In februariry 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 CAR T-celtherapie. 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-geregisseerd CAR T-celtherapie 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 verklaarde: "Er is een tekort aan curatieve therapieën die worden toegediend na een chronische terugval." Gezien de slechte prognose van patiënten die terugvallen na behandeling met carnitine, is er een dringende onvervulde vraag naar nieuwe therapieën.
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 non-Hodgkin-lymfoom 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 patiënten in het cohort hadden recidiverende/refractaire LBCL, inclusief diffuse LBCL niet anders gespecificeerd, getransformeerd folliculair lymfoom, marginale zone lymfoom, chronische lymfatische leukemie/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.
Van de 41 ingeschreven patiënten werd het CAR T-celproduct met succes vervaardigd voor 38 (95%), aangezien 2 onvoldoende T-cellen hadden voor leukaferese. De gemiddelde duur tussen leukaferese en infusie was 18 dagen.
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 lymfoom. 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.
De mediane follow-uptijd voor alle patiënten was 18.4 maanden (spreiding: 1.5-38.6), op welk moment de ORR 68% was en het CR-percentage 53%. De mediane PFS was 2.9 maanden (95% betrouwbaarheidsinterval [BI], 1.7-NR) en de mediane OS was 22.5 maanden (95% BI, 8.3-NR).
Bij dosisniveau 1 (n = 29) werden patiënten gevolgd gedurende een mediaan van 14.1 maanden (spreiding: 1.5-38.6), wat een ORR van 66% en een CR van 52% aantoonde. De mediane progressievrije overleving was 3.0 maanden (95% BI, 1.6-NR) en de mediane totale overleving was NR (95% BI, 8.3-NR).
Bij dosisniveau 2 (n = 9) was de mediane follow-up 27.1 maanden (spreiding: 24.7-33.5), de ORR was 78% en het CR-percentage was 55%. De mediane PFS was 2.6 maanden (95% betrouwbaarheidsinterval: 1.3-NR) en de mediane OS was 22.5 maanden (95% betrouwbaarheidsinterval: 5.5-NR).
Slechts 1 van de 20 patiënten die een CR bereikten, was teruggevallen vanaf de data-cutoff, wat aangeeft dat CR's duurzaam zijn. Tegen de derde maand hadden alle patiënten die vooruitgang hadden geboekt met de behandeling dit gedaan.
Bij 95% van de patiënten cytokine-afgiftesyndroom 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 hemofagocytische lymfohistiocytose.
Eén patiënt op dosisniveau 2 stierf op dag 40 aan sepsis, en één patiënt ontwikkelde behandelingsgerelateerde myelodysplasie/acute myeloïde leukemie zonder bewijs van LBCL-terugval 11 maanden na ontvangst van CD22-gerichte therapie.
Het aanbevolen dosisniveau voor fase 2 werd vastgesteld op 1.
Eerder gepubliceerde informatie beschrijft de behandeling van de eerste drie patiënten.
Alle twee patiënten hadden kenmerken met een hoog risico en hebben ten minste vijf eerdere behandelingslijnen gekregen, waaronder CD19-gerichte CAR T-celtherapie. Een van de patiënten had eerder twee CAR T-celtherapieën gekregen, waarvan de tweede gericht was op CD19 en CD20. Alle drie de patiënten bereikten een CR, waarbij patiënt 3 een CR bereikte op dag 28. CR's werden meer dan drie jaar bewaard.
Frank merkte ook op dat "de verspreiding van CAR22 tien keer groter en persistenter is dan 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.
Referenties
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B cellymfoom 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-gerichte CAR T-celtherapie induceert volledige remissies in CD19-gerichte CAR-refractair grootcellig B-cellymfoom. Bloed. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
