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 C-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-directed C-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 uttalte: "Det er mangel på kurative terapier administrert etter kronisk tilbakefall." Gitt den dårlige prognosen for pasienter som får tilbakefall etter å ha mottatt karnitinbehandlinger, er det et presserende udekket etterspørsel etter nye terapier.
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.
All patients in the cohort had relapsed/refractory LBCL, including diffuse LBCL not otherwise specified, transformed follicular lymphoma, marginal zone lymphoma, kronisk lymfocytisk leukemi/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.
Av 41 registrerte pasienter ble CAR T-celleproduktet vellykket produsert for 38 (95 %), da 2 hadde utilstrekkelig T-celler for leukaferese. Gjennomsnittlig varighet mellom leukaferese og infusjon var 18 dager.
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.
Median oppfølgingstid for alle pasienter var 18.4 måneder (område: 1.5-38.6), da ORR var 68 % og CR-raten var 53 %. Median PFS var 2.9 måneder (95 % konfidensintervall [KI], 1.7-NR) og median OS var 22.5 måneder (95 % KI, 8.3-NR).
Ved dosenivå 1 (n = 29) ble pasientene fulgt i en median på 14.1 måneder (område 1.5-38.6), og viste en 66 % ORR og en 52 % CR-rate. Median progresjonsfri overlevelse var 3.0 måneder (95 % KI, 1.6-NR) og median total overlevelse var NR (95 % KI, 8.3-NR).
Ved dosenivå 2 (n = 9) var median oppfølging 27.1 måneder (område: 24.7-33.5), ORR var 78 %, og CR-raten var 55 %. Median PFS var 2.6 måneder (95 % konfidensintervall: 1.3-NR) og median OS var 22.5 måneder (95 % konfidensintervall: 5.5-NR).
Bare 1 av de 20 pasientene som oppnådde en CR hadde fått tilbakefall ved dataavbruddet, noe som indikerer at CR-er er holdbare. Innen den tredje måneden hadde alle pasienter som hadde gjort fremgang i behandlingen gjort det.
Hos 95% av pasientene, 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 hemofagocytisk lymfohistiocytose.
En pasient på dosenivå 2 døde av sepsis på dag 40, og en pasient utviklet behandlingsrelatert myelodysplasi/akutt myeloide leukemi uten tegn på LBCL-tilbakefall 11 måneder etter å ha mottatt CD22-rettet behandling.
Det anbefalte dosenivået for fase 2 ble bestemt til å være 1.
Tidligere publisert informasjon detaljerte behandlingen av de tre første pasientene.
Alle to pasienter hadde høyrisikokarakteristikker og har mottatt minst fem tidligere behandlingslinjer, inkludert CD19-rettet CAR T-celleterapi. En av pasientene hadde tidligere mottatt to CAR T-cellebehandlinger, hvorav den andre var rettet mot CD19 og CD20. Alle tre pasientene oppnådde en CR, og pasient 3 oppnådde en CR på dag 28. CR ble oppbevart i mer enn tre år.
Frank bemerket også at "spredningen av CAR22 er ti ganger større og mer vedvarende enn 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.
Referanser
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 induserer fullstendig remisjon ved CD19-rettet CAR-refraktær storcellet B-celle lymfom. Blod. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
