What is t-cell exhaustion?

What is T-cell exhaustion? Well, it's simply the T-cells getting tired of being stimulated and being active. And this T-cell exhaustion and even immune paresis is a bigger part of the myeloma picture, even for all cancers. Because our immune system, the T-cells are primed towards taking out the cancer cells as well. And they get tired or exhausted by doing that as the cancer cells can become overwhelming in their activity, as well as have certain surface markers that inhibit the T-cells, or checkpoints, as they're called. So the idea of introducing checkpoint inhibitors into treatment for cancer patients in general has been the reversal of that T-cell exhaustion by inhibiting the checkpoints so that the T-cells can do their job once again. Is there a way to measure if the T-cells are good or exhausted? That is in the research domain in what a lot of us are doing, because you have to look at many different kinds of proteins and surface markers on T-cells to see how active they are, what kind they are. And this is the whole discussion around immune profiling in myeloma. So at the time of diagnosis, at the time of the MGUS to small ring to active myeloma transition, during therapy, trying to correlate it with response. So it's a bit more complicated to look at that, but it can be done. What can I do to keep my T-cells from getting exhausted? Can I collect my T-cells and store them? We know very little at this point about how to do that, especially for patients who have had their myeloma for a long time and have been through many, many lines of treatment. We know that their T-cells aren't as happy and productive as they should be. There are some research protocols that are starting up to look to see whether we can collect people's T-cells very early on, as opposed to waiting after they receive lots and lots of treatment, and then kind of bank them like we would bank stem cells to be able to use later on. So I would say stay tuned. I think this field is in its infancy right now. Is there anything a patient can do to improve their T-cells? I don't think that there are any supplements that you can take to improve your immune health or T-cell health, but I think the best thing that any myeloma patient can do is get into a good remission and try to work out the best strategies in staying in remission with their care team, because that's when the T-cell activity and health improves. What therapies should a patient avoid to keep their T-cells more preserved? We don't know the answer to that question. Typically the kind of therapies that really impact the lymphocytes long term have been utilized more for lymphoma patients or ALL patients, but not for myeloma typically. Most of the drugs, even the alkylators, that can influence the lymphocyte counts and viability, that too recovers over time in vast majority of patients. All the early trials that have been done with IDA cell and Cytlocell is in patients who have had a lot of alkylator therapy in the past and still had good T-cells to manufacture those products. Are there certain types of therapies that are harder on T-cells? I don't think we know, because even when we think that a particular drug has a specific way of helping to kill myeloma cells, the more we learn about that drug, the more complicated it becomes. So a perfect example is daratubumab, which in a simple way is supposed to target the protein on the surface of the myeloma cells, but we've subsequently learned that it does all sorts of things to a variety of immune cells, including a variety of T-cells. So myeloma is very, very complicated and I can't give you a simple answer to that one. Is it better to do immunotherapies earlier on when your T-cells are healthier? I think that that's the logical progression of how these treatments will be used, that they will probably be used in earlier lines of therapy for the reasons you just mentioned, specifically that patients with more advanced disease will tend to have immune systems that are more impaired. For instance, the CAR T-cells that are being made from their blood, from the cells from their blood, may not be as effective or you may not be able to get as many effective cells from that type of product. So I think that once these products are approved, they will be used in earlier lines of therapy when patients' immune systems are more fit or intact and able to result in a better product potentially. Are there ways to collect and store healthy T-cells early on in treatment for later use? Not at this time because most of the CAR T-cell therapies that are being done are on freshly collected T-cells. We don't know what the function of those T-cells will be if we collect them ahead of time and freeze them. And when we thaw them, we don't know how active they will be or what their viability will be. But beyond T-cells, there are other types of cells that are being looked at as well. Cell killer cells are a kind of immune cell that is being looked at for these CAR kind of strategies too. The Penn Group has some interesting data where what they're doing, and we'll find out more in the future, is they're collecting T-cells from manufacture right after induction therapy in high-risk myeloma patients and they're putting them away. And they think that this may be a better strategy because you now have cells that are fresher that haven't been exposed to a lot of therapy. And we think this makes sense, but we have to prove it.