Universal CAR T-Cells Look Promising as Therapy for T-Cell ALL

July 2020 Vol 11, No 7

The first off-the-shelf chimeric antigen receptor (CAR) T-cell platform targeting CD7 induced a complete response (CR) with no minimal residual disease (MRD) in 4 of the first 5 adults with adult relapsed/ refractory T-cell acute lymphoblastic leukemia (T-ALL) who were treated with the universal CAR T-cell therapy known as GC027.

The preliminary data demonstrate the feasibility of GC027, which does not require genetically engineering the product from the patient’s own T-cells and therefore can be delivered more quickly than autologous CAR T-cell production. Patients are not required to undergo antibody “preconditioning” treatment, which is generally used to clear a path for allogeneic CAR T-cells to work.

The data were presented by Xinxin Wang, MD, at the 2020 virtual meeting of the American Association for Cancer Research.

GC027 is the first in-clinic universal CAR T-cell therapy for T-cell malignancies. A challenge to the use of CAR T-cell therapy in the treatment of T-ALL is that T-ALL shares many of the same antigens with normal T-cells, so “targeted therapies for T-ALL will also target normal T-cells,” said Dr Wang. “Another challenge is potential lymphoblast contamination in an autologous CAR T product, which can be avoided by universal CAR T.” CD7 is a promising target for T-ALL because it is expressed in >95% of T-ALL patients.

Since GC027 is an allogeneic product, to avoid graftversus- host disease (GVHD), the expression of T-cell receptor alpha was ablated by genomic disruption through the use of the CRISPR/Cas9 system. CD7 locus was also disrupted to avoid fratricide during CAR T-cell production, said Dr Wang, from Gracell Biotechnologies Ltd, Shanghai, China, the developer of GC027.

The efficacy of GC027 was tested in 5 adults with CD7-positive relapsed/refractory T-ALL at 3 dose levels: 6 ×106 (dose level 1), 1 × 107 (dose level 2), and 1.5 × 107 (dose level 3) cells/kg. Patients received a single infusion. One patient received dose level 1, 3 patients received dose level 2, and 1 received dose level 3. Being a universal CAR T product, GC027 was manufactured from T-cells of human leukocyte antigen unmatched healthy donors prior to patients being enrolled into the trial.

The median age of patients was 24 years. They had received a median of 5 prior lines of therapy. Baseline bone marrow tumor burden was 38.2%.

Data cutoff was February 6, 2020. At first evaluation (day 28), all 5 patients achieved a CR with or without complete blood count recovery, and 4 achieved CR with MRD negativity. One patient achieved CR with MRD positivity at day 14 but relapsed at day 29. The 4 patients who achieved MRD negativity remained so to day 161.

GC027 expansion was observed in all patients by quantitative polymerase chain reaction. “We started to see GC027 in the peripheral blood as early as day 5, and the peak around day 7 to 14,” said Dr Wang.

All 5 patients tolerated the single infusion without neurotoxicity or acute GVHD. Grade ≥3 toxicities included prolonged cytopenia in 3 patients, pulmonary infections in 3 (all grade 3), and febrile neutropenia in 5 (all grade 3). Cytokine release syndrome (CRS) occurred in all 5 patients; 4 grade 3 events and 1 grade 4. CRS symptoms were manageable and resolved after treatment and supportive care. No patient experienced neurotoxicity.

One advantage to off-the-shelf allogeneic cells is potentially higher T-cell quality from healthy donors, said discussant Yvonne Y. Chen, MD, associate professor, Department of Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles.

“We need to remember that most of our patients have been heavily pretreated, and so the quality of their T-cells may have already been compromised by the many rounds of chemo or radiation that they have experienced prior to receiving CAR T-cell therapy,” she said. “So it’s possible that one simply can’t make good CAR T-cells out of these patients’ cells, and this is one of the major arguments for doing allogeneic T-cell therapy.”

An unknown is the persistence of T-cells using this strategy, said Dr Chen. “In the allogeneic setting, because we could in principle, we could make lots of these cells, repeated dosing may be a feasible strategy, but then we have to consider the possibility of immunogenicity, keeping in mind that CARs by definition are unnatural protein products,” she said.

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Last modified: July 9, 2020

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