Last-resort cancer therapy holds back disease for more than a decade

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.

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.

CAR-Ts are now being tested in much earlier lines of therapy.

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.

novobiocin is an antibiotic developed decades ago but recently "rediscovered" as offering anti-carcinogenic against some cancers which resist PARP inhibitors. in short, it targets an enzyme (polymerase theta) critical to these cancers.

thanks for sharing this story.

i'm so sorry for your loss, but it is amazing how such persistence and critical thinking offered your father and family another treasured year of life. he must have been unbelievably proud.

[0] https://www.dana-farber.org/newsroom/news-releases/2021/anti...

Or is it the cancerous tissue itself that has to be sequenced?

Thank you for sharing your story. It was beautiful.

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/

(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.)

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.