ASH 2022 | AMELI-01: safety and efficacy of UCART123v1.2 in R/R AML
David Sallman, MD, Moffitt Cancer Center, Tampa, FL, discusses the results of the AMELI-01 Phase I trial of UCART123v1.2 in adult patients with relapsed refractory (R/R) CD123+ acute myeloid leukemia (AML; NCT04106076). UCART123v1.2 is an anti-CD123 allogeneic CAR-T product, that has been genetically modified to minimize the occurrence of graft-versus-host disease (GvHD). Overall, results suggest UCART123v1.2 is well tolerated, though severe cytokine release syndrome (CRS) did occur, and that three-drug lymphodepletion optimizes CAR-T expansion and patient responses. This interview took place at the 64th ASH Annual Meeting and Exposition congress in New Orleans, LA.
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Transcript (edited for clarity)
In relapsed/refractory acute myeloid leukemia, there’s really, again, a very poor standard of care. And unfortunately, although CAR-T has brought forth a paradigm shift in other blood cancers like lymphoma, myeloma and acute lymphoblastic leukemia, we really do not have a CAR-T to date that has really been looking that promising, although a number of trials that are undergoing. So this is the first presentation of the AMELI-01, which is an allogeneic off-the-shelf CAR targeting CD123...
In relapsed/refractory acute myeloid leukemia, there’s really, again, a very poor standard of care. And unfortunately, although CAR-T has brought forth a paradigm shift in other blood cancers like lymphoma, myeloma and acute lymphoblastic leukemia, we really do not have a CAR-T to date that has really been looking that promising, although a number of trials that are undergoing. So this is the first presentation of the AMELI-01, which is an allogeneic off-the-shelf CAR targeting CD123. It’s also been genetically modified for safety to not cause sort of graft-versus-host disease, given these are allogeneic cells, while at the same time has a knockout of CD52. This allows us to add a drug, alemtuzumab, to intensify the lymphodepletion, which is likely needed for allogeneic CARs in order to get the most robust expansion.
So from a safety perspective, we enrolled two cohorts, one with just fludarabine cyclophosphamide and one with fludarabine cyclophosphamide and alemtuzumab. Across all the cohorts, it has overall been safe, but cytokine release syndrome definitely occurs. It actually occurred in 100% of patients and unfortunately two patients did have grade five events, so we can have severe toxicity, although for the majority of patients was overall well tolerated.
When we look at the expansion data, what we really learned in this trial was we have to do fludarabine, cyclophosphamide, alemtuzumab because without that, we really get rapid lymphocyte recovery and very relatively poor expansion in patients that did not get alemtuzumab, actually about 10 times higher expansion in patients that got the three-drug lymphodepletion.
When we look at efficacy, we did see patient responses in both cohorts, but if we look at the cohort of patients that, again, got all three drugs, we did see two responses. One patient had a 60% down to 5% blast reduction and was taken off study to go to a donor lymphocyte infusion. And then really a remarkable patient that had failed multiple lines of therapy, had relapsed after transplant, had grade four cytopenias and a high blast burden, this patient was treated on study and actually achieved a complete remission by the end of cycle one and is actually an MRD-negative complete remission for over one year without the need for second transplant, as well as without donor lymphocyte infusion. Really one of the most marked responses I would say in the field of CAR-T for AML.
So really going forward, I think to further improve safety, we’re adding prophylactic tocilizumab to try to mitigate the severity of the cytokine release syndrome, as well as given this as an off-the-shelf product, it really allows us to do multi-dosing. So for the first time, we’re going to sort of dose at day zero, but since we know that we have adequate lymphodepletion through the whole month, we’ll give a second dose around that two-week mark with really the goal to further augment efficacy. And again, this trial continues to accrue and we look forward to putting more patients on it.
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Disclosures
Takeda: Consultancy; Shattuck Labs: Membership on an entity’s Board of Directors or advisory committees; Kite: Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Incyte: Speakers Bureau; Syndax: Membership on an entity’s Board of Directors or advisory committees; Magenta: Consultancy; Intellia: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Aprea: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity’s Board of Directors or advisory committees; AbbVie: Membership on an entity’s Board of Directors or advisory committees; Syntrix Pharmaceuticals: Research Funding; Lixte: Patents & Royalties: LB-100; Nemucore: Membership on an entity’s Board of Directors or advisory committees.
