În 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 Terapia cu celule 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 cu celule 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 a declarat: „Există o lipsă de terapii curative administrate după recăderea cronică”. Având în vedere prognosticul prost al pacienților care recidivează după ce au primit terapii cu carnitină, există o cerere urgentă nesatisfăcută pentru terapii noi.
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 limfom non-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, leucemie limfocitară cronică/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.
Din 41 de pacienți înrolați, produsul cu celule T CAR a fost fabricat cu succes pentru 38 (95%), deoarece 2 aveau celule T insuficiente pentru leucafereză. Durata medie dintre leucafereză și perfuzie a fost de 18 zile.
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 limfom. 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.
Durata mediană de urmărire pentru toți pacienții a fost de 18.4 luni (interval: 1.5-38.6), moment în care ORR a fost de 68% și rata CR a fost de 53%. Mediana PFS a fost de 2.9 luni (interval de încredere [IC] 95%, 1.7-NR), iar OS mediană a fost de 22.5 luni (IC 95%, 8.3-NR).
La nivelul de doză 1 (n = 29), pacienții au fost urmăriți pentru o perioadă mediană de 14.1 luni (interval, 1.5-38.6), demonstrând o ORR de 66% și o rată de CR de 52%. Supraviețuirea mediană fără progresie a fost de 3.0 luni (IC 95%, 1.6-NR) și supraviețuirea globală mediană a fost NR (IC 95%, 8.3-NR).
La nivelul de doză 2 (n = 9), urmărirea mediană a fost de 27.1 luni (interval: 24.7-33.5), ORR a fost de 78%, iar rata CR a fost de 55%. Mediana PFS a fost de 2.6 luni (interval de încredere 95%: 1.3-NR) și OS mediană a fost de 22.5 luni (interval de încredere 95%: 5.5-NR).
Doar 1 din cei 20 de pacienți care au obținut un CR a recidivat la data limită, ceea ce indică faptul că CR sunt durabile. Până în a treia lună, toți pacienții care au făcut progrese la tratament au făcut acest lucru.
La 95% dintre pacienți, sindromul de eliberare de citokine 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 limfohistiocitoză hemofagocitară.
Un pacient la nivelul de doză 2 a murit de sepsis în ziua 40, iar un pacient a dezvoltat mielodisplazie/leucemie mieloidă acută legată de tratament fără dovezi de recidivă a LBCL la 11 luni după ce a primit terapie direcționată de CD22.
Nivelul de doză recomandat pentru faza 2 a fost determinat a fi 1.
Informațiile publicate anterior au detaliat tratamentul primilor trei pacienți.
Toți cei doi pacienți au avut caracteristici de risc ridicat și au primit cel puțin cinci linii de tratament anterioare, inclusiv terapia cu celule T CAR direcționată de CD19. Unul dintre pacienți a primit anterior două terapii cu celule T CAR, dintre care al doilea a vizat CD19 și CD20. Toți cei trei pacienți au obținut un CR, pacientul 3 realizând un CR în ziua 28. CR au fost păstrate mai mult de trei ani.
Frank a mai remarcat că „răspândirea CAR22 este de zece ori mai mare și mai persistentă decât 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.
Referinte
1. Frank MJ, Sahaf B, Baird J, et al. CD22 CAR T cell therapy induces durable remissions in patients with large B limfom 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. Terapia cu celule T CAR direcționată de CD22 induce remisii complete în limfomul cu celule B mari refractar la CAR CD19. Sânge. 2021;137(17):2321-2325. doi:10.1182/blood.2020009432
