| Abstract: |
Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation–AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities. © 2023 The American Society of Hematology |
| Keywords: |
immunohistochemistry; adult; human tissue; protein expression; treatment outcome; aged; middle aged; major clinical study; clinical trial; constipation; fatigue; neutropenia; diarrhea; hypophosphatemia; side effect; neuroimaging; neurotoxicity; t lymphocyte; t-lymphocytes; phenotype; progression free survival; infection; neutrophil count; neoplasm recurrence, local; anemia; thrombocytopenia; steroid; chill; dizziness; febrile neutropenia; fever; hypotension; length of stay; b cell lymphoma; cancer regression; immunoglobulin g; tumor recurrence; brain disease; peripheral edema; sepsis; chimeric antigen receptor; lactate dehydrogenase; real time polymerase chain reaction; headache; large cell lymphoma; lymphoma, large b-cell, diffuse; leukocyte count; corticosteroid; cytokine release; immunoglobulin deficiency; follicular lymphoma; outpatient care; lymph node biopsy; adoptive immunotherapy; immunotherapy, adoptive; cd19 antigen; antigens, cd19; autologous hematopoietic stem cell transplantation; genomic dna; multiple organ failure; arm weakness; cd22 antigen; hemophagocytic syndrome; programmed death 1 ligand 1; leukapheresis; demographics; overall response rate; diffuse large b cell lymphoma; tocilizumab; humans; human; male; female; article; pembrolizumab; nodal marginal zone lymphoma; t cell exhaustion; maximum concentration; chimeric antigen receptor t-cell immunotherapy; coronavirus disease 2019; receptors, chimeric antigen; cd22 protein, human; sialic acid binding ig-like lectin 2
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