Fevral oyidary 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-hujayra terapiyasi. 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-hujayra terapiyasi 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 shunday dedi: "Surunkali relapsdan keyin qo'llaniladigan shifobaxsh davolash usullari kam." Karnitin terapiyasini olgandan keyin qayt qilgan bemorlarning yomon prognozini hisobga olgan holda, yangi davolash usullariga shoshilinch ravishda qondirilmagan talab mavjud.
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 Xodgkin bo'lmagan limfoma 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, surunkali limfotsitik leykemiya/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.
Ro'yxatga olingan 41 bemorning 38 tasi (95%) uchun CAR T-hujayra mahsuloti muvaffaqiyatli ishlab chiqarildi, chunki 2 tasida leykaferez uchun T hujayralari etarli emas edi. Leykaferez va infuziya o'rtasidagi o'rtacha muddat 18 kun edi.
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 limfoma. 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.
Barcha bemorlar uchun o'rtacha kuzatuv vaqti 18.4 oyni tashkil etdi (diapazon: 1.5-38.6), bu vaqtda ORR 68% va CR darajasi 53% edi. O'rtacha PFS 2.9 oy (95% ishonch oralig'i [CI], 1.7-NR) va o'rtacha OS 22.5 oy (95% CI, 8.3-NR) edi.
Dozaning 1 darajasida (n = 29) bemorlar 14.1% ORR va 1.5% CR tezligini ko'rsatib, o'rtacha 38.6 oy (diapazon, 66-52) davomida kuzatildi. O'rtacha rivojlanishsiz omon qolish 3.0 oy (95% CI, 1.6-NR) va o'rtacha umumiy omon qolish NR (95% CI, 8.3-NR) edi.
Dozaning 2 darajasida (n = 9) o'rtacha kuzatuv 27.1 oy (diapazon: 24.7-33.5), ORR 78% va CR darajasi 55% edi. O'rtacha PFS 2.6 oy (95% ishonch oralig'i: 1.3-NR) va o'rtacha OS 22.5 oy (95% ishonch oralig'i: 5.5-NR) edi.
CR ga erishgan 1 nafar bemordan faqat 20 nafarida ma'lumotlar to'xtatilgandan so'ng qaytalanish kuzatilgan, bu esa CRning bardoshli ekanligini ko'rsatadi. Uchinchi oyga kelib, davolanishda muvaffaqiyatga erishgan barcha bemorlar buni qilishdi.
In 95% of patients, sitokinlarni chiqarish sindromi 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 gemofagotsitik limfogistiyositoz.
2-darajali dozada bo'lgan bir bemor 40-kuni sepsisdan vafot etdi va bir bemorda CD11-yo'naltirilgan terapiyani olgandan keyin 22 oy o'tgach, LBCL relapsisiz davolanish bilan bog'liq miyelodisplaziya/o'tkir miyeloid leykemiya rivojlandi.
2-bosqich uchun tavsiya etilgan doza darajasi 1 deb aniqlandi.
Ilgari e'lon qilingan ma'lumotlar birinchi uchta bemorni davolash haqida batafsil ma'lumot berdi.
Ikkala bemor ham yuqori xavfli xususiyatlarga ega edi va kamida beshta oldingi davolash liniyalarini, shu jumladan CD19-yo'naltirilgan CAR T-hujayrali terapiyasini olgan. Bemorlardan biri ilgari ikkita CAR T-hujayra terapiyasini olgan, ikkinchisi CD19 va CD20ga qaratilgan. Barcha uch bemor CR ga erishdi, 3-bemor esa 28-kuni CR ga erishdi. CRlar uch yildan ortiq vaqt davomida saqlangan.
Frank shuningdek, "CAR22 tarqalishi CAR19ga qaraganda o'n baravar ko'p va barqarorroq" ekanligini ta'kidladi.
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.
Manbalar
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, Kreyg J va boshqalar. CD22-yo'naltirilgan CAR T-hujayrali terapiya CD19-yo'naltirilgan CAR-refrakter katta B-hujayrali lenfomada to'liq remissiyalarni keltirib chiqaradi. Qon. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
