Pada bulan Februariry 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 sel-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.
diarahkan oleh CD19 Terapi sel-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 menyatakan, "Ada kelangkaan terapi kuratif yang diberikan setelah kambuh kronis." Mengingat prognosis buruk pasien yang kambuh setelah menerima terapi karnitin, ada permintaan mendesak yang belum terpenuhi untuk terapi baru.
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.
Semua pasien dalam kohort mengalami LBCL kambuhan/refraktori, termasuk LBCL difus yang tidak disebutkan secara spesifik, limfoma folikular yang berubah, limfoma zona marginal, leukemia limfositik 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.
Dari 41 pasien yang terdaftar, produk sel T CAR berhasil diproduksi untuk 38 (95%), karena 2 memiliki sel T yang tidak mencukupi untuk leukapheresis. Durasi rata-rata antara leukapheresis dan infus adalah 18 hari.
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.
Waktu tindak lanjut rata-rata untuk semua pasien adalah 18.4 bulan (kisaran: 1.5-38.6), di mana ORR adalah 68% dan tingkat CR adalah 53%. Median PFS adalah 2.9 bulan (95% interval kepercayaan [CI], 1.7-NR) dan median OS adalah 22.5 bulan (95% CI, 8.3-NR).
Pada tingkat dosis 1 (n = 29), pasien diikuti selama rata-rata 14.1 bulan (kisaran, 1.5-38.6), menunjukkan 66% ORR dan tingkat CR 52%. Kelangsungan hidup bebas perkembangan rata-rata adalah 3.0 bulan (95% CI, 1.6-NR) dan kelangsungan hidup keseluruhan rata-rata adalah NR (95% CI, 8.3-NR).
Pada tingkat dosis 2 (n = 9), rata-rata tindak lanjut adalah 27.1 bulan (kisaran: 24.7-33.5), ORR adalah 78%, dan tingkat CR adalah 55%. PFS rata-rata adalah 2.6 bulan (interval kepercayaan 95%: 1.3-NR) dan median OS adalah 22.5 bulan (interval kepercayaan 95%: 5.5-NR).
Hanya 1 dari 20 pasien yang mencapai CR yang kambuh pada batas data, menunjukkan bahwa CR tahan lama. Pada bulan ketiga, semua pasien yang telah membuat kemajuan dalam pengobatan telah melakukannya.
Pada 95% pasien, sindrom pelepasan 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 limfohistiositosis hemofagositik.
Satu pasien pada tingkat dosis 2 meninggal karena sepsis pada hari ke-40, dan satu pasien mengembangkan myelodysplasia terkait pengobatan/leukemia myeloid akut tanpa bukti kekambuhan LBCL 11 bulan setelah menerima terapi yang diarahkan oleh CD22.
Tingkat dosis yang direkomendasikan untuk fase 2 ditentukan menjadi 1.
Informasi yang diterbitkan sebelumnya merinci perawatan dari tiga pasien pertama.
Semua dua pasien memiliki karakteristik berisiko tinggi dan telah menerima setidaknya lima lini pengobatan sebelumnya, termasuk terapi sel T CAR yang diarahkan oleh CD19. Salah satu pasien sebelumnya telah menerima dua terapi sel T CAR, yang kedua menargetkan CD19 dan CD20. Ketiga pasien mencapai CR, dengan pasien 3 mencapai CR pada hari ke 28. CR disimpan selama lebih dari tiga tahun.
Frank juga mencatat bahwa “penyebaran CAR22 sepuluh kali lipat lebih besar dan lebih persisten daripada 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.
Referensi
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B limfoma sel 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, dkk. Terapi sel T CAR yang diarahkan oleh CD22 menginduksi remisi lengkap pada limfoma sel B besar refraktori yang diarahkan oleh CD19. Darah. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
