In a single-center phase I trial reported in The Lancet, Frank et al found that CD22-directed chimeric antigen receptor (CAR) T-cell therapy (CAR22) showed activity in patients with large B-cell lymphoma (LBCL) whose disease progressed on CD19-directed CAR T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen.
Study Details
The study enrolled 40 eligible patients at Stanford University between October 2019 and October 2022. All patients underwent leukapheresis, with CAR22 successfully manufactured and administered in 38 patients (95%). Of the 38 patients, 37 had disease progression after CD19 and 1 had CD19-negative disease.
After lymphodepleting therapy, patients received one of two dose levels of CD22, consisting of single infusions of 1 × 10⁶ CAR-positive cells/kg (dose level 1, n = 29) or 3 × 10⁶ CAR-positive cells/kg (dose level 2, n = 9). Patients had received a median of four lines of previous therapy (range = 3–8).
Key Findings
The maximum tolerated dose, and recommended phase II dose, was identified as 1 × 10⁶ CAR-positive cells/kg. Among the 29 patients receiving this dose, none developed a dose-limiting toxicity or grade ≥ 3 cytokine-release syndrome, immune effector cell–associated neurotoxicity syndrome, or immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome. Among nine patients receiving dose level 2, two had dose-limiting toxicities, consisting of reversible grade 3 left ventricular systolic dysfunction with concurrent grade 3 pulmonary edema in one patient and persistent grade 3 alanine aminotransferase and aspartate aminotransferase elevations in the other.
Among all 38 patients, objective response was observed in 26 (88%), with a complete response seen in 20 (53%). Median response duration was 27.8 months (95% confidence interval = 5.1 months to not evaluable). Among 29 patients receiving dose level 1, an objective response was observed in 19 (66%), with a complete response in 15 (52%). Among nine patients receiving dose level 2, an objective response was observed in seven (78%), with a complete response seen in five (56%).
The investigators concluded, “This trial identifies CD22 as an immunotherapeutic target in [LBCL] and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase I dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach.”
Matthew J. Frank, MD, of the Center for Cancer Cell Therapy, Stanford Cancer Institute, and David B. Miklos, MD, of the Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, are the corresponding authors for The Lancet article.
Disclosure: The study was funded by the National Cancer Institute, Leukemia & Lymphoma Society, and others. For full disclosures of the study authors, visit thelancet.com.
