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CAR-T Follow Up

The Novartis/Penn team working on CAR-T therapies reports a long-term follow-up on their patients (well, as long-term as its possible to get in this field). Here’s the paper, here at Science Translational Medicine, and here’s the press release. The upshot is, that if you’re cured by this technique, you seem to stay cured. The first patient to receive the treatment has now gone five years with no sign of leukemia.

Out of the 14 patients in that trial, 8 responded, and four of those appear to have been complete remissions. There were four partial responses (with effects measured in months), and six patients who did not appear to respond at all. In those, the modified T-cells did not seem to expand in vivo, which would account for the lack of response. (If they had expanded and still nothing happened, that would have been a puzzle indeed). The key is to figure out why the treatment failed in these cases (so far, one gets the impression that this is a mystery), and how to fix that. Combining this technique with other therapies hasn’t really been tried yet, either.

So there’s definitely something major here, and definitely room to improve it. That’s what Novartis, and Juno, and Kite (and who knows who else) are frantically working to do right now. The biggest prizes are to extend this idea to more tumor classes, and to make it scalable to larger numbers of patients. The second one is a big challenge, and the first is even bigger. People have been antigen-hunting for quite a while now, looking for something that’s fit to turn the immune system on in other types of tumors, and it’s slow going. But you have to be sure, because if the immune system can strip a couple of pounds of aberrant white blood cells out of your system, so vigorously that it nearly overloads your kidneys, then it can do the same with lots of other tissues, too, some of which you might prefer to keep. Ripping out a couple of pounds of motor neurons or Kupffer cells would be suboptimal, to say the least.

8 comments on “CAR-T Follow Up”

  1. Barry says:

    maybe I’m missing something obvious here. Have CAR therapies been run with PD-1 blockade?

  2. Steve says:

    It’s not just the antigen specificity that’s a problem when transiting to solid tumors. First, it should be noted that the CAR-T work you cite was not tumor specific; it takes out ALL B cells, including the malignant clone, so even in this case there is not tumor specificity. Further, there is also a world of difference between using CAR-T for liquid vs solid tumors. Even lymphomas have been refractory to CAR-T. Tissue penetration is very difficult as solid tumors have disrupted vasculature that causes high interstitial pressure, excluding small molecule drugs (one of the big problems with chemotherapies) as well as immune cells. Solid tumors secrete a wide variety of immunosuppressive compounds that inhibit CAR-T (IDO, TGF-beta, IL-10, PGE2, etc., etc.) and recruit immunosuppressive cells (Tregs, MDSC, etc). It’s a tough situation and even though CAR-T are a big advance there’s lots of work left to do.

  3. Pennwe says:

    Modality limitations aside, a few folks from West Philly should probably consider blocking off their calendars for the week of December 10, 2016.

  4. Cytokine-bud says:

    @Steve . Yes. Well put.

    @ Barry. I’m suspect eventually, but when severe immune related toxicities are not uncommon, I’m not sure anyone in the CAR-T race is eager to throw a PD-1 blocker in there before they get an approval. I’m not sure a PD1 would address the solid tumor issues either as per Steve.

  5. LiqC says:

    It is my impression that combining CART with anti-PD1 would be like cutting the brakes in your 1989 Toyota Corolla on which you just installed a Ferrari engine. You’d better have at least really good steering (right antigens and right kind of preexisting anitumor immunity), or autoimmune effects will be out of control.

  6. Barry says:

    Derek asked why only some patients respond. PD-1 is a likely explanation. Of course, the successes of CAR to date have been deleting a whole tissue, not just a tumor. There are only a few tissues that we can afford to delete root and branch.

  7. Morten G says:

    @barry
    Yeah, but good treatments for pancreatic cancer would be nice. Lots of organs get removed in connection with cancer treatment.

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