ATHENA chimeric antigen receptor (CAR)-T, a CD19-directed CAR-T cell immunotherapy comprised of allogeneic T cells prepared for the treatment of relapsed or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL). The cells are from healthy adult volunteer donors that are knocked out of TRAC and Power3 (SPPL3) genes ex vivo using CRISPR-Cas9 gene editing components. In this study, a second-generation anti-CD19 CAR prototype was constructed, bearing murine FMC63 single-chain variant fragment (scFv) together with intracellular CD28 co-stimulatory and CD3ζ signaling domains linked by a CD28 sequence comprising the hinge and transmembrane domains.
This is a single center, prospective, open-label, single-arm, phase 1/2 study. A total of around 30 patients with r/r B-cell NHL will be enrolled in the study and receive allogeneic CD19-CAR-T cell infusion. Phase 1 (n=6 to 18) is a dose escalation part, and phase 2 (n=10 to 12) is a expansion cohort part. The primary objective of this study was to evaluate the safety and efficacy of ATHENA CAR-T cell therapy in patients with r/r B-cell NHL.
Age 18-70 (inclusive).
Diffuse large B-cell lymphoma (DLBCL) not otherwise specified;
Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
Transformed follicular lymphoma (TFL);
Expected survival time < 3 months per Principal Investigator's opinion.
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.
Autologous stem cell transplant with therapeutic intent within 3 months of planned ATHENA CAR-T infusion.
History of allogeneic stem cell transplantation.
Single group
TRAC and Power3 (SPPL3) Genes Knock-out Allogeneic CD19-targeting CAR-T cell (ATHENA CAR-T)
Biological/VaccinePhase 1 dose escalation (3+3) : dose 1 (1 × 10\^6 cells/kg) , dose 2 (3 × 10\^6 cells/kg), dose 3 (1 × 10\^7 cells/kg); Phase 2 : dose of RP2D. No more than 2 × 10\^5 per kilogram of allogenic residual CD3+T cells harbouring in grafts can only be released for recipient infusion.
Fludarabine
DrugIntravenous fludarabine 30\~50 mg/m\^2/day on days -5, -4, and -3.
Cyclophosphamide
DrugIntravenous cyclophosphamide 500\~1000 mg/m\^2/day on days -5, -4, and -3.
Phase 1: Incidence of adverse events (AE) defined as DLT
DLT is defined as any AE related to the investigational drug that occurs within 28 days after administration of the ATHENA CAR-T and meets any one of the criteria listed in the DLT criteria. The severity of AE will be assessed according to NCI-CTCAE v5.0. cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by ASTCT in 2019. Graft-versus-host-disease(GvHD) according to criteria defined by the Mount Sinai Acute GVHD International Consortium. * Grade 3 aGVHD that does not resolve to Grade 1 or 2 within 7 days, with the exception of isolated skin involvement aGVHD; * Grade 4 CRS or grade 3 CRS that does not resolve to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS; * Any other Grade ≥4 and Grade 3 AE related to the ATHENA CAR-T that lasts for ≥14 days, except hematology toxicity.
Phase 1: RP2D
The RP2D was determined through phase 1 study.
Phase 2: 3-month objective response rate (ORR)
ORR is defined as the proportion of patients who have achieved complete response (CR) and partial response (PR) assessed by investigators and based on the Lugano 2014 assessment criterion.
Phase 2: CR rate
CR rate is defined as the proportion of patients who have achieved CR assessed by investigators and based on the Lugano 2014 assessment criterion.
Phase 1 and phase 2: Pharmacokinetics: Levels of ATHENA CAR-positive T cells circulating in blood over time
Number and copy number of ATHENA CAR-T cells were assessed by number in peripheral blood. Blood samples were collected before and one year after cell infusion (until CAR-T cells were not detected for two consecutive times) to detect the number and copy number of CAR-T cells, and to evaluate the pharmacokinetics of CAR-T.
Phase 1 and phase 2: Pharmacodynamics: Levels of CD19+ cells and serum cytokines in peripheral blood
The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein (CRP), ferritin.
Phase 1: 3-month ORR
ORR is defined as the proportion of patients who have achieved CR and PR assessed by investigators and based on the Lugano 2014 assessment criterion.
Phase 1: OS
The definition of OS has already been mentioned above
Phase 1: Levels of donor-specific antibody (DSA) in blood.
DSA refers to the specific antibody produced in the recipient's body targeting donor antigens after receiving CAR-T cell infusion from healthy donors.
Phase 1: Levels of human anti-mouse antibodies (HAMA)
The levels of human against murine scFv antibodies in blood
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