A novel, bispecific CD19/CD22 chimeric antigen receptor T-cell (CAR-T) therapy was tolerable and resulted in responses among patients with acute lymphoblastic leukemia (ALL), according to results from a phase 1 trial presented at the American Association for Cancer Research (AACR) Virtual Annual Meeting I 2020.
The novel CAR-T therapy was developed “with the hypothesis that dual antigen-targeting strategies may prevent antigen negative escape,” Haneen Shalabi, DO, of the National Cancer Institute and lead author and presenter of the study, said.
The phase 1, dose-escalation study treated 13 young patients with ALL with the CD19/CD22 CAR-T therapy at 3 different dose levels, including 3 x 105, 1 x 106, and 3 x 106. The bispecific construct contained FMC63 (CD19 scFv) linked with m971 (CD22 scFv) and a 4-1 BB costimulatory domain.
Patients underwent lymphodepletion with fludarabine plus cyclophosphamide prior to their CAR-T infusion. The primary endpoints were safety and toxicity, and the secondary endpoints were efficacy, chimeric antigen receptor (CAR) expansion, and CAR persistence.
At baseline, the median age was 19.6 (range, 5.4-28.5). Patients had received previous treatments, including hematopoietic stem cell transplant (54%), CD19-targeted therapy (69%), prior CD19 CAR T cell therapy (38.4%), blinatumomab (61.5%), CD22-targeted therapy (38.4%), inotuzumab (30.7%), and CD22 CAR-T therapy (15.4%). Extramedullary disease was present in 46.2% of patients.
“CAR T cells were well tolerated and toxicities were reversible in all patients,” Dr Shalabi said.
Cytokine release syndrome (CRS) developed in 46% of patients, 15.4% of which was grade 3 or higher. Both patients who developed grade 3 or higher CRS had received the 1 x 106 dose level of the CD19/CD22 CAR-T product and both required treatment with tocilizumab. One patient developed neurotoxicity, and had received the 3 x 106 dose level.
Of the 12 patients evaluable for efficacy, a complete response (CR) was achieved by 42% (5) of patients, including all patients who received the 1 x 106 or 3 x 106 dose levels of the CD19/CD22 CAR-T therapy. There were 2 nonresponders.
Two patients who received 1 x 106 CAR-T and all patients who received the 3 x 106 dose level were negative for minimal residual disease (MRD), with the remaining CRs demonstrating bone marrow clearance. Four of the 5 patients who were MRD negative were also naive to CAR-T therapy.
Of the 5 patients who achieved a CR, 2 relapsed with CD19-positive/CD22-positive disease and 3 remained in remission at a median 7 months after CAR T cell infusion.
Several patients, however, who were MRD negative in the bone marrow did not achieve CR in their extramedullary disease. Dr Shalabi said that these “discrepant results between marrow and extramedullary disease suggests potentially limited CAR-T trafficking to sites of extramedullary disease.” She suggested that “treatment at higher dose levels may be needed to overcome this limitation.”
CAR T-cell expansion occurred in all patents who responded, with a median peak in peripheral blood of 7%. At day 28, there were 1.3% CAR T cells in the bone marrow. The persistence of the CAR T cells in peripheral blood was a median of 45.6 days, as measured by flow cytometry.
Dr Shalabi concluded that this “early experience with bispecific CD19/CD22 CAR T cells demonstrates clinical activity with reversible CRS and limited neurotoxicity.” She noted that future studies will explore a 1 x 107 dose level, intensification of lymphodepletion prior to CAR-T infusion, and consideration of the potential role of immune checkpoint inhibitors to augment CAR-T in extramedullary disease.
Shalabi H, Yates B, Shahani S, et al. Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL. Presented at: American Association for Cancer Research (AACR) Virtual Annual Meeting I 2020; April 27-28, 2020. Abstract CT051.
This article originally appeared on Cancer Therapy Advisor