Noong Pebrerory 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 Therapy ng T-cell ng 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.
Nakadirekta sa CD19 Therapy ng T-cell ng 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.
Sinabi ni Frank, "May kakulangan ng mga nakakagamot na therapies na ibinibigay pagkatapos ng talamak na pagbabalik." Dahil sa mahinang pagbabala ng mga pasyenteng nagbabalik pagkatapos makatanggap ng mga carnitine therapies, mayroong isang kagyat na hindi natutugunan na pangangailangan para sa mga nobelang therapy.
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 lymphoma 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.
Ang lahat ng mga pasyente sa cohort ay nagkaroon ng relapsed/refractory LBCL, kabilang ang diffuse LBCL na hindi tinukoy kung hindi man, binago ang follicular lymphoma, marginal zone lymphoma, talamak na lymphocytic leukemia/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.
Sa 41 na naka-enroll na mga pasyente, ang produkto ng CAR T-cell ay matagumpay na ginawa para sa 38 (95%), dahil ang 2 ay may hindi sapat na T cells para sa leukapheresis. Ang average na tagal sa pagitan ng leukapheresis at pagbubuhos ay 18 araw.
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 lymphoma. 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.
Ang median follow-up time para sa lahat ng mga pasyente ay 18.4 na buwan (saklaw: 1.5-38.6), kung saan ang ORR ay 68% at ang CR rate ay 53%. Ang median PFS ay 2.9 na buwan (95% confidence interval [CI], 1.7-NR) at ang median OS ay 22.5 na buwan (95% CI, 8.3-NR).
Sa antas ng dosis 1 (n = 29), sinundan ang mga pasyente para sa isang median na 14.1 na buwan (saklaw, 1.5-38.6), na nagpapakita ng isang 66% ORR at isang 52% na rate ng CR. Ang median na walang pag-unlad na kaligtasan ay 3.0 buwan (95% CI, 1.6-NR) at ang pangkalahatang kaligtasan ng median ay NR (95% CI, 8.3-NR).
Sa antas ng dosis 2 (n = 9), ang median na follow-up ay 27.1 buwan (saklaw: 24.7-33.5), ang ORR ay 78%, at ang CR rate ay 55%. Ang median PFS ay 2.6 na buwan (95% confidence interval: 1.3-NR) at ang median OS ay 22.5 na buwan (95% confidence interval: 5.5-NR).
1 lang sa 20 pasyente na nakamit ang isang CR ang nag-relapse sa data cutoff, na nagpapahiwatig na ang mga CR ay matibay. Sa ikatlong buwan, lahat ng mga pasyente na nakagawa ng progreso sa paggamot ay nagawa na.
Sa 95% ng mga pasyente, cytokine release syndrome 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 hemophagocytic lymphohistiocytosis.
Isang pasyente sa antas ng dosis 2 ang namatay sa sepsis sa araw na 40, at isang pasyente ang nakabuo ng myelodysplasia na nauugnay sa paggamot/acute myeloid leukemia na walang ebidensya ng pagbabalik ng LBCL 11 buwan pagkatapos makatanggap ng CD22-directed therapy.
Ang inirekumendang antas ng dosis para sa phase 2 ay natukoy na 1.
Ang naunang nai-publish na impormasyon ay nakadetalye sa paggamot ng unang tatlong pasyente.
Ang lahat ng dalawang pasyente ay may mataas na panganib na mga katangian at nakatanggap ng hindi bababa sa limang naunang linya ng paggamot, kabilang ang CD19-directed CAR T-cell therapy. Ang isa sa mga pasyente ay dati nang nakatanggap ng dalawang CAR T-cell therapies, ang pangalawa ay naka-target sa CD19 at CD20. Nakamit ng lahat ng tatlong pasyente ang isang CR, kung saan ang pasyente 3 ay nakamit ang isang CR sa araw na 28. Ang mga CR ay pinananatiling higit sa tatlong taon.
Nabanggit din ni Frank na "ang pagkalat ng CAR22 ay sampung beses na mas malaki at mas patuloy kaysa sa 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.
Mga sanggunian
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B cell lymphoma 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. Ang CD22-directed CAR T-cell therapy ay nag-uudyok ng kumpletong remissions sa CD19-directed CAR-refractory large B-cell lymphoma. Dugo. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
