U veljačiry 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 Terapija T-stanicama CAR-a. 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 Terapija T-stanicama CAR-a 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 je izjavio: "Postoji nedostatak ljekovitih terapija koje se primjenjuju nakon kroničnog recidiva." S obzirom na lošu prognozu pacijenata kod kojih se bolest vrati nakon terapije karnitinom, postoji hitna nezadovoljena potražnja za novim terapijama.
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 ne-Hodgkinov limfom 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, kronična limfocitna leukemija/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.
Od 41 uključenog pacijenta, proizvod CAR T-stanice uspješno je proizveden za 38 (95%), budući da su 2 imala nedovoljno T stanica za leukaferezu. Prosječno trajanje između leukafereze i infuzije bilo je 18 dana.
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.
Medijan vremena praćenja za sve pacijente bio je 18.4 mjeseca (raspon: 1.5-38.6), u kojoj je točki ORR bio 68%, a stopa CR bila je 53%. Medijan PFS-a bio je 2.9 mjeseci (95% interval pouzdanosti [CI], 1.7-NR), a medijan OS bio je 22.5 mjeseci (95% CI, 8.3-NR).
Na razini doze 1 (n = 29), pacijenti su praćeni medijan od 14.1 mjeseci (raspon, 1.5-38.6), pokazujući 66% ORR i 52% CR stopu. Medijan preživljenja bez progresije bio je 3.0 mjeseca (95% CI, 1.6-NR), a medijan ukupnog preživljenja bio je NR (95% CI, 8.3-NR).
Na razini doze 2 (n = 9), medijan praćenja bio je 27.1 mjesec (raspon: 24.7-33.5), ORR je bio 78%, a stopa CR bila je 55%. Medijan PFS-a bio je 2.6 mjeseci (95% interval pouzdanosti: 1.3-NR), a medijan OS bio je 22.5 mjeseci (95% interval pouzdanosti: 5.5-NR).
Samo 1 od 20 pacijenata koji su postigli CR imao je recidiv od graničnih podataka, što ukazuje da su CR trajni. Do trećeg mjeseca svi pacijenti koji su napredovali u liječenju to su i učinili.
U 95% bolesnika, sindrom oslobađanja citokina 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 hemofagocitna limfohistiocitoza.
Jedan je pacijent na razini doze 2 umro od sepse 40. dana, a jedan je pacijent razvio mijelodisplaziju/akutnu mijeloičnu leukemiju povezanu s liječenjem bez dokaza relapsa LBCL-a 11 mjeseci nakon primanja terapije usmjerene na CD22.
Preporučena razina doze za fazu 2 utvrđena je kao 1.
Prethodno objavljeni podaci detaljno su govorili o liječenju prva tri pacijenta.
Sva dva pacijenta imala su karakteristike visokog rizika i primili su najmanje pet prethodnih linija liječenja, uključujući terapiju CAR T-stanica usmjerenu na CD19. Jedan od pacijenata prethodno je primio dvije terapije CAR T-stanicama, od kojih je druga bila usmjerena na CD19 i CD20. Sva tri pacijenta postigla su CR, s tim da je pacijent 3 postigao CR 28. dana. CR su čuvani više od tri godine.
Frank je također primijetio da je "širenje CAR22 deseterostruko veće i postojanije od 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.
Reference
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B stanični limfom 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-usmjerena CAR T-stanična terapija izaziva potpune remisije u CD19-usmjerenom CAR-refrakternom velikom B-staničnom limfomu. Krv. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
