Jae H. Park, MD, discusses the challenges in using CAR T-cell therapy in adult patients with acute lymphoblastic leukemia, and also highlights the potential role for off-the-shelf CAR T cells.
Jae H. Park, MD
A CD19-directed chimeric antigen receptor (CAR) T-cell therapy is approved by the FDA and available for treatment of pediatric patients up to 25 years old with acute lymphoblastic leukemia (ALL). However, there continues to be an unmet medical need for the treatment of adult patients with the disease, explained Jae H. Park, MD.
Adult patients face additional challenges with the use of CAR T cells as treatment. In particular, they have experienced more prior lines of therapy that weakens the immune system. Moreover, their T cells are more difficult to collect under these circumstances—or the T cells may not be as potent.
Currently, off-the-shelf CAR T cells are under evaluation in this patient population.
“Hopefully off-the-shelf CAR T cells will help fill in some gaps. We have to see if this will be effective in those patients who haven’t been receiving autologous CAR T-cell products,” said Park. “We still need to see fuller data, but this appears important for our patients.”
In an interview with OncLive during the 24th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma, Park an attending physician, Leukemia Service and Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, discussed the challenges in using CAR T-cell therapy in adult patients with ALL, and also highlighted the potential role for off-the-shelf CAR T cells.
OncLive: What CAR T-cell therapies are available for the treatment of patients with ALL?
Park: Regarding CD19-targeted CAR T-cell therapy, we only have 1 CAR T-cell therapy approved for the treatment of ALL—but only in patients up to the age of 25. That is what we have to date. We don’t have an approved product for patients 26 years and older, so there are several ongoing clinical trials for this.
One is close to the finish-line; the phase III just closed accrual: the ZUMA-3 trial. We are awaiting the final results of those data; the preliminary data were presented at the 2019 ASH Annual Meeting.
What is also interesting is that there are other ways of targeting CD19 with CAR T-cell therapy. There are several different products. One is a slightly different single-chain Fv with a CD19-targeted CAR T-cell therapy. We have seen preliminary data in the pediatric space showing a lower rate of severe cytokine release syndrome (CRS), which is interesting. If this happens to be proven true, this may suggest a safer option for our adult patients with ALL that is targeting the same antigen differently. However, we are still waiting to see these results.
The other is an allogenic off-the-shelf product. There are challenges in getting these patients with aggressive disease autologous CAR T-cell products, or generating T cells from these patients, so off-the-shelf donor-derived CAR T cells are [under evaluation]. Preliminary data have been presented before, and there is an ongoing international study looking at the efficacy in the larger population. We await the data for those products as well.
The CD19 and CD22 bispecific CAR T cells targeting CD19 and CD20 at the same time were presented at the 2019 ASH Annual Meeting with the hope of reducing the rate of CD19-negative relapse by targeting 2 antigens simultaneously. Again, we are also awaiting the final results of the data. There are a lot of ongoing clinical trials testing the efficacy of CAR T-cell therapy with the ultimate goal of bringing safer and effective CAR T-cell therapy to any patients with ALL but especially adults, which is a critical unmet need.
What are some other major challenges with CAR T cells for adult patients with ALL?
The challenge is reducing cytokine release syndrome (CRS) and neurotoxicity. The reason this clinical development of CAR T-cell therapy has been a little bit slower than in pediatrics is because of poor tolerability of CRS and neurotoxicity in adults. There is a lot of interest in making improvements on the currently available CAR T-cell product. There are ongoing clinical trials looking at several different ways to mitigate and hopefully prevent CRS and neurotoxicity by targeting interleukin-1 receptor or a JAK inhibitor, such as itacitinib or an anti-VEGF agent earlier in combination with corticosteroids. These are all different ways to look at the CAR T-cell products, with an ultimate goal of delivering a safer product to adult patients with ALL.
Could you discuss the potential advantages of using off-the-shelf CAR T cells in these patients?
The off-the-shelf products [appear beneficial] for those patients who have a very low lymphocyte count because they just received, for example, chemotherapy or are coming off an allogenic transplant; their immune system still has not fully recovered so they have low lymphocytes to begin with. Collecting T cells from those patients will be very challenging, although it is not impossible. However, those are the patients we predict to have a harder time with product generation, so off-the-shelf CAR T cells will benefit those patients.
The second advantage is the progression part. Some patients, even if they were able to have T cells collected, simply do not do well during the 3- to 4-week period of time while the CAR T cells are being generated from their own T cells. If they do not respond to their salvage or bridge therapy, they may not make it to receive the CAR T-cell therapy.
This is a concern, and this does happen. This a reason to think about using this off-the-shelf CAR T-cell therapy early on rather than autologous CAR T-cell therapy. Despite our best attempts, the disease could be very refractory, and we have very little tools to control the disease in those patients, so they may not be able to get bridged to autologous CAR T-cell therapy. Off-the-shelf products may be meaningful in this population.
Third, even if patients were able to get the CAR T cells, the T cells are still being generated in patients who have gone through many rounds of chemotherapy. Their potency and the function or capability may be different than those from the presumably healthy donor T cells that haven’t received chemotherapy.
These data are preliminary, but it will be better for these reasons. It may generate a better duration of response. If patients are already getting a higher rate of response from 80% to 90% with autologous CAR T-cell therapy, the relapses are common. The question is whether donor T cells would be better in maintaining the same degree of a complete response for these patients.
What is your take-home message from your presentation at the 24th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma?
The important message is there is a lot of interest in CAR T cells, more so than in the past. There are concerns, rightfully so, especially with the toxicity. One of the important things is to think about administering this therapy early. It may not be the right therapy for all patients who relapse in ALL, but a lot of factors to go into this.
The important thing to think about is using CAR T-cell therapy early and consult early. ALL is a rare disease, so we strongly encourage reaching out [to find a center that administers this treatment]. All of us are available and happy to help. For patients who do not have access to CAR T-cell therapy clinical trials, we also do know what other centers may have them; this is a relatively small field. We can help you get connected to physicians in nearby areas or in other parts of the company, so we can choose the right therapies for our patients.
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