This week we talk about CAR Ts, lupus, and antigen-presenting cells.

We also discuss Hashimoto’s, potential cures, and allergies.

Recommended Book: The Avoidable War by Kevin Rudd

Transcript

Chimeric antigen receptors, usually shorthanded as CARs, are a type of protein structure that receives and transmits signals within biological systems.

The term "CAR T cell" refers to chimeric antigen receptors that have been altered so that these structures can give T cells, which are a component of the human body's immune system, attacking stuff that our immune systems identify as being foreign or otherwise potentially harmful, it gives these T cells the ability to target specific antigens, rather than responding in a general sense to anything that seems broadly off.

So while T cells are generally deployed en masse to tackle all sorts of issues all throughout our bodies all the time, CAR T cells can tell them, hey, see this specific thing? This one thing I'm pointing at? Go kill that thing. And then they do.

The potential to use CAR Ts for T cell-aiming purposes started to pop up in scientific literature in the late-1980s and early-1990s, and in the mid-90s there was a clinical trial testing the theory that T cells could be guided in this way to targeted cells throughout the body that are infected with HIV.

That clinical trial failed, as did tests using CAR T approaches to sic T cells on solid tumors; there just didn't seem to be enough persistence in the T cells, in their targeting, to do much good in this regard.

Second-generation CARs improved upon that original model, and that led to tests with more follow-through, better focus for those guided T cells, basically, and that improved their capacity to clear solid tumors in tests.

By the early 2010s, researchers were able to completely clear solid cancers from patients, leading to complete remissions in some of them, though those patients were also treated with more conventional therapies beforehand.

These new approaches led to the first two FDA-approved CAR T cell treatments in the US in 2017, for a type of leukemia and a type of lymphoma.

As of late-2023, there were six such treatments approved for use by the FDA, most of them leveraged only for cancer patients who didn't respond well to conventional treatments, or who continued to relapse after several rounds of cancer therapy. It's a last line of defense, at this point, in part because it's still relatively new, and in part because the current collection of CAR T therapies seem to work best when the cancers have already been weakened by other sorts of attack.

What I'd like to talk about today is another potential use for this same general technology and therapy approach that, until recently, was considered to be a really pie-in-the-sky sort of dream, but which is rapidly becoming more thinkable.

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There's a theory that essentially all human beings have some kind of immunodeficiency: something that our immune systems don't do well, don't do at all, or don't do in the expected, baseline way.

Any one of those immunodeficiency types can result in issues throughout a person's life, ranging from a higher-than-normal susceptibility to specific infections to a tendency to accidentally target healthy cells or biota, which can then result in all sorts of secondary issues for the host of those cells or biota.

One especially pernicious and increasingly common issue in this space is what's called autoimmunity, which refers to the tendency of one's immune system to attack one's own cells and tissues and organs.

If these autoimmune attacks are substantial and consistent enough, they can cause a disease in the afflicted body components, and diseases caused in this way are called autoimmune diseases.

You've almost certainly heard of some of the more common of these diseases:

Lupus, for instance, varies in its specifics, but arises when someone's immune system attacks their skin or muscles or joint tissues or components of their nervous system, resulting in an array of problems that has earned this disease the categorization as a "great imitator" condition, because it replicates the symptoms of a slew of other diseases and disorders.

Folks with celiac disease experience all sorts of gut issues, primarily centralized in the small intestine, that disallow the comfortable and healthful consumption of gluten, which is present in all sorts of foods and which, if consumed, can cause incredibly uncomfortable and painful side effects, alongside other gut-related problems.

Type 1 diabetes is an autoimmune disease, as is multiple sclerosis, rheumatoid arthritis, Addison's disease, Grave's disease, and Hashimoto's thyroiditis, in which one's immune system slowly destroys one's own thyroid, causing all sorts of problems, including, potentially, hypothyroidism and sometimes a rare type of cancer called thyroid lymphoma.

All of these issues are associated with a variety of other issues beyond their initial, simplified portfolio of symptoms because our bodies are ecosystems, all the things connected to all the other things, so it's borderline impossible to tweak one thing without causing ripples throughout the rest of the system.

If part of that system attacks another part of the system, then, there will be waves of long- and short-term consequences resulting from both the attack and the damage caused by the attack, so these issues, though in some cases quite mild, depending on the person who has them, can also flare-up periodically, after being triggered by something or for no apparent reason, and they can change in nature over time, perhaps seeming like nothing, flying under the radar most of our lives, until one day they pop up out of the woodwork, wreaking all sorts of havoc that can be debilitating and terrifying, especially since the person experiencing those issues generally doesn't know what's happening and may initially attribute them to something else.

