| HN has the most enlightening corrections, I appreciate
| you :)
| mmaunder wrote:
| Thanks for the explanation. How does this mechanism compare to
| how rituximab works? Thanks again!
| doctoring wrote:
| 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.
| ramraj07 wrote:
| The other "elephant in the room" for this and pretty much Most
| immunotherapies is they don't penetrate solid tumors.
| mateo1 wrote:
| How is that? Is their vasculature different?
| ray__ wrote:
| 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.
| f6v wrote:
| Not familiar with tumor immunology but I'd imagine it could be
| challenging to get CAR-Ts to infiltrate the tumor on demand.
| metiscus wrote:
| 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.
| diskzero wrote:
| 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.
| eecc wrote:
| My condolences
| hh3k0 wrote:
| My deepest condolences for your loss.
| doctoring wrote:
| 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.
| mft_ wrote:
| > 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.
| Dwolb wrote:
| Off topic, having seen your wife go through her experience,
| if you personally had the same issues, would you choose the
| same treatment path?
|
| I watched my dad go through a failed bone marrow transplant
| and my current stance is "no".
|
| Curious to hear your thoughts if you're able to share.
| diskzero wrote:
| 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.
| [deleted]
| pseudolus wrote:
| The New York Times recently ran a story about the same therapy.
| [0].
|
| [0] https://www.nytimes.com/2022/02/02/health/leukemia-car-t-
| imm...
| AtlasBarfed wrote:
| 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.
| uf00lme wrote:
| A universal cancer treatment seems like the holy grail, it may
| never happen but I like to have hope that science will find it
| e.g., https://www.nature.com/articles/s41590-019-0578-8.epdf
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