Universal CAR T-Cells a Promising Off-the-Shelf Therapy for T-Cell Acute Lymphoblastic Leukemia By Wayne Kuznar

TOP - July 2020, Vol 13, No 4 - Value-Based Care

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 relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) who received treatment with the universal CAR T-cell therapy currently labeled GC027.

The preliminary data demonstrate the feasibility of GC027, which does not require genetically engineering the drug 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 an 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, PhD, Gracell Biotechnologies, Shanghai, China, the developer of GC027, at the 2020 American Association for Cancer Research virtual annual meeting.

First Off-the-Shelf Therapy for T-Cell Malignancies

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,” she said. CD7 is a promising target for T-ALL because it is expressed in >95% of patients with T-ALL.

Because GC027 is an allogeneic drug, the expression of TCR-alpha was ablated by genomic disruption using the CRISPR/Cas9 system, to avoid graft-versus-host disease (GVHD). The CD7 locus was also disrupted to avoid fratricide during CAR T-cell production, said Dr Wang.

The efficacy of GC027 was tested in 5 adults with CD7-positive relapsed or refractory T-ALL at 3 dose levels, including 6 × 106 cells/kg (dose level 1), 1 × 107 cells/kg (dose level 2), and 1.5 × 107 cells/kg (dose level 3). All patients received a single infusion: 1 patient received dose level 1; 3 patients received dose level 2; and 1 received dose level 3.

GC027 is a universal CAR T-cell drug, and it was manufactured from the T-cells of human leukocyte antigen–unmatched healthy donors before the patients were enrolled in the study.

The patients’ median age was 24 years, and they received a median of 5 previous lines of therapy. The baseline bone marrow tumor burden was 38.2%.

The 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 patients achieved a CR with MRD negativity. One patient achieved a CR with MRD positivity at day 14, but that patient had a relapse at day 29. The 4 patients who achieved MRD negativity remained MRD-negative by 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 (N = 3), pulmonary infections (N = 3, all grade 3), and febrile neutropenia (N = 5, all grade 3). Cytokine release syndrome (CRS) occurred in all 5 patients, 4 of whom had grade 3 and 1 had grade 4. The symptoms of CRS were manageable and resolved after treatment and supportive care. None of the patients had neurotoxicity.

One advantage to off-the-shelf allogeneic cells is potentially higher T-cell quality from healthy donors, said discussant Yvonne Y. Chen, PhD, Co-Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center, 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,” Dr Chen 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,” she added.

The persistence of T-cells using this strategy remains unknown, she noted. “In the allogeneic setting—because we could in principle 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 CAR T-cells by definition are unnatural protein products,” Dr Chen pointed out.

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Last modified: July 30, 2020