Në shkurtry 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 Terapia me qeliza T CAR. 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 Terapia me qeliza T CAR 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 tha: "Ka mungesë të terapive kurative të administruara pas rikthimit kronik." Duke pasur parasysh prognozën e dobët të pacientëve të cilët rikthehen pas marrjes së terapive me karnitinë, ekziston një kërkesë urgjente e paplotësuar për terapi të reja.
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 limfoma jo-Hodgkin 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, leuçemia limfocitare kronike/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.
Nga 41 pacientë të regjistruar, produkti i qelizave T CAR u prodhua me sukses për 38 (95%), pasi 2 kishin qeliza T të pamjaftueshme për leukaferezë. Kohëzgjatja mesatare midis leukaferezës dhe infuzionit ishte 18 ditë.
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 limfome. 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.
Koha mesatare e ndjekjes për të gjithë pacientët ishte 18.4 muaj (varg: 1.5-38.6), në të cilën pikë ORR ishte 68% dhe shkalla e CR ishte 53%. PFS mesatare ishte 2.9 muaj (95% intervali i besueshmërisë [CI], 1.7-NR) dhe OS mesatare ishte 22.5 muaj (95% CI, 8.3-NR).
Në nivelin e dozës 1 (n = 29), pacientët u ndoqën për një mesatare prej 14.1 muajsh (varg, 1.5-38.6), duke demonstruar një ORR 66% dhe një normë CR 52%. Mbijetesa mesatare pa progresion ishte 3.0 muaj (95% CI, 1.6-NR) dhe mbijetesa mesatare e përgjithshme ishte NR (95% CI, 8.3-NR).
Në nivelin e dozës 2 (n = 9), ndjekja mesatare ishte 27.1 muaj (varg: 24.7-33.5), ORR ishte 78%, dhe shkalla e CR ishte 55%. PFS mesatare ishte 2.6 muaj (95% intervali i besueshmërisë: 1.3-NR) dhe OS mesatare ishte 22.5 muaj (95% intervali i besimit: 5.5-NR).
Vetëm 1 nga 20 pacientët që arritën një CR kishte relapsuar që nga ndërprerja e të dhënave, duke treguar se CR-të janë të qëndrueshme. Në muajin e tretë, të gjithë pacientët që kishin bërë përparim në trajtimin e kishin bërë këtë.
Në 95% të pacientëve, sindromi i çlirimit të citokinës 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 limfohistiocitoza hemofagocitare.
Një pacient në nivelin e dozës 2 vdiq nga sepsa në ditën e 40-të dhe një pacient zhvilloi mielodisplazi/leuçemi mieloide akute të lidhur me trajtimin pa dëshmi të rikthimit të LBCL 11 muaj pas marrjes së terapisë së drejtuar nga CD22.
Niveli i rekomanduar i dozës për fazën 2 u përcaktua të ishte 1.
Informacioni i publikuar më parë detajon trajtimin e tre pacientëve të parë.
Të dy pacientët kishin karakteristika me rrezik të lartë dhe kanë marrë të paktën pesë linja trajtimi paraprak, duke përfshirë terapinë me qeliza T CAR të drejtuar nga CD19. Njëri nga pacientët kishte marrë më parë dy terapi me qeliza T CAR, e dyta prej të cilave synonte CD19 dhe CD20. Të tre pacientët arritën një CR, me pacientin 3 që arriti një CR në ditën e 28. CR-të u mbajtën për më shumë se tre vjet.
Frank gjithashtu vuri në dukje se "përhapja e CAR22 është dhjetëfish më e madhe dhe më e vazhdueshme se 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.
Referencat
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B limfoma qelizore 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. Terapia me qeliza T CAR të drejtuara nga CD22 shkakton remisione të plota në limfomën e qelizave B të mëdha refraktare të drejtuara nga CD19. Gjakut. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
