Şubat ayındary 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 hücre tedavisi. 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 CAR T hücre tedavisi 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, "Kronik nüksetmeden sonra uygulanan iyileştirici tedavilerin bir kıtlığı var" dedi. Karnitin terapileri aldıktan sonra nüks eden hastaların kötü prognozları göz önüne alındığında, yeni terapiler için karşılanmamış acil bir talep vardır.
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 Hodgkin dışı lenfoma 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, kronik lenfositik lösemi/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.
Kayıtlı 41 hastanın 38'inde (%95) CAR T-hücre ürünü başarıyla üretildi, çünkü 2'sinde lökaferez için yetersiz T hücresi vardı. Lökaferez ve infüzyon arasındaki ortalama süre 18 gündü.
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 lenfoma. 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.
Tüm hastalar için medyan takip süresi 18.4 aydı (aralık: 1.5-38.6), bu noktada ORR %68 ve CR oranı %53 idi. Medyan PFS 2.9 aydı (%95 güven aralığı [CI], 1.7-NR) ve medyan OS 22.5 aydı (%95 GA, 8.3-NR).
Doz seviyesi 1'de (n = 29), hastalar medyan 14.1 ay (1.5-38.6 aralığı) boyunca takip edildi ve %66 ORR ve %52 CR oranı gösterdi. Medyan progresyonsuz sağkalım 3.0 aydı (%95 CI, 1.6-NR) ve medyan genel sağkalım NR'ydi (%95 CI, 8.3-NR).
Doz seviyesi 2'de (n = 9), medyan takip süresi 27.1 aydı (aralık: 24.7-33.5), ORR %78 ve CR oranı %55 idi. Medyan PFS 2.6 aydı (%95 güven aralığı: 1.3-NR) ve medyan OS 22.5 aydı (%95 güven aralığı: 5.5-NR).
Veri kesintisi itibariyle CR elde eden 1 hastadan sadece 20'i relaps göstermiştir, bu da CR'lerin kalıcı olduğunu göstermektedir. Üçüncü aya gelindiğinde, tedavide ilerleme kaydeden tüm hastalar bunu yapmıştı.
Hastaların% 95'inde, sitokin salınım sendromu 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 hemofagositik lenfohistiyositoz.
2. doz seviyesindeki bir hasta 40. günde sepsis nedeniyle öldü ve bir hastada CD11'ye yönelik tedaviyi aldıktan 22 ay sonra LBCL nüksetme kanıtı olmaksızın tedaviyle ilişkili miyelodisplazi/akut miyeloid lösemi gelişti.
Faz 2 için önerilen doz düzeyi 1 olarak belirlendi.
Daha önce yayınlanan bilgiler, ilk üç hastanın tedavisini detaylandırdı.
Her iki hasta da yüksek risk özelliklerine sahipti ve CD19'a yönelik CAR T hücre tedavisi dahil olmak üzere en az beş tedavi dizisi aldı. Hastalardan biri daha önce, ikincisi CD19 ve CD20'yi hedefleyen iki CAR T hücre tedavisi almıştı. Üç hasta da bir CR'ye ulaştı ve 3. hasta 28. günde bir CR'ye ulaştı. CR'ler üç yıldan fazla tutuldu.
Frank ayrıca, "CAR22'nin yayılmasının, CAR19'dan on kat daha fazla ve daha kalıcı olduğunu" belirtti.
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.
Referanslar
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B hücreli lenfoma 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 ve diğerleri. CD22'ye yönelik CAR T hücre tedavisi, CD19'a yönelik CAR'a dirençli büyük B hücreli lenfomada tam remisyonlara neden olur. Kan. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
