In Februariery 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 MOTOR T-selterapie. 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 MOTOR T-selterapie 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 het gesê: "Daar is 'n gebrek aan genesende terapieë wat toegedien word na chroniese terugval." Gegewe die swak prognose van pasiënte wat terugval nadat hulle karnitienterapieë ontvang het, is daar 'n dringende onvervulde vraag na nuwe terapieë.
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 nie-Hodgkin-limfoom 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, chroniese limfositiese leukemie/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.
Van 41 ingeskrewe pasiënte is die CAR T-selproduk suksesvol vir 38 (95%) vervaardig, aangesien 2 onvoldoende T-selle vir leukaferese gehad het. Die gemiddelde duur tussen leukaferese en infusie was 18 dae.
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 limfoom. 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.
Die mediaan opvolgtyd vir alle pasiënte was 18.4 maande (reeks: 1.5-38.6), op watter stadium die ORR 68% was en die CR-koers 53%. Die mediaan PFS was 2.9 maande (95% vertrouensinterval [CI], 1.7-NR) en die mediaan OS was 22.5 maande (95% CI, 8.3-NR).
By dosisvlak 1 (n = 29) is pasiënte gevolg vir 'n mediaan van 14.1 maande (reeks, 1.5-38.6), wat 'n 66% ORR en 'n 52% CR-koers toon. Mediaan progressievrye oorlewing was 3.0 maande (95% CI, 1.6-NR) en mediaan algehele oorlewing was NR (95% CI, 8.3-NR).
By dosisvlak 2 (n = 9), was die mediaan opvolging 27.1 maande (reeks: 24.7-33.5), die ORR was 78% en die CR-koers was 55%. Die mediaan PFS was 2.6 maande (95% vertrouensinterval: 1.3-NR) en die mediaan OS was 22.5 maande (95% vertrouensinterval: 5.5-NR).
Slegs 1 van die 20 pasiënte wat 'n CR bereik het, het teruggeval vanaf die data-afsnypunt, wat aandui dat CR's duursaam is. Teen die derde maand het alle pasiënte wat vordering gemaak het met behandeling dit gedoen.
In 95% of patients, sitokienvrystellingsindroom 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 hemophagocytic lymphohistiocytosis.
Een pasiënt op dosisvlak 2 het op dag 40 aan sepsis gesterf, en een pasiënt het behandelingsverwante myelodisplasie/akute myeloïede leukemie ontwikkel sonder bewyse van LBCL-terugval 11 maande nadat hy CD22-gerigte terapie ontvang het.
Die aanbevole dosisvlak vir fase 2 is as 1 bepaal.
Voorheen gepubliseerde inligting het die behandeling van die eerste drie pasiënte uiteengesit.
Al twee pasiënte het hoërisiko-eienskappe gehad en het ten minste vyf vorige behandelingslyne ontvang, insluitend CD19-gerigte CAR T-selterapie. Een van die pasiënte het voorheen twee CAR T-sel terapieë ontvang, waarvan die tweede CD19 en CD20 gerig was. Al drie pasiënte het 'n CR behaal, met pasiënt 3 wat 'n CR op dag 28 behaal het. CR's is vir meer as drie jaar gehou.
Frank het ook opgemerk dat "die verspreiding van CAR22 tien keer groter en meer aanhoudend is as 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.
Verwysings
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, Craig J, et al. CD22-gerigte CAR T-sel terapie veroorsaak volledige remissies in CD19-gerigte CAR-refraktêre groot B-sel limfoom. Bloed. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
