Conference Coverage

Compound CAR T – a double whammy with promise for AML


 

FROM EHA CONGRESS

Six of eight relapsed/refractory acute myeloid leukemia patients, and one patient with accelerated phase chronic myelogenous leukemia, had no sign of residual disease 4 weeks after receiving compound CAR T therapy targeting both CD33 and CLL1.

Six patients moved on to subsequent hematopoietic stem cell transplantation (HSCT); the seventh responder withdrew from the study for personal reasons, according to a report at the virtual annual congress of the European Hematology Association.

Much work remains, but the initial results suggest that “CLL1-CD33 compound CAR T cell therapy could be developed as a bridge to transplant, a supplement to chemotherapy, or a standalone therapy for patients with acute myeloid leukemia” and other myeloid malignancies. The approach might also allow for reduced intensity conditioning or nonmyeloablative conditioning for HSCT, said lead investigator Fang Liu, MD, PhD, of the department of hematology at the Chengdu Military General Hospital, in Sichuan province, China.

It’s “a topic that will interest a lot of us.” For the first time, “a compound CAR with two independent CAR units induced remissions in AML,” said Pieter Sonneveld, MD, PhD, of the Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands, who introduced Dr. Liu’s presentation.

Chimeric antigen receptor (CAR) T cell therapy works well for B-cell malignancies, but translation to AML is “yet to be accomplished.” Meanwhile, despite progress against AML, about one-third of patients still relapse, “and prognosis for relapsed or refractory AML is dismal,” Dr. Liu and her team said.

CAR T is generally aimed against a single target, but AML bears heterogeneous cells that offset killing by single target therapies, resulting in disease relapse.

That problem suggested targeting multiple antigens simultaneously. CLL1 is an “ideal target,” Dr. Liu said, because the myeloid lineage antigen is highly expressed in AML, but absent in normal hematopoietic stem cells. CD33, meanwhile, is expressed on bulk AML cells in the majority of patients.

The CAR T cells were manufactured from autologous cells in eight of the subjects, and from a human leukocyte antigen-matched sibling donor cells for the ninth. The patients were lymphodepleted with fludarabine and cyclophosphamide, then infused with the therapeutic cells by a dose escalation at approximately 1-3 x 106/kg in a single or split dose.

On disease reevaluation within 4 weeks, seven of nine patients – all with relapsed or refractory disease after multiple conventional treatments – were minimal residual disease negative by flow cytometry. The other two had no response, one of whom was CD33 positive but CLL1 negative, “indicating the importance of [the] CLL1 target in CAR T treatment,” the investigators said.

All nine patients developed grade 4 pancytopenia; eight had cytokine release syndrome (CRS), which was grade 3 in two; and four subjects developed neurotoxicity, which was grade 3 in three.

Five subjects had mild liver enzyme elevations; four had a coagulation disorder; four developed diarrhea; three developed sepsis; two fungal infections; and three pneumonia. One subject had a skin rash and one developed renal insufficiency.

The adverse events resolved after treatment. “Early intervention with steroids had a positive effect on the reduction of CRS and neurotoxicity,” the team noted.

Of the six patients who went on to HCST, one had standard myeloablative conditioning, but the rest had reduced intensity conditioning. Five subjects successfully engrafted with persistent full chimerism, but one died of sepsis before engraftment.

The median age was 32 years. The median bone marrow blast count before treatment was 47%. Seven subjects had de novo AML; one – a 6-year-old girl – had juvenile myelomonocytic leukemia that transformed into AML; and one had accelerated phase chronic myelogenous leukemia.

A phase 1 trial is underway (NCT03795779).

The work was funded by iCell Gene Therapeutics. Several investigators were employees. Dr. Liu didn’t report any disclosures.

SOURCE: Liu F et al. EHA Congress. Abstract S149.

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