What strategies are being explored to improve CAR-T cell therapy?

What are some strategies that people are considering to make CAR T cells last longer? I think that is the number one issue, right? Even though these treatments have been really successful for a lot of patients, most patients eventually do relapse. So I think there are efforts to improve the CAR T themselves, so different ways of engineering them, to try maybe collecting the cells earlier, before patients have had a lot of treatment, to see if the T cells are healthier. There's been a lot of approaches to try to understand that or actually improve the product itself. And then the other big approach is to combine CAR T cells with other treatments. So can you give, say, an imid such as linalytomide or pomalidomide or maybe one of the newer cell mods like hibertomide after CAR T, maybe that would have improved immune function, helped the CAR T function better? Can you combine CAR T with a bispecific antibody, for instance, and get improved function? I think those are all different studies that are being developed and are currently underway and we'll have answers hopefully in the next couple of years about ways to improve the efficacy. And then I think the last thing that we are also doing is can you move CAR Ts to earlier in the treatment algorithm so that patients get them when their disease is maybe less aggressive, hasn't relapsed multiple times, and will you have improved function if you treat patients maybe in the first line or second line? And so I think that also is being tested. You know, CAR T therapy certainly is the new kid on the block for treatment options for multiple myeloma, very exciting treatment option. I think many people are hoping that, you know, will this be a cure for patients with multiple myeloma? We have seen with the current two FDA approved CAR T that they're not necessarily the end-all solution at this time. We know with IDA cell, the average progression-free period is somewhere between eight months to a year, depending on the dose the patient receives and other factors. And with Cilta cell, we, you know, we'll hear from ASCO this year that much longer progression-free survival on that particular study, but we are still seeing that patients can progress off of this. And so the question is, you know, can we make CAR T work better? I think absolutely. We're just seeing literally the beginning of the era for CAR T therapy. Currently, these are made from patient's own cells, so it's very individualized, right? The patient's own T cell health that goes into that final product can make a difference. There's a lot with the CAR construct and how we do the engineering of that genetic piece. Every little part of it could make a big difference in terms of that strength, that sensitivity of targeting the myeloma cells. And there's still a lot that we're learning about, you know, sure, the CAR T may do some initial killing of the myeloma cell that we can see on the scans, we can measure on the bone marrow biopsy, but, you know, is there downstream changes to the overall immune system to help keep the patients in remission and thereby, you know, to help keep them longer? So a lot of really big questions in which within each of these, lots of active research that are happening to see, you know, how we can make that work better. I would say of the most immediate clinical results that we're seeing that I'm most excited about are clinical trial results that we also heard some updates at ASCO 2023, which is with these rapid manufacturing CAR T. So these are also, you know, different CAR constructs. We've heard about one from what's called PHE 885 that is a trial that's being sponsored by Novartis. And we heard about a trial coming from China with CAR T that's targeting BCMA and CD19. And both of these CAR T's are literally being manufactured within one to two days. As opposed to the, you know, either cell, so to cell that the turnaround time is a little over a month on average on the clinical trial. So a big difference in turnaround time in these CAR T products, which by itself could mean that, you know, if the patient could be getting these cells back faster, potentially many more patients could be treated, whereas there would have been patients that couldn't wait that long for the CAR T to be made. But what we're also seeing with these rapid manufacturing is the less time these T cells spend outside of the patient's body, the more fit, if you will, when they come back into the patient. So these seem to be more active. The dose that's needed to treat these patients are log folds, you know, 10 folds lower than what's used with the approved CAR T. And they're still very active on what we have seen in these, you know, early clinical trial results. So just even that aspect of tweaking the manufacturing seems to make a difference in how active these cells could be. And of course, there are many different ways and very different aspects of those manufacturing that could be further developed. So I think, you know, right there from a proof of concept standpoint, there are many opportunities to make the CAR T potentially work even better. And so hopefully at some point we could say this could be a one-time treatment. Patient could be in remission for a very long time. If you know what we may talk about medically as a functional cure, even if we can't necessarily this will never come back, but keeping patients treatment free for a very, very long time. That's something that we're all working towards. So this is the first generation of CAR T cells, or the first wave, I should say, of CAR T cells because they're second and third generation CAR T's in terms of their structures. The way that we're thinking about CARs now is to see if we can utilize two different targets to make the CARs more cancer specific or that particular cancer specific. So those questions are being asked. The second way is to try to push cells towards the memory T cell phenotype. And this is by having equal amounts of CD4 and CD8 positive T cells. Then there is another strategy of spiking the culture in which the T cells are growing or being manufactured with certain inhibitors like PI3 kinase inhibitor to push cells towards that phenotype. And then exploring the possibility of using IMEDs or checkpoint inhibitors after patients have recovered from CAR T cells therapy to see if you can make these T cells live longer. And not just live longer, does that actually help in sustaining the response because that's the eventual goal. Would harvesting and storing healthy T cells and using them later make the CAR T product better? It's an interesting concept. So the idea of storing your T cells just like one would store stem cells, I think what you're proposing is not an unreasonable thing. Logistically, you can imagine that it's a problem of where do you store these things and how many do you store and who's going to pay for the storage and how long you're going to keep them stored. But I could potentially, but it's clear that probably the earlier on in the course of disease that you take T cells, the healthier they are. So theoretically, they would be the better T cells to use if you could do that. So it's not an unreasonable concept. I just think from a practical perspective, it may be a little bit more complicated to implement.