[doctoring]

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.

[diskzero]

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.

[doctoring]

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_]

> 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]

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]

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.

[hh3k0]

My deepest condolences for your loss.

[diskzero]

Thank you.

[eecc]

My condolences

[diskzero]

Many thanks.

[_0ffh]

That must have been harsh. Please accept my condolences!

[diskzero]

Thanks. Yes, I hope life will be kind to you and you don't have to experience anything similar.

[ThePowerOfFuet]

I'm so sorry for your loss.

[diskzero]

Thank you.

[ramraj07]

The other “elephant in the room” for this and pretty much Most immunotherapies is they don’t penetrate solid tumors.

[adamredwoods]

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.

[mateo1]

How is that? Is their vasculature different?

[ray__]

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.

[mateo1]

Thank you for the detailed answer.

[jdavis703]

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?

[est31]

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]

Yes ( well, maybe not "all" ). For example, Yescarta® is an FDA approved CAR T-cell therapy for patients with refractory b-cell lymphoma. From https://www.gilead.com/-/media/files/pdfs/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 "

[doctoring]

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]

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_]

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.

[inter_netuser]

They are regenerated in 2-3 months.

[mft_]

CAR-Ts can persist ("engraft") and cause long-term supression of the normal B-cells, and happily the malignant B-cells also.

[inter_netuser]

how common is that?

[spopejoy]

> This destroys all your B-cells in your body, right?

If you have DLBCL/FL, all treatments go after B-cells. CAR-T is just better at doing that and nothing else.

[pfdietz]

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]

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]

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]

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]

That’s awesome! Best of luck!!

[adamredwoods]

Iowa State alums! Me too.

[pabs3]

Are you looking at cats too? ;)

[realce]

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]

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]

HN has the most enlightening corrections, I appreciate you :)

[f6v]

Not familiar with tumor immunology but I’d imagine it could be challenging to get CAR-Ts to infiltrate the tumor on demand.

[metiscus]

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.

[kick_in_the_dor]

Very interesting! Any idea why this only works for a decade? Or has it only been a therapy for that long?

[sulam]

This is how long it's worked so far, the title is a bit misleading.

[mmaunder]

Thanks for the explanation. How does this mechanism compare to how rituximab works? Thanks again!

[doctoring]

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.