CD22-Directed CAR T-Cell Therapy Mediates Durable Complete Responses in Adults with Relapsed or Refractory Large B-Cell Lymphoma after Failure of CD19-Directed CAR T-Cell Therapy and High Response Rates in Adults with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

BACKGROUND: CD22 is expressed on the majority of B-cell malignancies. Autologous CAR T-cells targeting CD22 (CAR22) have yielded objective response rates (ORR) of 70-90% in pediatric patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL), including those who had previously failed CD19-directed CAR T-cell (CAR19) therapy. Based on these encouraging results, we evaluated CAR22 in adult patients with R/R ALL and for the first time in patients with R/R large B-cell lymphoma (LBCL), including those who had failed prior autologous CAR19 therapy.

METHODS: This single-institution phase I dose escalation clinical trial (NCT04088890) is evaluating a CAR construct incorporating the m971 CD22 single chain variable fragments and 41BB/CD3z endodomains integrated within autologous T-cells via lentiviral transduction. After lymphodepletion with fludarabine and cyclophosphamide, patients were infused with fresh or cryopreserved CAR T-cells after a 7- to 11-day closed manufacturing process utilizing the CliniMACS Prodigy device (Miltenyi). The current cohort includes patients treated at dose level 1 (DL1), which was 1x10⁶ CAR+ cells/kg. Primary objectives assessed the ability to successfully manufacture CAR22 and safety. Overall response rate (ORR) at 28 days post-infusion (D28) was a secondary objective.

RESULTS: Three patients with LBCL have been enrolled with a median age of 53 years (range, 51-57) and a median of 6 (range, 5-8) prior lines of therapy. All three patients received prior CAR19 and had refractory disease to second-line or later therapy (n=3); had not undergone autologous hematopoietic stem cell transplantation (HSCT) (n=3); had MYC and BCL2 gene rearrangements (double-hit lymphoma; n=2); had high tumor burden (SPD >50 cm²; n=2); had a history of primary refractory disease (n=1); or had never achieved CR to any therapy (n=1). Six patients with ALL have been enrolled with a median age of 43.5 years (range, 23-62) and a median of 6 (range, 4-8) prior lines of therapy. All six patients received prior allogeneic HSCT and had Ph-positive disease (n=3); had central nervous system (CNS) involvement (n=3); had extramedullary disease (n=2); had high disease burden (BM blasts >5%; n=2); had received prior CD19-directed therapy (n=5); or had received prior CD22-directed therapy (n=3). Successful manufacturing of cells at DL1 was achieved in all patients. All patients (LBCL n=3, ALL n=6) reached day 28 and are included in the safety and response analysis presented here; updated results will be presented at the meeting. Eight patients (88.9%) experienced cytokine release syndrome (CRS); all were Grade 1-2. There were no cases of immune effector cell-associated neurotoxicity syndrome (ICANS). No differences in toxicities were seen across the patient age spectrum and no Grade 5 toxicities occurred following CAR22 infusion. In LBCL, all patients achieved a response at D28 (ORR=100%; CR, n=1, PR, n=2). Both patients with a D28 PR improved to CR by day 90 and 180. All patients remain in CR, with a median follow-up of 8.4 months (range, 6-9.3). In ALL, all patients achieved a CR at D28 (ORR=100%; MRD-, n=5, MRD+, n=1). After a median follow up of 5.1 months (range, 1-8.2), three patients relapsed at 2.5, 4, and 5.5 months after infusion; one patient died while undergoing subsequent therapy 7.3 months post-infusion. CD22 expression by flow cytometry was downregulated or absent in two patients after relapse. Peak CAR expansion as detected by peripheral blood flow cytometry reached a median level of 90.1 (LBCL; range, 85.4-350) and 43.4 (ALL; range, 0.9-399.6) CAR+ cells/µL between D14 and D21. In two LBCL patients with progression following CAR19, CAR22 levels were 11.7 and 55.9 fold higher than prior CAR19 levels at peak expansion.

CONCLUSIONS: Infusion of CD22-targeting CAR T-cells in R/R LBCL and ALL is safe and well tolerated. Manufacturing of CAR22 was uniformly successful. To date, 3 of 3 heavily treated adult patients with LBCL whose disease relapsed after prior CAR19 have each achieved CR durable to at least 6 months. All adult ALL patients have achieved CR following CAR22, with some early relapses observed. Accrual is ongoing.