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CAR T-cells for AML
an immuno-suppressive microenvironment,50 failure of persistence of the CART population,51,52 or unacceptable or unexpected on-target off-tumor toxicity.53 As early results from CART trials for AML become available in the coming years, we will gain a better understanding of their relative role vis-à-vis that of other recently approved ther- apies for this disease targeted against specific genetic lesions (FLT3, IDH1/2) or survival pathways (BCL2). The T-cell manufacturing process is complicated and time- consuming, with the median time from enrollment to infusion in the ELIANA trial of CART-19 being 45 days (range 30-105 days),1 and so the availability of well-toler- ated, targeted, non-immunosuppressive therapies may improve the feasibility of bridging patients to potentially curative immunotherapy by providing disease control and clinical stability.
How close are we ... really?
Although the first CART trials for AML are now appear- ing in the clinical sphere, it is likely that other barriers will need to be overcome before this therapy becomes widely available. It remains to be seen if the ‘bridge to transplant’ approach is feasible, if it provides a sufficient duration of CART persistence, and how the on-target off-tumor toxic- ity of the various constructs, combinations and target anti-
gens will be tolerated. We suspect that CART therapy will not be suitable or efficacious for all patients with AML, for example, frail elderly patients who are at higher risk of tox- icity, or for those lacking access to expensive personalized therapies, by virtue of geographic and economic factors. However, select patients with AML are now being treated on CART trials and in the next 1-2 years data are likely to tell us more about the patient, disease and treatment char- acteristics that can predict success in this arena. We think of the future of CART cell therapy for AML as the next step in alloHSCT: a complex, resource-intensive but feasi- ble approach intended to provide curative therapy to selected patients. In addition, the lessons learned in treat- ing AML with CAR T cells may reveal other targetable pathways to be exploited in combination with immune- based or pharmacological therapies. We await the impact of CART therapy on AML with cautious optimism, noting the recent shower of drug approvals that followed a long dry spell in AML therapeutics. We are hopeful that the combination of alloHSCT and CAR T-cell therapy (the old master and new arrival in adoptive cellular therapy) may prove to be the key to unlocking relapsed-refractory AML. We, and many others, continue to create and develop new solutions to make CAR T cells for AML a safe, deliverable and effective reality.
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