Bispecific CAR T-Cells Show Promise in Children and Young Adults with Relapsed B-Cell Acute Lymphoblastic Leukemia

A bispecific chimeric antigen receptor (CAR) T-cell product directed against CD19 and CD22 antigens induced a complete response (CR) in 5 of 12 (42%) evaluable children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL).

In a phase 1 dose-escalation study, 8 of the 12 patients with ALL achieved an objective response, and 5 of 8 (63%) patients who received treatment at dose level 2 or 3 achieved a CR. All 5 patients with a CR were negative for minimal residual disease (MRD), said Haneen Shalabi, DO, Assistant Research Physician, Pediatric Oncology Branch, National Cancer Institute, during a presentation at the 2020 American Association for Cancer Research virtual annual meeting. Cytokine release syndrome (CRS) was reversible and neurotoxicity was limited.

Antigen loss escape is a major reason for relapse after CAR T-cell therapy because tumors escape treatment by losing the antigen that the T-cells are targeting. “Our hypothesis was that by simultaneously targeting CD19 and CD22, we could diminish the risk of antigen loss,” said Dr Shalabi.

Of the 15 patients with ALL enrolled in the study, 13 had received treatment, including 4 patients at dose level 1 (3 × 105 transduced CAR T-cells), 4 at dose level 2 (1 × 106 CAR T-cells), and 5 at dose level 3 (3 × 106 CAR T-cells). All of the patients received lymphodepleting therapy with fludarabine and cyclophosphamide before CAR T-cell infusion. The study enrolled a heavily immunotherapy-pretreated population, with 9 (69%) patients receiving previous CD19-targeted CAR T-cell therapy and 5 (38.4%) receiving previous CD22-targeted CAR T-cell therapy. A total of 54% of the patients had previous hematopoietic stem-cell transplantation (HSCT). The median patient age was 19.6 years. A total of 6 (46.2%) patients had extramedullary disease.

Dose-Dependent Effects

The antileukemic effect of CD19/CD22 CAR T-cells was dose dependent. Of the 5 patients who had a CR and attained MRD negativity, 4 were naïve to CAR T-cell therapy.

In all, 2 of the 5 patients with a CR have relapsed with CD19-positive, CD22-positive disease; 1 patient relapsed posttransplant at 265 days after infusion and 1 relapsed at 123 days. Both patients were antigen-positive. A total of 3 patients remain in remission at a median of 7 months postinfusion; 1 patient has an ongoing CR at 7 months without interval therapy and 1 has ongoing CR at 6 weeks postinfusion and is awaiting a second HSCT.

A total of 6 patients had multifocal extramedullary disease in addition to bone marrow disease. Three patients who had clearance of bone marrow disease had persistent extramedullary disease at day 28.

“Discrepancies were seen in marrow response versus extramedullary disease,” said Dr Shalabi. “Discrepant results between marrow and extramedullary disease suggest potentially limited CAR T trafficking to the site of extramedullary disease. Treatment at higher dose levels may be needed to overcome this limitation, and close monitoring and longer follow-up is needed.”

Toxicities were reversible in all patients. A total of 6 (46.1%) patients had CRS, and 2 (15.4%) patients had grade 3 CRS, both at dose level 2. One patient had neurotoxicity at dose level 3.

Limited CAR persistence likely contributed to antigen-positive relapses, said Dr Shalabi. “CAR T-cell expansion was observed in all responders; however, persistence has been limited,” she noted. In the peripheral blood, the median peak percentage of CAR T-cells was 7% (range, 0%-55%) and in the bone marrow at day 28, the median peak was 1.3% (range, 0%-22%). “In the peripheral blood, we can detect CAR T-cells to a median of 45.6 days, with a range of 13 to 87 days,” Dr Shalabi commented.

The investigators plan to explore an additional dose level (1 × 107 CAR T-cells) as well as the intensification of lymphodepletion in patients with previous CAR treatment in an effort to overcome immune-mediated rejection.

The 63% CR rate at the 2 highest dose levels is “quite promising, especially considering that the therapy was very well-tolerated with reversible CRS and neurotoxicity,” commented Yvonne Y. Chen, PhD, Co-Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

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