Hot ROd CARs

CARs being chimeric antigen receptors. They are a key contribution to immunotherapy of cancer. The technology is based on genetic modification of the t cell receptor of a CD8 killer T-cell replacing it's variable region with the variable region of a tumor specific monoclonal antibody. Remarkably this creates a cell which specifically kills the cancer cells. A link to a Wikipedia article.

This approach has been very successful in treating Leukemia, but not so successful in treating solid tumors -- the tumor micro environment is not hospitable to killer T-cells. There are a large number of known aspects of the tumor micro-environment which tend to protect tumors from activated killer T-cells

1) Perhaps the most important is myeloid derived suppressor cells -- these are immature granualicytes and macrophages which are attracted to the tumor. Among other things, they produce anti-inflamatory IL-10, and also produce the free radical Nitric Oxide (NO).

2) Tumor inflitrating T-regs which produce and display anti inflammatory TGF beta.

3) Cancer cells display checkpoint "don't kill me signals" including PDL1 and CTLA4 ligand.

4) There are generally low Oxygen, low glucose, low Ph, and high lactic acid levels.

Many of the issues involve specific interaction with specific receptors on the t-cells (eg PD1, CTLA4, IL10 receptor, TGF beta receptor). I think that, since one is already genetically modifying the t-cells, one can also delete those receptors so they do not respond to the anti-inflamatory signals. The NO issue is different -- it is a non specific oxidizing agent. I think here one can make cells which always produce the antioxidant response by deletign KEAP1 which inactivates NRF2 which triggers the anti oxidant response.

So I think it is possible to produce souped up CARs which invade solid tumors.

There is a potential risk of putting killer t-cells which can't be regulated into a patient, so I would also insert the gene for herpes TK so they can be specifically killed by gancyclovir.

This approach makes sense to me. It involves a whole lot of work aiming at a possible future approval of a clinical trial. I can see why it hasn't been done (and will have another post about reducing the cost and effort involved) but I think it makes sense to try.