Em fevereirory 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 Terapia de células 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.
CD19-directed Terapia de células 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 afirmou: “Há uma escassez de terapias curativas administradas após recaída crônica”. Dado o mau prognóstico dos pacientes que recaem após receber terapias com carnitina, há uma demanda urgente não atendida por novas terapias.
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 linfoma não-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, Leucemia linfocítica crônica/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.
Dos 41 pacientes inscritos, o produto CAR T-cell foi fabricado com sucesso para 38 (95%), pois 2 tinham células T insuficientes para leucaférese. A duração média entre a leucaferese e a infusão foi de 18 dias.
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 linfoma. 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.
O tempo médio de acompanhamento para todos os pacientes foi de 18.4 meses (intervalo: 1.5-38.6), momento em que a ORR foi de 68% e a taxa de RC foi de 53%. A PFS mediana foi de 2.9 meses (intervalo de confiança de 95% [IC], 1.7-NR) e a SG mediana foi de 22.5 meses (IC de 95%, 8.3-NR).
No nível de dose 1 (n = 29), os pacientes foram acompanhados por uma média de 14.1 meses (intervalo, 1.5-38.6), demonstrando uma ORR de 66% e uma taxa de RC de 52%. A sobrevida livre de progressão mediana foi de 3.0 meses (IC 95%, 1.6-NR) e a sobrevida global mediana foi NR (IC 95%, 8.3-NR).
No nível de dose 2 (n = 9), o acompanhamento médio foi de 27.1 meses (intervalo: 24.7-33.5), a ORR foi de 78% e a taxa de CR foi de 55%. A PFS mediana foi de 2.6 meses (intervalo de confiança de 95%: 1.3-NR) e a SG mediana foi de 22.5 meses (intervalo de confiança de 95%: 5.5-NR).
Apenas 1 dos 20 pacientes que atingiram uma RC apresentou recaída até o corte dos dados, indicando que as RCs são duráveis. No terceiro mês, todos os pacientes que haviam feito progresso no tratamento o haviam feito.
Em 95% dos pacientes, síndrome de liberação de citocinas 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 linfo-histiocitose hemofagocítica.
Um paciente no nível de dose 2 morreu de sepse no dia 40, e um paciente desenvolveu mielodisplasia/leucemia mieloide aguda relacionada ao tratamento sem evidência de recidiva de LBCL 11 meses após receber terapia direcionada a CD22.
O nível de dose recomendado para a fase 2 foi determinado como 1.
Informações publicadas anteriormente detalhavam o tratamento dos três primeiros pacientes.
Todos os dois pacientes tinham características de alto risco e receberam pelo menos cinco linhas de tratamento anteriores, incluindo terapia com células CAR T dirigidas por CD19. Um dos pacientes já havia recebido duas terapias de células CAR T, a segunda das quais direcionadas a CD19 e CD20. Todos os três pacientes atingiram um CR, com o paciente 3 atingindo um CR no dia 28. Os CRs foram mantidos por mais de três anos.
Frank também observou que “a disseminação do CAR22 é dez vezes maior e mais persistente do que o 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.
Referências
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B linfoma celular 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. A terapia com células T CAR direcionadas a CD22 induz remissões completas no linfoma de células B grandes refratárias a CAR direcionadas a CD19. Sangue. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