I actually speak with experience in that regard, as I have Hashimoto's, and only found out about it a few years ago—and it took nearly a year to figure out what was suddenly causing all sorts of health problems that seemed to arise from nowhere, but which were apparently lurking there, waiting to crest the surface of awareness, for the thirty-plus years it took me to reach that point.

So autoimmune diseases are varied but stem from the same core issue of our immune systems attacking some component of the bodies they're meant to defend, and though the majority of such disordered immune system behaviors will lead to nothing, causing no damage and possibly being counteracted by some other component of our complex internal ecosystems, some cause damage leading to disease, and some of those diseases are significant and life-altering or life-threatening.

About 50 million Americans have one of the more than 100 tracked autoimmune diseases, and it's estimated that something like 4% of the total human population has at least one autoimmune disease, though methods of identifying and tracking such things are imperfect, and methods for doing so vary greatly from country to country.

It's long been known that women suffer from a lot more and more intense autoimmune diseases than men—about 80% of people who have autoimmune diseases are women—and the results of recent research suggest this may be because a molecule called Xist (which deactivates one of a woman's two X chromosomes, preventing the dangerous overproduction of proteins in their bodies) seems to play a role in the production of molecular complexes that are linked to a lot of the autoimmune diseases we track, those complexes triggering chemical responses that spark the cascade of other issues that then result in autoimmune problems.

This is still very new science and a lot of the more thorough looks into the Xist molecule have been in mice, so far, so while some exploration of this same process has been done in humans, this is still pretty speculative right now.

That said, better understanding this molecule and its triggers, and other potential, similar triggers, might someday help us bypass or reduce the influence of those chemical responses, which could in turn reduce the incidence or impact of these diseases.

For the foreseeable future, though, we'll probably be plagued, on a significant scale, by autoimmune diseases. And the number of people suffering from these things seems to be going up; there's some evidence that folks are more prone to some autoimmune diseases after being infected with COVID-19, which suggests there might be a long-term infection component of these sorts of issues, with the viruses and bacteria we encounter over the course of our lives messing with our bodily functions just enough to tweak the variables that inform our autoimmune behaviors, sometimes permanently and negatively.

But incidences of autoimmune disease have been on the rise for years, and there's some evidence that points at what we might call the Western Diet and its spread around the world for some of this increase, as the real uptick began about 40 years ago, when the American version of the Western Diet started to go global in a big way, and in the wake of that spread we've seen inflammatory bowel disease surge in the Middle East and Asia, along with the seeming export of Type 1 Diabetes, multiple sclerosis, and rheumatoid arthritis across parts of the world that had never really seen them on any scale before, but which, after the installation of a bunch of McDonalds and the introduction of highly processed foods to global supermarkets, began to show up in a big way.

This is also still pretty speculative, so take this with a grain of salt, and it's also worth noting that environmental variables like the food we eat is only one component of this issue, even if a more direct causal relationship could be proven: you can eat nothing but ultra processed foods and never develop and autoimmune disease, and you can eat a perfect whole foods diet and develop one; none of these seeming amplifiers are being flagged as absolute causes: this seems to be something we're prone to, regardless, and the way we live and how we eat and maybe even the microsplastics in our environments are maybe tweaking the likelihood of autoimmune predispositions becoming autoimmune issues—they're probably not sparking the potential for those issues out of whole cloth, though, based on what we currently know, at least.

Whatever's causing or fanning the flames of this increase in autoimmune issues, though, a recent series of announcements is becoming more significant as those numbers increase.

Therapies based on research that was initially conducted back in the early 2000s suggest that it may be possible to either kill or dampen the impact of the cells that attack our own bodies as part of an autoimmune disfunction.

It was reported back in 2022 that five people suffering from a severe autoimmune disease had those diseases driven into remission by a therapy that uses CAR T cells to tell the body to attack the patient's B cells, which in the case of these patients, were the cells responsible for their lupus.

So this therapy programmed some of their T cells to attack their B cells, which were causing their symptoms, including lung inflammation, fatigue, arthritis, and fibrosis of their heart valves, and those symptoms then cleared up; the attacks stopped, and so did their symptoms.

Even more interesting is that once the B cells were wiped out, the ones behaving badly, the therapy was halted, their B cells populations started to tick back up because the T cells stopped attacking them, but the new B cells didn't engage in the damaging behavior—they did what they were supposed to do, rather than attacking their host.

The subjects' immune systems were also tested, as the researchers didn't want solve one problem but cause another, impairing their patents' immune systems in such a way that they were then prone to all sorts of other infections.

