Universal CAR-T Platform Shows Promising Efficacy in Relapsed/Refractory AML

Initial findings from a proof-of-concept study led by Martin Wermke, MD, from the Technical University of Dresden in Germany, suggest that UniCAR, a universal, rapidly switchable second-generation chimeric antigen receptor (CAR) T-cell therapy platform, could offer a new treatment option for patients with relapsed/refractory acute myeloid leukemia (AML). The study was published in Blood.

Allogeneic hematopoietic cell transplantation represents the only curative option for patients with AML, but only for those who are eligible. CAR T-cell therapy has proven effective in B-cell malignancies and plasma cell–derived neoplasia, but “the transfer of conventional [CAR T-cell] technology to AML has been hampered by the fact that potential target antigens being overexpressed on leukemic blasts are also found on normal myeloid progenitor cells generating a risk for lasting aplasia,” Dr. Wermke and coauthors explained.

For example, while CD123-targeting CAR T-cell therapy has induced remissions in AML, it has also led to long-lasting myelosuppression. “This illustrates the clinical need for innovative approaches to put the power of [CAR T-cell] technology under the control of reliable and fast-acting on/off switches in order to avoid and/or abrogate acute and long-term side effects,” they wrote.

The UniCAR platform uses targeting molecule TM123 and a single-chain variable fragment that is directed against the CD123 antigen. In general, the targeting molecule “confers specificity against the cancer antigen of choice and due to the high flexibility of the tumor-binding domain, multiple antigens in solid tumors and hematologic malignancies can be targeted,” the investigators explained.

The Blood report describes outcomes for the first three patients with relapsed/refractory AML who were dosed and completed the treatment regimen. All three patients – aged 54, 65, and 80 years – had previously received chemotherapy. Two of the three had previously undergone hematopoietic cell transplantation.

Following apheresis, all participants underwent bridging therapy, which did not include cytoreduction. Prior to the start of treatment, the patients received a lymphodepleting regimen consisting of intravenous (IV) fludarabine 30 mg/m2 per day, combined with IV cyclophosphamide 300 mg/m2 per day for three days.

Treatment consisted of TM123 administered intravenously for 24 days. On day one, patients received autologous UniCAR T cells. The first patient received 100×106 UniCAR T cells and TM123 0.5 mg per day. The second patient was treated with 250×106 UniCAR T cells and TM123 0.5 mg per day, and the third patient received 250×106 UniCAR T cells and TMI123 1 mg/day. (TABLE)

One of the three patients who completed treatment has received a second TM123 cycle. Another patient’s treatment is ongoing, with a planned UniCAR T cell dose of 500×106 and TMI123 1 mg per day.

“Treatment proved to be tolerable with encouraging signs of efficacy,” the researchers stated. Myelosuppression was reported after lymphodepletion, but recovered following TM123 withdrawal on day 24 in all patients. According to the investigators, this finding provides evidence for a rapid “off switch” of UniCAR after treatment with TM123, which has a half-life of 0.45 hours. Clinical pharmacokinetic data for the first three patients treated validated the accelerated elimination.

The investigators observed no dose-limiting toxicities. Two patients experienced grade one cytokine release syndrome, but this resolved within 48 hours of antibiotic use. All patients experienced expansion of UniCAR T cells at rates similar to that reported with other CD123 CAR T-cell products. The UniCAR T cells were reportedly detectable up to six months following administration of treatment.

Since the time of the study’s publication, all patients have demonstrated a clinical response to treatment, the authors noted. A partial remission was observed in one patient, while two patients had complete remission with incomplete hematologic recovery (CRi). In one patient with CRi, the disease was still under control approximately 100 days after administration of treatment, while the other patient with CRi experienced regrowth after one month.

“These initial clinical results of [UniCAR T-cell CD123] represent, to our understanding, [the first evidence] for a well-tolerated rapidly switchable [CAR T-cell] product,” the authors concluded. “The efficacy seen so far, even at the lowest dose level, is encouraging.” The small number of patients treated limit the study’s findings, but the researchers noted that “the data obtained provide clinical proof-of-concept for the opportunity to abrogate side effects by withdrawal of TM123.”

Study authors report no relevant conflicts of interest.


Wermke M, Kraus S, Ehninger A, et al. Proof-of-concept for Rapidly Switchable Universal CAR-T Platform with UniCAR-T-CD123 in relapsed/refractory AML. Blood. 2021 Feb 23. [Epub ahead of print]