Dual-Specific CAR T-Cell Therapy Targets CD19 and CD22 in Patients with Acute Lymphoblastic Leukemia
A chimeric antigen receptor (CAR) T-cell therapy that targets CD19 and CD22 molecules has demonstrated safety and efficacy, in patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia, with response rates consistent with CAR T-cell therapies that target CD19 alone.
Preclinical testing showed superior efficacy against CD19 and CD22 when using 2 separate CARs and dual transduction compared with a single bispecific CAR, according to data presented at ASH 2018.
“SCRI-CAR19x22 has shown a low toxicity profile to date,” said Rebecca A. Gardner, MD, Attending Physician, Seattle Children’s Hospital, WA. “Whether this is involved with the impact of our early intervention strategy versus product manufacturing remains to be determined. However, our complete response rate of 83% is on par with what we see in CD19 CAR T-cell therapy alone, and the majority of our patients have had very high disease burden.”
CD19-targeted CAR T-cell therapies have been shown in multiple trials to reduce remissions effectively in >90% of patients, as Dr Gardner explained. However, event-free survival at 1 year is often >50%, and approximately 50% of recurrences result from antigen escape.
Dual Targeting in ALL
To reduce antigen escape and optimize the durability of remission, Dr Gardner and colleagues designed SCRI-CAR19x22, a CAR T-cell treatment with dual specificity that is capable of simultaneously targeting CD19 and CD22.
For this phase 1 clinical trial, the investigators are currently testing SCRI-CAR19x22 in pediatric patients and young adults with CD19- or CD22-positive relapsed or refractory B-cell precursor ALL. The study design starts with apheresis and drug manufacturing. Patients then undergo a bone marrow and lumbar puncture to assess their disease burden. They proceed with lymphodepleting chemotherapy, most often with fludarabine and cyclophosphamide. Finally, patients receive a CAR T-cell infusion, followed by a disease assessment with bone marrow and lumbar puncture, at days 10 and 21, and a bone marrow aspiration at day 63.
For toxicity mitigation, an early intervention strategy is used, with the goal of managing patients with persistent, mild cytokine release syndrome (CRS) to prevent transition to severe CRS. Tocilizumab (Actemra) is used for the treatment of CRS associated with persistent fevers, recurrent low blood pressure, and hypoxia, and dexamethasone is used for persistent or increasing symptoms.
Low Toxicity Profile, High Response Rate
Overall, 13 patients received an infusion as of the presentation at the meeting, with 2 patients exiting the study before day 30 with progressive disease. No dose-limiting toxicities occurred in the 11 patients who had a full evaluation.
The researchers observed an average of 5 days between the onset of CRS and the CAR T-cell infusion (range, 3-9 days). The majority of CRS events were mild, she noted, with 8 patients reporting grade 1 CRS, and 1 patient with grade 3 CRS requiring 4 hours of low-dose vasopressors. A total of 5 patients received tocilizumab, and 6 patients received dexamethasone.
“We’ve seen only mild neurotoxicity in 2 subjects, and this was a grade 1 tremor, grade 1 memory impairment, and grade 1 confusion,” Dr Gardner reported.
All 15 patients enrolled in the study had the treatment manufactured; however, 1 patient died before the CAR T-cell infusion, and 1 patient was pending infusion when these results were presented. Of the 13 patients who received a CAR T-cell therapy infusion, 10 had complete responses, and 9 of them were negative for minimal residual disease.
The complete response rate was 83%, which is comparable with previous studies of CD19 CAR T-cell therapy alone, said Dr Gardner, adding that the majority of infused patients have had very high disease burden.
“Because we did mandate uniform expression of CD19 and CD22, patients had a variety of expression patterns,” she stated. “Two subjects who did not obtain a complete response had progressive disease leading up to their CAR T-cell infusion, and despite engraftment and expansion of their CAR T-cells, did not demonstrate therapeutic benefit.”
An analysis of engraftment of CAR T-cells in vivo did not demonstrate a dose-level impact based on peak CAR T-cell expansion in the peripheral blood or the area under the curve. However, the researchers did observe dominance of the CD19 CAR T-cells uniformly in all patients with respect to peak expansion in the peripheral blood and area under the curve.
“The in vivo engraftment is really predominated by the CD19 CAR T-cells, and the impact of the dual- targeting strategy on reduction of antigen escape remains to be determined,” Dr Gardner concluded. “We are currently planning for a phase 2 study to fully investigate.”
Blinatumomab (derived from “B-lineage–specific antitumor mouse monoclonal antibody”) is a bispecific CD19-directed CD3 T-cell engaging antibody that binds to1-3:CD19 (expressed on the surface of cells of B-lineage origin)CD3 (expressed on the surface of T cells).More than 90% of cases of B-cell precursor acute lymphoblastic leukemia (ALL) express CD19 in more [ Read More ]
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