A New CAR T-Cell Target for T-Cell Acute Lymphocytic Leukemia?

The anti-CD7 chimeric antigen receptor (CAR) T-cell therapy TruUCAR GC027 demonstrated promising efficacy in treating adults with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL), according to findings from a first-in-human study presented at EHA25 Virtual, the 25th European Hematology Association Annual Congress.

T-ALL comprises about 20% to 25% of cases of adult ALL, explained presenter Xinxin Wang, PhD, of Gracell Biotechnologies in Shanghai, China, and CD7 is present on more than 95% of T-ALL samples. However, the development of CAR T-cell therapy targeting CD7 has been limited in this setting by CD7 expression on normal T cells and potential contamination by T-ALL cells.

TruUCAR GC027 is a universal CAR T-cell product that is manufactured using lentivirus and leukapheresis products from HLA-mismatched healthy donors, she explained. It also contains second-generation CAR T cells with genomic disruption of the T-cell receptor (TCR) alpha and CD7 to help prevent graft-versus-host disease (GVHD) and fratricide. The product demonstrated T-cell expansion and antileukemic activity in mouse models.

In this single-arm, open-label study, investigators enrolled adults with relapsed or refractory T-ALL and a projected survival of longer than 3 months. Participants also had to be suitable for allogeneic transplantation.

Dr. Wang presented results from the first 5 patients (age range = 19-38 years) who had undergone a 6-day enhanced preconditioning chemotherapy followed by a single infusion of TruUCAR GC027. Patients received CAR T-cell doses of 0.6×107 cells/kg (n=1), 1×107 cells/kg (n=3), and 1.5×107 cells/kg (n=1).

All patients achieved a complete response (CR) or CR with incomplete hematologic recovery (CRi), and 3 patients achieved a measurable residual disease (MRD)-negative CR (<0.01% threshold; assessed by flow cytometry) at 1 month following infusion. Dr. Wang noted that the MRD-negative complete responders remained MRD-negative at follow-up evaluations (on days 61, 118, and 161 post-infusion), without bridging to transplant.

One patient achieved CR at day 14, but was still MRD positive, and the leukemia progressed at day 29; the patient later died from disease relapse.

Four patients experienced grade 3 cytokine release syndrome (CRS) and one experienced grade 4 CRS, an adverse event commonly associated with CAR T-cell therapy. Symptoms and signs of CRS resolved after anti-CRS treatment and supportive care, the investigators reported. While no patients experienced any grade of neurotoxicity or acute GVHD, all 5 experienced grade 3 febrile neutropenia.

Expansion of the T-cell product was observed in all patients – both on flow cytometry and quantitative polymerase chain reaction, Dr. Wang reported. This included what she called “robust expansion” in all 4 patients who experienced MRD-negative CR. There did not appear to be a correlation between disease burden and T-cell expansion, she added.

“The first-in-clinic universal CAR T-cell therapy for relapsed/refractory T-ALL demonstrated a very promising early response rate,” Dr. Wang said. “With these promising early results of GC027, further evaluation is warranted.”

Study authors report relationships with Gracell Biotechnologies, which sponsored the trial.

Reference

Wang X, Li S, Gao L, et al. First-in-human, universal anti-CD7 CAR-T therapy for relapsed and refractory T-cell acute lymphoblastic leukemia (R/R T-ALL). Abstract S115. Presented as part of EHA25 Virtual, June 12, 2020.