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Abstract
BackgroundThe rapid evolution of cell-based immunotherapies such as chimeric antigen receptor T-cells for treatment of hematological cancers has precipitated the need for a platform to expand these cells ex vivo in a safe, efficient, and reproducible manner. In the Quantum® Cell Expansion System (Quantum system) we evaluated the expansion of T-cells from healthy donors in a functionally-closed environment that reduces time and resources needed to produce a therapeutic dose.MethodsMononuclear cells from leukapheresis products from 5 healthy donors were activated with anti-CD3/CD28 Dynabeads® and expanded in the Quantum system for 8–9 days using xeno-free, serum-free medium and IL-2. Harvested cells were phenotyped by flow cytometry and evaluated for cytokine secretion by multiplex assays.ResultsFrom starting products of 30 or 85 × 106 mononuclear cells, CD3+ T-cell populations expanded over 500-fold following stimulation to provide yields up to 25 × 109 cells within 8 days. T-cell yields from all donors were similar in terms of harvest numbers, viability and doubling times. Functionality (secretion of IFN-γ, IL-2 and TNF-α) was retained in harvested T-cells upon restimulation in vitro and T-cells displayed therapeutically-relevant less-differentiated phenotypes of naïve and central memory T-cells, with low expression of exhaustion markers LAG-3 and PD-1.ConclusionsThe Quantum system has been successfully used to produce large quantities of functional T-cells at clinical dosing scale and within a short timeframe. This platform could have wide applicability for autologous and allogeneic cellular immunotherapies for the treatment of cancer.
Highlights
There have been remarkable recent advances in cellular immunotherapies to treat cancer, in particular in the expansion and use of gene-modified T-cells, expressing chimeric antigen receptors (CARs), for the treatment of advanced hematologic cancers
We demonstrate that the Quantum system is a versatile platform for the manufacture of T-cells that retain functionality and that display phenotypes of relevance for cancer immunotherapy
T‐cell expansion characteristics in the Quantum system peripheral blood mononuclear cells (PBMCs) from 5 healthy donors were seeded in the Quantum system at either 30 × 106 or 85 × 106 viable cells and harvested 8 days or 9 days later
Summary
There have been remarkable recent advances in cellular immunotherapies to treat cancer, in particular in the expansion and use of gene-modified T-cells, expressing chimeric antigen receptors (CARs), for the treatment of advanced hematologic cancers. Recent U.S Food and Drug Administration (FDA) approvals of tisagenlecleucel [1, 2], which targets B-cell acute lymphoblastic leukemia (B-ALL) and relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL), and of axicabtagene ciloleucel (axi-cel) [3], which targets r/r DLBCL, are evidence of the promise of these approaches for the future treatment of cancer These cellular therapies require the manufacture of up to billions of autologous T-cells for re-infusion to the patient and technologies that can address the labor intensity, costs and requirements for Good Manufacturing Practice (GMP) to achieve these cell numbers are being sought. In the Quantum® Cell Expansion System (Quantum system) we evaluated the expansion of T-cells from healthy donors in a functionally-closed environment that reduces time and resources needed to produce a therapeutic dose
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