That didn't seem to be the case: their immune responses were similar to those of other people, and that led them to conclude that the reprogrammed T cells were primarily targeting the bad B cells, not wiping out the whole of their immune functionality; which was a real issue with earlier versions of this concept which were tested about five decades ago, most of which basically demolished a patients' immune system and hoped for the best, leading to unfortunately predictable and terrible outcomes.

In the year or so since that initial trial was conducted, ten more people have had their severe autoimmune diseases forced into remission by this approach, and there's now hope that it might also work on other such conditions, beyond the three that it has been shown to work on, so far. 

There's another, related approach being tested that aims to help the body develop a better sense of self-awareness, boosting its tolerance for what it wrongly perceives to be bad stuff, so that it doesn't have such a hair-trigger for attacking things it thinks are dangerous and foreign, slowly but surely upping the cap for attack until it no longer does so, or doesn't at a level that causes diseases symptoms.

One approach to achieving this outcome uses a synthetic versions of what're called antigen-presenting cells, which pop around our bodies picking up little bits of antigens—which are detritus like chemicals and bacteria and pollen and so on, stuff that isn't part of us—and then they meet up with our T cells and tell them which of these things should be attacked, and which should be ignored because they're safe.

The synthetic version of this system sends in nanoparticle replications of these antigen-presenting cells, using them to flag the stuff that's being errantly attacked as good, changing the T cells' opinion of those things over time, basically, but it's also possible to achieve something of the same by manipulating how the natural antigen-presenting cells operate.

It may also be possible to use these signifiers to tell the T cells to attack the B cells, in the case of wanting to help folks with certain types of lupus, for instance, accomplishing what those other therapies accomplish but via different, less-invasive and more straightforward means.

What we're seeing right now, then, is a change in how we think about autoimmune diseases and what causes them, and we're taking recent research and understandings about the mechanisms of how this stuff functions and trying to decide how best to recalibrate and even hijack those mechanisms to correct for issues in the system; the idea being to tweak one small thing, perhaps just once, and to consequently permanently change how the system functions in favor of healthier, happier outcomes.

We are still at the beginning stages of this, but the pace at which these sorts of therapies are being developed and moved to clinical trials is heartening.

It's possible that at some point in the next decade or two we could see commonly available treatments for things like lupus and Hashimoto's, which would be great, in my 100% biased opinion, but also for related issues like allergic reactions, which would make use of the same general theory and process to tell our immune systems not to freak out when they're exposed to, for instance, peanut proteins or pollen, changing the lives of even more people, as long as we can figure out how best to consistently and safely administer these therapies to folks who currently suffer from such things.

Show Notes

https://www.cell.com/cell/fulltext/S0092-8674(08)00624-7

https://www.frontiersin.org/articles/10.3389/fimmu.2018.02359/full

https://www.nejm.org/doi/10.1056/NEJMc2107725

https://www.science.org/doi/10.1126/science.1142963

https://www.nature.com/articles/s41584-023-00964-y

https://www.theguardian.com/science/2022/jan/08/global-spread-of-autoimmune-disease-blamed-on-western-diet

https://www.washingtonpost.com/science/2024/02/01/why-women-have-more-autoimmune-diseases/

https://www.scientificamerican.com/article/autoimmunity-has-reached-epidemic-levels-we-need-urgent-action-to-address-it/

https://archive.ph/0outq

https://www.nature.com/articles/d41586-024-00169-7

https://pubmed.ncbi.nlm.nih.gov/25277817/

https://www.theguardian.com/science/2022/sep/15/scientists-hail-autoimmune-disease-therapy-breakthrough-car-t-cell-lupus

https://www.biopharmadive.com/news/crispr-cancer-cell-therapy-autoimmune-lupus/701528/

https://www.wsoctv.com/news/trending/fda-issues-warning-secondary-cancer-risk-linked-car-t-therapies/RPAPN44ZCRFWFOROZOZLG2ZKG4/

https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

https://www.nytimes.com/2024/01/23/health/fda-cancer-car-t-warning.html

https://phys.org/news/2024-01-nanoparticles-anaphylaxis-side-effects-mouse.html

https://hillman.upmc.com/mario-lemieux-center/treatment/car-t-cell-therapy/fda-approved-therapies

https://en.wikipedia.org/wiki/CAR_T_cell

https://en.wikipedia.org/wiki/Engineered_CAR_T_cell_delivery

https://en.wikipedia.org/wiki/Cellular_adoptive_immunotherapy#Chimeric_Antigen_Receptor_(CAR)_T_Cell_Therapy

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