Februárbanry 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-sejt terápia. 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-sejt terápia 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 kijelentette: „Hiány van a krónikus visszaesés után alkalmazott gyógyító terápiákban.” Tekintettel a karnitinterápia után visszaeső betegek rossz prognózisára, sürgősen kielégítetlen igény mutatkozik új terápiák iránt.
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 nem-Hodgkin limfóma 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, krónikus limfocita leukémia/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.
A 41 beiratkozott beteg közül 38-nak (95%) sikerült CAR T-sejtes terméket gyártani, mivel 2-ben nem volt elegendő T-sejt a leukaferézishez. A leukaferézis és az infúzió közötti átlagos időtartam 18 nap volt.
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 lymphoma. 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.
A medián követési idő minden beteg esetében 18.4 hónap volt (tartomány: 1.5-38.6), ekkor az ORR 68%, a CR arány pedig 53% volt. A medián PFS 2.9 hónap volt (95% konfidencia intervallum [CI], 1.7-NR), a medián OS pedig 22.5 hónap (95% CI, 8.3-NR).
Az 1. dózisszintnél (n = 29) a betegeket átlagosan 14.1 hónapig követték (tartomány: 1.5-38.6), ami 66%-os ORR- és 52%-os CR-arányt mutatott. A progressziómentes túlélés mediánja 3.0 hónap volt (95% CI, 1.6-NR), a medián teljes túlélés NR (95% CI, 8.3-NR).
A 2. dózisszinten (n = 9) a medián követési idő 27.1 hónap (tartomány: 24.7-33.5), az ORR 78%, a CR arány 55% volt. A medián PFS 2.6 hónap volt (95%-os konfidencia intervallum: 1.3-NR), a medián OS pedig 22.5 hónap (95%-os konfidencia intervallum: 5.5-NR).
A CR-t elért 1 beteg közül csak 20 esett vissza az adatok határáig, ami azt jelzi, hogy a CR-ek tartósak. A harmadik hónapban minden olyan beteg megtette ezt, aki előrehaladt a kezelésben.
A betegek 95% -ában citokin felszabadulás szindróma 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 hemophagocytás lymphohistiocytosis.
Egy beteg a 2. dózisszintű szepszisben halt meg a 40. napon, és egy betegnél kezeléssel összefüggő myelodysplasia/akut mieloid leukémia alakult ki, LBCL-relapszus jele nélkül 11 hónappal a CD22-irányított terápia után.
A 2. fázis ajánlott dózisszintjét 1-ben határozták meg.
A korábban közzétett információk részletesen ismertették az első három beteg kezelését.
Mind a két beteg magas kockázatú jellemzőkkel rendelkezett, és legalább öt korábbi kezelési vonalat kapott, beleértve a CD19-re irányított CAR T-sejt-terápiát. Az egyik beteg korábban két CAR T-sejtes terápiát kapott, amelyek közül a második a CD19-et és a CD20-at célozta meg. Mindhárom beteg CR-t ért el, a 3. beteg pedig a 28. napon. A CR-eket több mint három évig tartották.
Frank azt is megjegyezte, hogy „a CAR22 terjedése tízszer nagyobb és tartósabb, mint a 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.
Referenciák
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B sejtes limfóma 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 és társai. A CD22-irányított CAR T-sejtes terápia teljes remissziót indukál a CD19-irányított CAR-refrakter nagy B-sejtes limfómában. Vér. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
