Establishment of CD19-CAR-T Cell Production and Treatment of Non-Hodgkin Lymphoma in the United Arab Emirates
Authors: Abu Haleeqa Mohamed I. , El-Najjar Inas , Afifi Yara K , Ali Sheima A , Alsaadawi Nameer , Dennison Jayakumar David , Sachdev Mansi , Obeidat Sakher A , Castillo Aleman Yandy Marx , Handgretinger Rupert , Ibrahim Asia , Wahdan Rasha , al Kaabi Fatema , Ventura-Carmenate Yendry , Hadi Loubna A , Hernández-Ramírez Antonio , Al Karam Maysoon 
Published: December 2024

Introduction:

CD19-chimeric antigen receptor T-cell (CAR-T) therapy is recognized as an efficacious treatment in relapsed/refractory (R/R) lymphoma. We established autologous CD19 CAR-T production and treatment at Abu Dhabi Stem Cells Center (ADSCC), to make it easily accessible locally. Previously patients had to travel abroad for treatment and faced delays due to cost involved as well as lack of treatment capacity. We report the feasibility, safety and efficacy of locally manufactured CD19 CAR-T cells administered fresh for the treatment of the first cohort of (Relapsed Refractory) R/R lymphoma patients in the Gulf region, Abu-Dhabi, UAE.

Methods:

The autologous clinical grade CD19 CAR-T cells product was locally produced in ADSCC GMP laboratories, using CliniMacs Prodigy® (Miltenyi Biotec) platform. Leukapheresis cells (LPH), containing targeted number of 2.0 x 109 CD3+T cells were obtained using the Spectra Optia® apheresis system (Terumo BCT, Inc.) running software v11.0 via peripheral venous access and the Mononuclear Cell Collection program. About 1 × 108 post-enrichment cells derived from LPH and contained CD4+ and CD8+ T cells were stimulated and transduced with a lentiviral vector (Lentigen Technology), provided by Miltenyi Biotec, encoding a CAR protein targeting CD19. CAR T cells were sampled daily until the end of production for the analyses of cell composition, viability, proliferation and transduction efficiency by flow cytometry.

A single fresh infusion of 3.0 x 106 CD19-CAR T Cells per Kg was administered following a lymphodepletion regimen utilizing Fludarabine 25 mg/m2 for 3 days and Cyclophosphamide 1000 mg/m2 for 1 day. CD19-CAR-T Cell expansion in peripheral blood was assessed by flow cytometry at Day 5, 10, 14, and 28 after infusion. Response was assessed using Lugano 2014 criteria at day 28. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed using 2018 ASTCTconsensus grading.

Results:

To date 5 patients (3 males and 2 females) have received treatment (December 2023- May 2024). Average age 51 (40-55) years. Median International Prognostic Index (IPI) was 3 (1-4), 4 patients were diagnosed with R/R diffuse large B cell lymphoma (DLBCL) of those 1 was transformed follicular lymphoma and 1 patient R/R mantle cell lymphoma. A median of 2 (2-4) lines of treatment were received. CAR-T median production time was 11 (8-12) days with a median transduction efficiency of 39.3% (36.7-53.9). All patients received a fresh product for infusion at a median time of 12 (11-13) days post lymphocyte collection. Peak CAR-T expansion was reached at a median of 11 (9-14) days, with an average peak level of 36% CAR-T, and a range of (5%-68%). At D28+ CAR-T cells were still present with average values of 11% and a range of (0%- 40%). Of the 5 treated patients, there were no ICANS observed. All had grade 1 CRS, no patient had grade 3 CRS. Three of these five did achieve a CMR, whilst 2 patients achieved a PMR on D28+ PET/CT.

Conclusions:

We have demonstrated the success of a quick manufacturing local process with 100% infusion of fresh product. In addition, we have seen low associated toxicity and good efficacy in R/R lymphoma patients. With this encouraging data we intend to expand our program, to be able to make CAR-T treatment accessible for all the UAE and the Gulf region.