Considerations and Next Steps For Patients Who Progress on CAR T-Cell Therapy

Considerations and Next Steps For Patients Who Progress on CAR T-Cell Therapy

Jae Park, MD: So again, for those patients who have received CD19 targeted CAR T-cell therapy and relapsed afterwards, and these are obviously very challenging population, we actually look into our own data and publish this data. Kind of looking at the outcome in Blood publication 2021 and looking at the outcome of these patients who relapse and progress after securing the CAR T-cell therapy. We in general, have seen a poor outcome. Not surprisingly, but what we have also seen is that Blinatumomab, and Inotuzumab, the other types of immunotherapy afterwards still could work in those patients, so whether they had a prior exposure to them or not. So, if they - even if they had prior Inotuzumab or Blinatumomab, if there is a - years ago, a month ago, and I think these are relatively good options to try. Assuming they still expressing 19 for Blinatumomab for example after CAR T-cell therapy, so these antigens need to be checked for expression again for CD19 and CD22. And if they're expressed, anything, either Blinatumomab or Inotuzumab could be safely used in this setting. Long-term efficacy or the duration of remission, maintaining that is always - is a challenge, nonetheless. Because a lot of these patients are not fit enough and have gotten so many therapies and may not be well enough to receive either their first, or second or third allogeneic transplant, so there still continues to remain challenge. And there are other therapies that are being developed, alternative targeting CD22, targeting, for example CAR T-cells, and in the - it's a relatively early data. But there's some preliminary data to suggest its efficacy, although duration of remission still remains unanswered, and still remains a challenge as these CAR T-cells, CD22 target a CAR T-cell. So far, has not been generating a high or long duration remission yet. So, I think we have more work to do in this setting, but I think it's important to keep in mind that these are there because they'll be effective. And lastly, I think other types of security and CAR T-cell therapy could also be considered tools, if they have received investigation a CAR, CD19 CAR, but they still express CD19. I think another type of CD19 CAR could still be considered, because not all CAR is the same. There are differences in CAR itself, the binding domain of SCFD the manufacturing, the method is different. So, there could be endorsing, they're being used as different, so I think just because they have failed, the one doesn't necessarily mean they're going to fail the others. If they're big enough, again well enough and express CD19, I think one other type of CAR T can certainly be considered.

So CD19 CAR T-cell therapy in general is a class. [00:18:00] The one consistent theme that we have seen is the very high initial response rates. Again, upwards of 60 to 80%, with the vast majority achieving MRD negativity, again indicating a good depth of response for these patients. Side effects wise, there are two large side effects. CRS Cytokine Release Syndrome and neurological side effects. The rates of these toxicities slightly do differ product to product, but all products have been associated with some degree of these side effects. Cytokine Release Syndrome is relatively - is a - the very early event that usually can start within 24 hours of cell infusion, and usually median days of three to five days after cell infusion. They respond very rapidly to Tocilizumab or anti-IL-6 receptor inhibitors, so they're very effective, and if those are not, then steroid is also effective for reversing - completely reversing and resolving Cytokine Release Syndrome. The other side effects, neurological side effects or neurotoxicity, do come little bit later and following CRS typically, although not always. So they can also happen independent of a CRS as well, the median time is a little bit delayed, five to seven days typically. So again following initial wave of a CRS, and then again the severity also depend on product to product, but they do not respond well to Tocilizumab, so Tocilizumab is not the mainstay of a therapy for neurotoxicity. Steroid is, and they do respond to them. They are not as rapidly resolving, so I think the early intervention for neurotoxicity has been the key aspect to mitigate or prevent severe neurotoxicity. So initially, when we were doing this CAR T-cell therapy ten years ago, eight years ago, then we were waiting or we were not intervening when they developed grade three neurotoxicity. Things have changed a lot in the last several years, and with better data suggesting that steroid doesn't impact the initial efficacy, or even the long-term efficacy. That we are now using steroid, at least a short-term steroid for grade one and two neurotoxicity, and that has been the key to us to prevent severe neurotoxicity. So while this toxicity can happen usually very early on, within the first week or two weeks of cell infusion, but these are largely manageable, predictable. And this, we can actually get most of our - the patients get through, but if they do receive, or if they experience severe neurotoxicity, some of these patients do get deconditioned, and they may have a prolonged hospitalization. So there's a lot of incentive reasons to develop or - the new product with the better toxicity profiles, and also to develop new ways to prevent the severe neurotoxicity. And there are many trials ongoing to address that, blocking IL-1 receptor and Akira, we are studying the neuro centers, Interleukin JAK1 and 2 inhibitor. They also have been studying - GM-CSF inhibitor have been studied as well, so hopefully, we can see more of these results being applied to ALL patients and to improve the safety of the product as well.