Possibly those things could help, I guess it remains to be experimentally determined. Anyway it's a decent proof of concept paper, although the in vivo data is a little weak.

Btw, they are giving a lot of doses already, every day at lower viral titers, and every 3rd day at high titers up to two weeks. Then they cut the experiments two weeks after that so we don't really get a good sense of how things would fare longitudinally but I can tell you from having read a lot of these papers that all of those mice will die pretty close to the controls, probably delayed by only a few days or a week.

I dont mean to be negative, as I can sense you are excited by the possibilities this strategy brings up, just trying to inject some realistic perspective into the data they show.

The technology they is referring to uses whole genome sequencing to identify InDel mutations in tumor cells then uses Cas9/gRNA specifc for those InDel sequences to induce double stranded DNA breaks, resulting in cell death. Since those sequences don't in theory exist elsewhere in the patient, it may be safe. Looks like a lot of different gRNAs are needed though for good efficacy.

They use lentivirus and AAVs to deliver them in vivo.

The in vivo efficacy data is...fine. The big thing here is the personalized medicine aspect.

PMID: 35217600

Aggressive cancers, such as those that are targeted by therapies like CAR-T cells or immune checkpoint inhibitors grow quite fast. I'm not arguing against multiple treatments, and probably it would improve responses, but are also likely to be insufficient to "cure" it, as the cancer cells not destroyed will continue to grow (at worst at a log phase) and you may never quite reach zero. Only a small number of cells need survive to continue growth of the tumor.

Moreover, one notable advantage for CAR-T cell or TIL therapies is that when patients respond very rapidly, there is little time for the tumors to develop escape mechanisms. After clearance there is also often immunological memory that can maintain clearance or control of subsequent growth.

Keep in mind that the method proposed here relies on the ability for the lentivirus to enter the cell of interest. In the same way that tumors that are refractory to treatment often unregulate immunosuppressive molecules to escape the immune system so is this therapy subject to escape by preventing entry.

There is also some stuff about safety of widely infecting cells with lentiviral vectors containing a myriad of gRNAs and hoping there will be no serious off target events, but considering we are already comparing it to another pretty dangerous therapy I will leave that one out. I assume you are primarily referring to CAR-T or TIL when you say immunotherapy.

To be frank, the results from that PNAS paper are really interesting but the degree of killing isn't the most impressive. Very worthwhile studying though. The personalized medicine aspect here is really fascinating.

I looked at that PNAS paper and it's pretty good, but isn't necessarily a substitute for cancer immunotherapy. The killing here is subject to transduction efficiency from lentivirus, which won't be 100%. You can see it in their data, that therapy doesn't clear the tumor.

Can potentially be very useful when used with cancer immunotherapy as a memory response is what is most likely to full cure the cancer.