$cience playing god - a rant about novel cancer therapies
info
2023-05-18
Genervter posted a link to this mini review article, interested in the mechanism of transfecting the T-Cells with mRNA, which will NOT be the focus of this text.
He will probably use the genius mind of his to find yet another mechanism on how the mRNA shots may hurt you.
What personally caught my attention are the underlying principles upon which this $cience is based.
Let’s jump right into it
B-cell cancers
This research concentrates on developing treatments for B-cell cancers, which originate in faulty B-lymphocytes, a type of white blood cell integral to the adaptive immune system (wikipedia).
They account for 85% of all cancers, usually start in a lymph node, but “can also form in particular sites such as bone, intestine, the spinal cord or brain”, follicles, spleen, bone marrow, stomach, skin, lungs, eyes … and could be linked to the presence of Epstein-Barr virus.
T-cells
Simultaneously, this research explores the modification of T-cells, a type of white blood cell that is also a key player in the adaptive immune response. T-cells originate from stem cells in the bone marrow and are initially "naive". As they encounter various pathogens, they differentiate and display a variety of receptors on their surface. These little f*kers are responsible for our allergies. ;)
T-cells are involved in several immunological processes, like
1 - immuno-modulated cell death (CD8+, CD4+) - killing cancer and virus-infected cells and using cytokines and activating B-cells..
2 - regulatory mechanism of distinguishing between healthy “self” cells and the “ill” cells or pathogens. T-cells are calling the shots of the immune reaction.
it’s complex.
The search for a holy grail anti-cancer treatment is no easy trek, but just reading the introduction gives me goosebumps.
This research proposes a genetic modification, an artificial change of the T-cells, incorporating a chimeric antigen receptor that would enable them to launch a full-scale assault against an individual's specific cancer. Sounds promising, right?
This approach leads to a form of personalized immunotherapy, which is tailored to the individual and can't be mass-produced. It's also considered a "living drug" because once these altered T-cells are deployed, it's uncertain what they'll do or how they'll behave; control over them is essentially lost.
The "mini review" emphasizes the potential risks of this technology, including
- toxicity,
- cytokine storm,
- wreaking havoc on the immune system,
- neurotoxicity, whose mechanism is not yet understood and
- off-tumor activity (auto-immunity).
Solution for these adverse reactions are divided into
passive and active.
PASSIVE
Transfecting T-cells with mRNA
In theory, it’s a clean solution. “No” genomic integration, the mRNA should degrade with time.
Problem? Repeated infusions could lead to an anaphylactic reaction.
I can’t help myself finding a parallel with the m1ψ mRNA, which was not proved to be fully cleared from the body by ANY study yet.
Affinity tuning
In principle, making them shoot on a very small target.
This, however, might also lead to cancer cell escape variants with low antigen expression (29)..
ACTIVE / INDUCIBLE
Suicide Genes
The concept of incorporating viral suicide genes into CAR T-cells has been suggested as a way to allow these cells to self-destruct, or be actively destroyed when necessary. Parts of herpes simplex for example. There will be some toxic metabolites, but this should be safe, or? We know now, that genomic cooking is always a very precise process, no way there might be some other remnants mixed in..
Elimination Markers
Equip them T-cells with yet another cancer marker, so that the body which was unsuccessful in eliminating the original cancer can fail to eliminate these modified cells as well.. After a couple of chemotherapy rounds this approach will surely work just fine.
Systemic T-Cell Inhibition
Suppress the immune system even further. I can’t even...
Adapter Mediated CARs
I’ll just cite the article here
However, large differences in adapter kinetics and subsequent effects on CAR T cells have been reported, … , affinity differences between the adapter and both target and CAR T cells, and biodistribution of the adapter molecules.
Split-CARs
Involves the activation of the CARs by administration of a specific drug, thereby limiting the CAR activity by the half-life of the drug.
Again a citation:
The split-CAR allows temporal and reversible control over the number of functional CARs, but the design does not prevent on-target, off-tumor toxicities as no spatial control is achieved due to a lack of control over the distribution of the drug.
Protease Inhibitors
This passage discusses a method to control the CAR T-cells by adding NS3 protease derived from the Hepatitis C virus. Just add NS3 protease inhibitor and the CARs will die. Worked in vitro. :D
However, the NS3 protease on itself could stimulate an immune response and the immune system might recognize and attack these modified cells. :D
TET-On Regulation
Regulating CARs at the transcriptional level. This involves controlling the process of transcribing the DNA code of the CAR into mRNA, which then guides the production of the CAR protein.
In this system, the mRNA for the CAR is only produced in presence of ie doxycycline. However, some basal level of CAR expression was noticed even without doxycycline. :D
One of the potential challenges with the TET-on system is that it's derived from both bacteria and viruses, which means it could stimulate an immune response.
Another issue is the lack of immediate control in case severe side effects occur, since the regulation occurs at the transcriptional level, which is a relatively slow process.
This is it. All very “promising” solutions, don’t you think?
I am no scientist, but wouldn't it be nice to focus on strengthening the innate immune system instead of subverting it?
Is this the best the scientist are able to come up with?
Also, it’s a real steal ;D
