I februarry 2023, a phase 1 trial at a single institution found that it was safe and possible for people with heavily pretreated large B-cell lymphoma (LBCL) to use CD22-directed chimeric antigen receptor (CAR) T-cell therapy after relapse on CD19-directed BIL T-cellebehandling. In addition, patients exhibited high overall response rates (ORRs), and complete responses (CRs) in these patients were found to be durable.
A presentation by lead study author Matthew J. Frank, MD, PhD, assistant professor of medicine in the Division of Bone Marrow Transplant & Cellular Therapy at the Stanford Cancer Institute, said, “A single infusion of CAR22 produced high response rates in heavily pretreated large B-cell lymphoma patients who relapsed after CAR19.” Frank is the director of the study and an assistant professor of medicine.
CD19-instrueret BIL T-cellebehandling has led to significant responses in patients with relapsed/refractory LBCL; however, if relapse occurs, patients have a very poor prognosis, and many exhibit CD19 loss or reduced expression.
Frank udtalte: "Der er mangel på helbredende terapier administreret efter kronisk tilbagefald." I betragtning af den dårlige prognose for patienter, der får tilbagefald efter at have modtaget carnitinbehandlinger, er der en presserende udækket efterspørgsel efter nye behandlinger.
CD22 is of interest as a target for CAR T-cell therapy as it can be found on the surface of malignant B cells in 95% of B-cell acute lymphoblastic leukaemias (ALLs) and LBCLs. CD22-directed CAR T-cell therapy has already demonstrated high response rates in patients with heavily pretreated ALL.
Adults with B-cell ALL and B-cell ikke-Hodgkin-lymfom were enrolled in the dose-escalation phase 1 study of CAR T-cell therapy directed at CD22. Frank presented at the Tandem Meetings the results of the LBCL cohort.
Alle patienter i kohorten havde recidiverende/refraktær LBCL, inklusive diffust LBCL ikke andet specificeret, transformeret follikulært lymfom, marginal zone lymfom, kronisk lymfocytisk leukæmi/small lymphocytic lymphoma, primary mediastinal B-cell lymphoma, and secondary central nervous system involvement. In addition, patients were resistant to CD19-directed CAR T-cell therapy or had CD19-negative disease in conjunction with any CD22 expression. Patients who had previously received CAR T-cell therapy had to have at least 30 days passed since their last infusion and less than 5% CAR-positive cells in their peripheral blood, according to flow cytometry.
Patients received either 1 x 106 (dose level 1) or 3 x 106 (dose level 2) of the CD22-targeted drug (dose level 2). Prior to infusion, patients received intravenous fludarabine (30 mg/m2) and cyclophosphamide (500 mg) to administer lymphodepleting chemotherapy.
The primary objectives of the study were manufacturing feasibility, the phase 2 dose recommendation, safety, and toxicity. The investigator-assessed ORR, duration of response, progression-free survival (PFS), overall survival (OS), CAR T associated toxicity, CD22 antigen expression, CAR-positive cell levels in the blood, and serum cytokine profiling were secondary endpoints.
Ud af 41 tilmeldte patienter blev CAR T-celleproduktet med succes fremstillet til 38 (95%), da 2 havde utilstrækkelige T-celler til leukaferese. Den gennemsnitlige varighed mellem leukaferese og infusion var 18 dage.
The median age of participants who received CAR T-cell therapy was 65 (range, 25-84), they had an ECOG performance status of 0 or 1, and they had received a median of 4 prior lines of therapy (range, 3-8). 74% of patients had diffuse LBCL, and 21% had transformed follicular lymfom. 39% of patients were diagnosed with non-germinal centre B-cell-like disease, and 18% had double-hit status. 97% of patients had previously received CD19-directed CAR T-cell therapy, and 18% had previously undergone autologous hematopoietic stem cell transplantation. 29 percent of patients did not achieve a CR to any prior therapy.
Den mediane opfølgningstid for alle patienter var 18.4 måneder (interval: 1.5-38.6), på hvilket tidspunkt ORR var 68 %, og CR-raten var 53 %. Median PFS var 2.9 måneder (95 % konfidensinterval [CI], 1.7-NR), og median OS var 22.5 måneder (95 % CI, 8.3-NR).
Ved dosisniveau 1 (n = 29) blev patienter fulgt i en median på 14.1 måneder (interval, 1.5-38.6), hvilket viste en 66 % ORR og en 52 % CR rate. Median progressionsfri overlevelse var 3.0 måneder (95 % CI, 1.6-NR), og median samlet overlevelse var NR (95 % CI, 8.3-NR).
Ved dosisniveau 2 (n = 9) var medianopfølgningen 27.1 måneder (interval: 24.7-33.5), ORR var 78 %, og CR-raten var 55 %. Median PFS var 2.6 måneder (95 % konfidensinterval: 1.3-NR), og median OS var 22.5 måneder (95 % konfidensinterval: 5.5-NR).
Kun 1 af de 20 patienter, der opnåede en CR, havde fået tilbagefald ved data cutoff, hvilket indikerer, at CR'er er holdbare. Ved den tredje måned havde alle patienter, der havde gjort fremskridt med behandlingen, gjort det.
Hos 95% af patienterne cytokinfrigivelsessyndrom was observed, with grade 1 events occurring in 37%, grade 2 in 55%, and grade 3 in 3%. 8% of patients experienced neurologic events of grade 1 severity, while 5% experienced events of grade 2 severity. 18% of patients also reported toxicity resembling hæmofagocytisk lymfohistiocytose.
En patient på dosisniveau 2 døde af sepsis på dag 40, og en patient udviklede behandlingsrelateret myelodysplasi/akut myeloid leukæmi uden tegn på LBCL-tilbagefald 11 måneder efter at have modtaget CD22-rettet behandling.
Det anbefalede dosisniveau for fase 2 blev bestemt til at være 1.
Tidligere offentliggjorte oplysninger detaljerede behandlingen af de første tre patienter.
Alle to patienter havde højrisikokarakteristika og har modtaget mindst fem tidligere behandlingslinjer, inklusive CD19-styret CAR T-celleterapi. En af patienterne havde tidligere modtaget to CAR T-cellebehandlinger, hvoraf den anden var målrettet CD19 og CD20. Alle tre patienter opnåede en CR, og patient 3 opnåede en CR på dag 28. CR'er blev opbevaret i mere end tre år.
Frank bemærkede også, at "spredningen af CAR22 er ti gange større og mere vedvarende end CAR19."
To learn more about patients who have relapsed after CD19-directed CAR T-cell therapy, a planned multicenter phase 2 trial of this agent is being set up. The trial will likely begin this summer.
Referencer
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B celle lymfom who relapse after CD19 CAR T cell therapy. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 2.
2. Baird JH, Frank MJ, Craig J, et al. CD22-rettet CAR T-celleterapi inducerer fuldstændig remission i CD19-rettet CAR-refraktær storcellet B-celle lymfom. Blod. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
