CAR Crazy
Here CAR stands for Chimeric Antigen Receptor and refers to CAR killer T-cells which are cells genetically engineered to kill other cells which display something detectable (and antigen) typical of a type of cancer. The crazy refers to my dream of improving CARs using the knowlsege from my long ago BA in biology.
The amazing thing about CARs is that they must be custom made for each patient. The genetically modified cells must be the patient’s cells or else the patient’s unmodified immune system will kill them. Even more amazingly, this isn’t really prohibitively expensive. I think the real cost is about $10,000 per patient — so much less than major surgery. Of course this and that share of overhead and markup and such gets the price for actual care of actual patients up to $60,000 or so, still not too huge.
I have some thoughts on how to make CARs more effective and some on how to make them cheaper. Both are based on ignorance and vanity and should not be taken seriously.
First, more effective. First, the less crazy idea. The CAR cells are in vitro before they are infused back into the patient. Therefore they can be subjected to treatments too extreme to be administered to a person.
One is stimulation with IL12 — too inflammatory to be used in people but used to stimulate ex vivo NK cells before they are infused (another therapy even more cutting edge than CAR (both of which have worked against leukemia and so don’t replace surgery — the literal cutting edge)). Another is high levels of IL-15, which stimulates killer T-cells but which, in high concentrations, causes capillaries to leak. IL-15 can end up in vescicles inside cells and stimulate the cells from within. This requires presentation by activated macrophages which is not a big problem. A problem for killer cells in the solid tumor microenvironment is reactive oxygen species (ROS; think hydrogen peroxide) produced by myeloid-derived suppressor cells around the tumor. CARs can be prepared for this by activating the innate antioxidant system before they meet the ROS.
Finally, a sometimes successful approach to immunotherapy is to block checkpoints. Cells can display “don’t kill me” signals which interact with don’t kill receptors on killer cells. Cancer cells often display don’t kill me signals. Blocking the don’t kill receptors on killer cells has had some success (recognized by a Nobel prize). One important don’t kill signal which has not been blocked is TGF-beta (I find no articles on therapeutic blocking of it) [update: this is out of date, there has been a trial of blocking TGF=beta which did not show promise https://pubmed.ncbi.nlm.nih.gov/39534099/]. I think this is because it is too important in preventing auto-immunity [update: I now think my guess was incorrect]. The receptor can safely be blocked on the CAR T-cells while they are in a test tube.
I think such treatment of CAR T-cells before they are infused might be useful.
Next a crazier CAR idea
@Waldmann,
The C in CAR is for “chimeric.” The receptors are chimeric in that they are an engineered combination of both antigen-binding and T-cell activating functions into a single receptor protein. I fixed it for you.
My wife worked on CAR-T cell clinical trials for years before she retired. I forwarded your post to get her comments (she’s asleep right now).
Thanks for correcting whatever I typed (I can’t even think of what I might have written – in my mind I was typing chimeric)
@Waldmann< You posted "chiral." Maybe it was autocorrect.
Good thinking! Thank you for your interest in the field. I presume you are Dr. Robert Waldmann, so I am providing links to the scientific/medical literature.
These are not crazy ideas & the community has been exploring them for some time. For example, in the “Gene edited CAR-T” method section of this paper (Cooper, et al. https://pmc.ncbi.nlm.nih.gov/articles/PMC6102094/), T cells were treated with IL2 and IL15 before putting the CAR gene into the T cells. This work was moved into a clinical trial (Ghobadi, et al. https://pubmed.ncbi.nlm.nih.gov/39149468/) and the remission rate (i.e., percentage of patients who no longer had detectable cancer) was 82% for the 13 patients for whom results were known when the trial was evaluated. This work stands out for its creation of CAR-T cells that can be put into ANY patient (allogeneic T cells). Heretofore only a patient’s own T cells (autologous T cells) could be used
An example of preclinical work (i.e., in mice) exploring the use of the “don’t eat me” signal provided by CD47 is from Yamada-Hunter, et al. https://www.nature.com/articles/s41586-024-07443-8.
I hope you will continue to attempt to keep abreast of research in this rapidly moving field.
Prof. Linda:
Welcome to Angry Bear. I was unaware of your comment. Joel mentioned it today. I was wondering from where Robert was obtaining the info to discuss. Thank you for adding to Robert’s commentary.
Bill @ Angry Bear
Well that scoops CAR crazy II (gene edited CARS) and CAR crazy III (allogeneic CAR T-cells).
I am DR Waldmann PhD in economics.
I still add IL15+ anti CD40 treated macrophages for trans endocytosis of IL15 .
I note that Cooper, et al. treat T-cell leukemia. CAR therapy has been very successful vs leukemia (and I thinkj Lymphoma) but not so successful vs solid tumors. Embarassed by my ignorance of a 7 year old paper, I will continue to post ideas.
I will include the links you kindly provided in my further crazy posts.
Thank you very much
Oh another bit of ignorance. I did not realize that it was necessary to crispr cas t-cell receptor alpha because I foolishly imagined that the CAR replaced the original TCR rather than adding another receptor. SIlly me
@Waldmann,
No prob. We don’t judge. Thanks for your post and your comments.
My nickel’s worth references induced pluripotent stem cell therapy which theoretically offers a uniform cell product which is in contradistinction to other autologus or allogenic cell therapy post editing product. Varius iPSC cell lines incorporate multiple edits. Liquid and solid tumour trials are currently underway, though autoimmune disease treatment is the revolutionary rage du jour. Good luck to all.