Updates in the Treatment of Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia - Episode 5
Emerging Therapies for Adults with R/R B-ALL
Jae Park, MD: So, I think they are - the interesting and the encouraging thing is, that there are, and many new generations of CAR T-cell therapy are being developed for patients with ALL. There are - there are several approaches to doing so, because we have several unmet need. One may be - the one is to improve the safety profiles, and there are some product targeting the same antigen, CD19 with a different SCFV design, a different manufacturing, trying to generate a better safety. So less severe CRS and less severe neurotoxicity, so some of these products are ongoing in clinical trials. One of them for example being Orelusk [ph] studies. So there's an international, a global study that's ongoing to see whether they can get a better safety profile, and hopefully with similar efficacy in this adult ALL patient population. And then there are approaches to reduce the relapse, and as I mentioned before, not only the toxicity, the other - the unmet need is that in preventing the relapse. So these patients do get very high initial response rate, over 70 to 80%, yet the majority of these patients do experience relapse during the follow-up period. So there still remains a major unmet need in our patient population. The way to reduce the relapse, and there could be several ways, and one such way there - being currently being in the clinical trust targeting two antigens at the same time, CD19 or CD20, or 19 and 22 together, are trying to address both antigens. And the less selective pressure for - to induce an antigen escape, so hopefully they will lead to better and deeper response and less relapse in the future. And there have been several reports that have been presented so far at ASH last year, and maybe we'll see more data upcoming ASCO as well. But the other day - way to reduce the relapse, it's the second or third generation or armored CAR T-cell therapy to enhance the potency of CD19 or CD22 targeted CAR T-cell therapy and such a little bit early on. But such effort is underway as well, and then the other way is the unmet need in ALL patients. Is that in about 25% of the patients still do not receive the intended autologous CD19 CAR T-cell therapy. And that's pretty consistent across all the trials that we enter, they eventually lead to approval as well too. It was about 20 to 25% of the patients, usually due to disease progressions or the complications from their bridging chemotherapy, or do not make it to autologous CAR T-cell therapy. So for those patients having a product that's readily available, we'll expand the access of the product to our patients. So to such approach it will be shorter manufacturing time, even with the autologous product may address the - one of the ways the other ways. The other ways will be off-the-shelf product, they're using alternate cell source such as NK cells or the off-the-shelf or allogeneic T-cells. So there could be other approaches too, to address that unmet need. And some of the - obviously several of these clinical trials are currently ongoing, some preliminary encouraging data being reported out so far.
So outside of the CAR T-cell therapy - and there are fortunately also several clinical trials and then the development of newer ways to do so. And then some of these are using existing platforms such as Blinatumomab and combining with PD-1 inhibitor to see what the additional immunomodulatory effect can overcome some of the limitations, or enhance the efficacy of the Blinatumomab, so that is ongoing. The other type of ADCs or Antibody Drug Conjugate targeting the same antigens CD19 or CD22, or CD20, but with a different chemotherapy or cytotoxic agents attached to it. Those will be the other ways to hopefully avoid some of the VOD deaths associated with Inotuzumab. Those have also been developed as well. For pH positive ALL patients which we didn't talk a lot about during this talk, is that they do have a tyrosine kinase inhibitor. There's a key cornerstone of a therapy such as dasatinib, Erlotinib and Ponatinib or Imatinib too, but higher generations TKI has been very effective. So Ponatinib in combination with Blinatumomab in the relapse setting, there we have seen high efficacy even in the frontline setting as well. With very good data that has come out of MD Anderson, the preliminary early data have a very high response rate. So in ph positive, these are ALL where I'm very optimistic that we can actually largely move away from the chemotherapy backbone altogether, and actually cure these patients with TKI, Tyrosine Kinase Inhibitor with Blinatumomab or other immunotherapeutic agents kind of in the setting. It's hugely exciting in the front. Then lastly also, T-cell ALL which we didn't also talk about. And there are some, the development has been very slow because there are no good antigens. They're specific for T-cell ALL despairs normal endogenous T-cells as well. But there are some genetically engineered CAR T-cells targeting CD5 and CD7, CD6, fours are also being studied in clinical trials as well for the - early encouraging data. And Venetoclax which is a BCL-2 antagonist, has been approved for treatment of a CLL in AML patients, also now being applied for ALL patients too. So there's an intergroup study that's combining Venetoclax with mini CBD in older ALL patients in frontline setting, and we're also starting Venetoclax in combination with a pediatric inspired chemotherapy combining Asparaginase to see whether we can enhance the initial response rates and long term efficacy of our young adult patients as well. So lots to come in the future, it's hugely exciting for us, [00:27:00] so our ultimate goal and my ultimate hope is that total duration of a therapy for ALL patients will be shorter, because we have to remember that even initial chemotherapy, usually two or three years long. So if we can cut this short with incorporation of this potent therapy, I think that's hugely beneficial for our patients. And then also to develop very effective therapy with less chemotherapy because we hate to see chemotherapy-induced complications even when they cure, will develop secondary cancers and that's always disheartening and heartbreaking. So hopefully, with all these new therapies, we can accomplish that goal in near future.
Transcript Edited for Clarity