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JackD4wkins t1_jebbuwn wrote

Reply to comment by Toranagas1 in Scientists discover how cancer cells evade immune system by BousWakebo

Immunotherapies are very limited in their applicability. They only work for specific variations of specific cancers...

Transduction efficiency does not need to be 100% on the first attempt. Multiple treatments of even just 50% efficacy result in cure with just 7-8 treatments, without the devastation of chemo or radiation. Nobody requires 100% efficacy from one dose for other treatments, why people place such a high standard on transduction is a mystery to me. "If you can't cure it with one shot, then its not worth doing" is the logic of madness

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Toranagas1 t1_jebh1oa wrote

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.

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JackD4wkins t1_jec6avt wrote

Reducing the number of cancer cells that survive the first round depends on how we encode the CRISPR enzyme. As long as we can identify a majority of oncogenic mutations - ideally 50+ - then the only limiting factor becomes dose size. With subsequent doses to catch the remaining cancer cells.

And yes theoretically a cancer could evolve to prevent lentivirus mediated transduction... luckily nature provides an near infinite number of viral vectors from which to choose, and we are already using directed evolution to breed specialized cancer-hunting viruses in massive quantities.

Edit: I appreciate you taking the time to point out limitations in the CINDELA method. It helps further improve.

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Toranagas1 t1_jeca51a wrote

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.

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