2023. február: The results of the trial demonstrated that a novel terapia T-buniek chimérického antigénneho receptora 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.
„Nikdy sme si nemysleli, že miera odozvy bude taká vysoká,“ Matthew Frank, MD, PhD, docent medicíny v oddelení transplantácie krvi a kostnej drene a bunkovej terapie na Stanfordskej univerzite, povedal Healio. "Je to veľmi efektívny a bezpečný CAR-T, ktorý sa podáva pacientom, ktorí budú mať z veľkej časti neuspokojenú potrebu."
pozadia
The CD22 protein on the surface of cancer cells is the terč 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 riadená CAR-T viedla k 70 % kompletnej odpovedi medzi 58 mladšími pacientmi s recidivujúcou alebo refraktérnou B-bunkovou ALL, ktorých choroba progredovala po skoršej CD19-riadenej CAR-T.
Frank uviedol: "Polovica našich pacientov stále recidivovala po použití komerčného CAR-T a bežnou príčinou relapsu bola downregulácia alebo delécia CD19." Očakávali sme reakcie použitím iného antigénu, ktorý sa javil ako sľubný pre mladých ľudí.
metodológie
Frank and coworkers tested their novel CD22-targeted CAR liečba T-buniek 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 lymfóm whose disease progressed after prior CD19-directed CAR-T therapy or had CD19-negative disease.
Všetci pacienti okrem jedného, ktorí boli liečení počas skúšania, predtým dostávali namierené proti CD19 Liečba T-bunkami CAR. Účastníci podstúpili lymfodepléciu pred podaním jednej infúzie CD22 CAR T buniek v dávke buď 1 106 buniek/kg (n = 29) alebo 3 106 buniek/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).
Kľúčové zistenia
36 people were diagnosed with syndróm uvoľnenia cytokínov. 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%).
Päť pacientov (13 %) malo neurotoxický syndróm spojený s imunitnými efektorovými bunkami. Počas štúdie neboli hlásené žiadne prípady závažného ICANS (stupeň 3 alebo vyšší).
Five patients, including three of the nine who received the larger dose, were diagnosed with CAR-associated hemofagocytárna lymfohistiocytóza (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.
Výskumníci zistili medián PFS 2.9 mesiaca (95 % interval spoľahlivosti [CI], 1.7 až nedosiahnutý) a medián OS 22.5 mesiaca (95 % IS, 8.3 až nedosiahnutý). Pokiaľ ide o medián PFS (3 mesiace vs. 2.6 mesiaca) a medián OS, nižšie a vyššie dávky preukázali porovnateľnú účinnosť (nedosiahnuté vs. 22.5 mesiaca).
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.
Klinické dôsledky
Keď sa experiment začal v roku 2018, málo sa pochopilo, prečo niektorí pacienti s CAR-T recidivujú. Frank uviedol, že základnou teóriou, mimo biológie nádoru, bola slabá zdatnosť T-buniek.
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.
Navrhovaná multicentrická štúdia fázy 2 s použitím CD22 CAR-T bude zahŕňať pacientov s veľkým B-bunkovým lymfómom, u ktorých došlo k relapsu po liečbe CAR-T zameranou na CD19. Obdobie prihlasovania sa pravdepodobne začne toto leto.
Referencies:
- Frank MJ a kol. Abstrakt 2. Prezentované na: Tandemové stretnutia | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, 15-19 February 2023; Orlando.
- Shah NN a kol. J Clin Oncol. 2020; doi:10.1200/JCO.19.03279.
