Feb 2023: The results of the trial demonstrated that a novel kimær antigenreseptor T-celleterapi elicited a response in adults with advanced large B-cell lymphoma who had relapsed following prior CAR-T.
According to statistics given during the Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, all but one of the 20 study patients who achieved an initial full response to therapy remained in remission as of the cutoff date.
"Vi hadde aldri trodd at svarprosentene ville være så høye," Matthew Frank, MD, PhD, assisterende professor i medisin i deling av blod- og margtransplantasjon og cellulær terapi ved Stanford University, fortalte Healio. "Det er en veldig effektiv og trygg CAR-T å gi til pasienter som stort sett vil ha et udekket behov."
Bakgrunn
The CD22 protein on the surface of cancer cells is the mål of an investigational autologous CAR T-cell treatment developed by Stanford University researchers. Using the CliniMACS Prodigy (Miltenyi Biotec) automated cell processing equipment, they produced the agent on-site over a 12-day period.
CD22-rettet CAR-T resulterte i en 70 % fullstendig responsrate blant 58 yngre pasienter med residiverende eller refraktær B-celle ALL hvis sykdom utviklet seg etter tidligere CD19-rettet CAR-T.
Frank uttalte: "Halvparten av pasientene våre fikk fortsatt tilbakefall etter å ha brukt kommersiell CAR-T, og en vanlig årsak til tilbakefall var nedregulering eller sletting av CD19." Vi forutså svar ved å bruke et annet antigen som virket lovende for ungdom.
metodikk
Frank and coworkers tested their novel CD22-targeted CAR T-celle behandling in a phase 1, single-institution, dose-escalation study.
The trial enrolled 38 persons (median age, 65 years; age range, 25-84; 55% men) with relapsed or refractory large B-cell lymfom whose disease progressed after prior CD19-directed CAR-T therapy or had CD19-negative disease.
Alle pasienter unntatt én som ble behandlet under forsøket hadde tidligere fått CD19-rettet C-T-cellebehandling. Deltakerne gjennomgikk lymfodeplesjon før de fikk en enkelt infusjon av CD22 CAR T-celler i en dose på enten 1 106 celler/kg (n = 29) eller 3 106 celler/kg (n = 9).
The primary outcomes of this study were feasibility, safety, and the recommended phase 2 dose. Secondary objectives included overall response rate as determined by the investigator, duration of response, PFS, OS, and CAR-T-associated toxicity. At a cutoff date of December 27, 2022, the median follow-up period was 18.4 months (range: 1.5-38.6).
Hovedfunnene
36 people were diagnosed with cytokinfrigivelsessyndrom. The only grade 3 adverse event occurred in the group receiving the highest dose. In the higher-dose group, grade 2 CRS occurred significantly more frequently (78% vs. 48%).
Fem pasienter (13 %) hadde nevrotoksisitetssyndrom assosiert med immuneffektorceller. Under forsøket ble det ikke rapportert noen tilfeller av alvorlig ICANS (grad 3 eller høyere).
Five patients, including three of the nine who received the larger dose, were diagnosed with CAR-associated hemofagocytisk lymfohistiocytose (HLH), a hyperinflammatory response marked by significant hyperferritinemia and multiorgan failure.
The examination of efficacy revealed an ORR of 68% and a complete response rate of 53% for all patients treated. A complete response was achieved by fifteen patients (52%) who received the lower dose, and five individuals (56%) who received the larger dose.
Forskere fant en median PFS på 2.9 måneder (95 % konfidensintervall [KI], 1.7 til ikke nådd) og en median OS på 22.5 måneder (95 % KI, 8.3 til ikke nådd). Når det gjelder median PFS (3 måneder vs. 2.6 måneder) og median OS, viste de lavere og høyere dosene sammenlignbar effektivitet (ikke nådd vs. 22.5 måneder).
As of the study’s end date, only one of twenty patients who had complete remission reported an illness return.
Researchers picked 1 106 cells/kg as the phase 2 dose recommendation because of its superior safety profile and comparable efficacy compared to the larger dose.
Kliniske implikasjoner
Da eksperimentet startet i 2018, ble det lite forstått om hvorfor noen CAR-T-pasienter får tilbakefall. Frank uttalte at den grunnleggende teorien, utenfor tumorbiologi, var dårlig T-cellekondisjon.
Frank told Healio, “We’ve kind of blown that [thesis] out of the water because we’re taking the same autologous T cells from patients who have had a prior CAR-T and still getting a nearly 70% response rate and a 53% full response rate that appears to be quite durable.” This medication is quite promising, as it has a good response rate and a reasonable safety profile.
En foreslått fase 2 multisenterstudie med CD22 CAR-T vil inkludere pasienter med stort B-celle lymfom som har fått tilbakefall etter behandling med CD19-rettet CAR-T. Påmeldingsperioden starter trolig i sommer.
Referanses:
- Frank MJ, et al. Sammendrag 2. Presentert på: Tandemmøter | Transplantasjons- og celleterapimøter for ASTCT og CIBMTR, 15.–19. februar 2023; Orlando.
- Shah NN, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03279.
