CAR IV
Since this is off topic for AngryBear I will post future CAR posts at my personal blog
This post is a restatement and extension of the first post in the series CAR Crazy
which discusses ex vivo treatment of killer T-cells with Chimeric Antigen Receptors (CAR) designed to cause the T-cells to kill cells which display an antigen to which a known monoclonal antibody sticks. In practice CAR T-cells are used to treat cancer. They have been very successful against leukemia, but not so successful against solid tumors.
In general the problem is that CARs are not suited to the tumor micro-environment, More in particular, there are two known problems. First solid tumors contain reactive oxygen species (ROS – think hydrogen peroxide) produces by tumor associated myeloid suppressor cells. Second tumors are infiltrated by regulatory T-cells (Tregs) which suppress other immune cells, at least partly by displaying activated Transforming growth Factor beta 1 (TGF beta). Tumor cells also may display don’t kill me signals which activate don’t kill (or kill yourself) receptors PL1, CTLA-4, and TIGIT – these don’t klill signals are called “checkpoints”
One issue with immunotherapy is that (as far as I can tell from my amateur efforts to survey the literature) no more than two checkpoints are inhibited (with monoclonal antibodies) for one patient. I assume the reason is that doctors know that the checkpoints evolved for a reason and fear that inhibiting all of them will cause autoimmune problems. This means that the fact that CAR T-cells are produced in vitro opens an opportunity: it is possible to treat them with all known checkpoint inhibitors without causing the test tube to attack itself (not that we care if it does). The inhibitors will be diluted as the CAR t-cells divide, ore really any time they produce more checkpoint receptors, but the very thorough checkpoint inhibition might still be useful.
Another issue is the ROS in tumors. To deal with this it is possible to activate the innate antioxidant system which consists of proteins coded by genes activated by the transcription factor Nrf2. This can be done with FDA not approved pharmaceutical ML334, by hydrogen peroxide in the test tube, or by sulforaphane (found in broccoli). The system is activated by ROS (in particular hydrogen peroxide which causes the Nrf2 binding inhibitor KEAP1to change conformation and fall off. The advantage of in vitro treatment is the give the CAR T-cells a head start.
Finally T-cells are activated by proteins called lymphokines. Some, including IL12 are too inflammatory to infuse into people. Another called IL15 can be given in a small concentration but not too large a concentration because then it causes capillaries to leak. In vitro CAR T-cells can be exposed to large concentrations of stimulatory lymphokines. One particular is that, scientists who culture and infuse NK cells have learned that IL 15 works better if it is displayed on cells than if it is floating freely. It is known that lymphocytes work better if preconditioned by IL15 exposed on macrophages https://pubmed.ncbi.nlm.nih.gov/37014858/ and that, in this case, a bit of the macrophage enters Tcells forming a double membraned vescicle with IL15 between the inner and outer membranes https://pubmed.ncbi.nlm.nih.gov/31871169/ . It seems to me that it is a good idea to add macrophages to the mix.
The hope is that with these treatments CAR T-cells will be more suited to the tumor microenvironment and effective in treating solid tumors.
Robert:
This appears to be an article or post on healthcare which is what I would classify it under on Angry Bear. By the way, when I am stricken with ITP, the good doctors finally work their way up to giving me four dosages of Rituxan.
You could ask Joel what he thinks on where to posts also.