[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 ___________________________________________________________________ (page generated 2022-02-03 23:00 UTC)