Dina Pébruariry 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 Terapi sél T-mobil. 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 Terapi sél T-mobil 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 nyatakeun, "Aya kakurangan terapi kuratif anu dikaluarkeun saatos kambuh kronis." Dibikeun prognosis anu goréng pikeun pasien anu kambuh saatos nampi terapi karnitin, aya paménta anu teu kapendak pikeun terapi novel.
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 non-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, leukemia limfosit kronis/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.
Tina 41 pasien anu kadaptar, produk sél T CAR suksés diproduksi pikeun 38 (95%), sabab 2 ngagaduhan sél T anu teu cekap pikeun leukaferesis. Durasi rata-rata antara leukaferesis sareng infus nyaéta 18 dinten.
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.
Waktu nurutan-up median pikeun sakabéh pasien éta 18.4 bulan (rentang: 1.5-38.6), di mana titik ORR éta 68% sarta laju CR éta 53%. PFS median nyaéta 2.9 bulan (95% interval kapercayaan [CI], 1.7-NR) sareng median OS nyaéta 22.5 bulan (95% CI, 8.3-NR).
Dina tingkat dosis 1 (n = 29), penderita dituturkeun pikeun median 14.1 bulan (rentang, 1.5-38.6), nunjukkeun 66% ORR sareng laju CR 52%. Médian survival bébas progression éta 3.0 bulan (95% CI, 1.6-NR) jeung median sakabéh survival éta NR (95% CI, 8.3-NR).
Dina tingkat dosis 2 (n = 9), median nurutan-up éta 27.1 bulan (rentang: 24.7-33.5), ORR éta 78%, sarta laju CR éta 55%. PFS median nyaéta 2.6 bulan (interval kapercayaan 95%: 1.3-NR) sareng OS median nyaéta 22.5 bulan (interval kapercayaan 95%: 5.5-NR).
Ngan 1 tina 20 pasien anu ngahontal CR parantos kambuh nalika potongan data, nunjukkeun yén CR awét. Nepi ka bulan katilu, sadaya pasien anu parantos kamajuan dina pengobatan parantos dilakukeun.
In 95% of patients, sindrom sékrési sitokin 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.
Hiji pasien dina tingkat dosis 2 maot tina sepsis dina dinten 40, sareng hiji pasien ngembangkeun myelodysplasia / leukemia myeloid akut anu aya hubunganana sareng tanpa bukti kambuh LBCL 11 bulan saatos nampi terapi anu diarahkeun CD22.
Tingkat dosis anu disarankeun pikeun fase 2 ditangtukeun janten 1.
Inpormasi anu diterbitkeun sateuacana ngajelaskeun perawatan tilu pasien anu munggaran.
Kadua pasien ngagaduhan ciri anu résiko luhur sareng nampi sahenteuna lima jalur perawatan sateuacana, kalebet terapi sél T CAR anu diarahkeun CD19. Salah sahiji pasien sateuacana nampi dua terapi sél T CAR, anu kadua nargétkeun CD19 sareng CD20. Katiluna penderita ngahontal CR a, kalawan sabar 3 achieving a CR dina dinten 28. CRs anu diteundeun pikeun leuwih ti tilu taun.
Frank ogé nyatakeun yén "panyebaran CAR22 sapuluh kali langkung ageung sareng langkung pengkuh tibatan 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.
Rujukan
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. Terapi sél T CAR anu diarahkeun ku CD22 nyababkeun remisi lengkep dina limfoma sél B ageung anu diarahkeun ka CD19. Getih. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
