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/refractory acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma.
In a phase 1 dose-escalation study, 8 of the 12 patients overall achieved an objective response, and 5 of 8 patients (63%) treated 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, during a presentation at the virtual 2020 meeting of the American Association of Cancer Research. Cytokine release syndrome (CRS) was reversible, and neurotoxicity was limited.
Antigen escape is a major reason for relapse following CAR T-cell therapy, as tumors escape from therapy by losing the antigen that the T-cells are targeting. “Our hypothesis was that by simultaneously targeting of CD19 and CD22, we could diminish the risk of antigen loss,” said Dr Shalabi, assistant research physician, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD.
Of the 15 patients enrolled in the study, 13 have been treated: 4 at dose level 1 (3 × 105 transduced CAR Tcells), 4 at dose level 2 (1 × 106 CAR-T cells), and 5 at dose level 3 (3 × 106 CAR T-cells). All patients received lymphodepleting therapy with fludarabine and cyclophosphamide prior to CAR T-cell infusion. The study enrolled a heavily immunotherapy pretreated population, with 9 patients (69%) having received prior CD19-targeted CAR T-cell therapy and 5 (38.4%) having received prior CD22-targeted CAR T-cell therapy. Fifty-four percent had prior hematopoietic stem cell transplantation (HSCT). Median patient age was 19.6 years. Six patients (46.2%) had extramedullary disease.
The antileukemic effect of CD19/CD22 CAR T cells was dose dependent. Four of the 5 patients who had a CR and attained MRD negativity were naive to CAR T-cell therapy.
Two of 5 patients have relapsed with CD19+/CD22+ disease; 1 relapsed posttransplant at 265 days after infusion and 1 at 123 days. Both patients were antigen positive. Three patients remain in remission at a median of 7 months postinfusion; 1 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.
Six 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 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. Six patients (46.1%) developed CRS, with 2 patients (15.4%) experiencing 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 said. 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.”
The investigators plan to explore an additional dose level (1 × 107 CAR T-cells) as well as intensification of lymphodepletion in patients with prior 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, MD, associate professor, Department of Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles.