Advances in Cell Therapy Research

01

    Auxolytic, in collaboration with researchers at Stanford University School of Medicine, has presented foundational research demonstrating a safe “off switch” for cell therapies.

    Protective mechanisms can mitigate potential risks associated with cell therapies, but currently rely on the introduction of transgenes. Their application is limited by immunogenicity or transgene silencing. This safe “off switch” is designed to create a control mechanism for human cells without the use of transgenes. Using genome editing techniques, we inactivated uridine monophosphate synthase (UMPS) in the pyrimidine de novo synthesis pathway in cell lines, pluripotent stem cells, and primary human T cells. The study demonstrated that this made proliferation dependent on exogenous uridine and enabled us to control cell growth by regulating uridine supply, both in vitro and in vivo following transplantation in xenograft models. Furthermore, disruption of this pathway confers resistance to 5-fluorolactate, enabling positive selection of UMPS-knockout cells. This approach will add an additional layer of safety to cell therapy, thereby facilitating the development of higher-risk strategies, particularly those with limited treatment windows.

Figure 1: Enrichment of UMPS-knockout T cells using 5-FOA

02

    One of the risks associated with chimeric antigen receptor T-cell (CAR-T) therapy is the development of immune-mediated toxicity, including cytokine release syndrome (CRS) and neurotoxicity (NT). Therefore, Rawan Faramand et al. conducted a clinical trial involving 75 patients with large B-cell lymphoma who received the standard-of-care CD19-targeted CAR-T cell product (axicabtagene ciloleucel) to identify high-risk factors for severe toxicity or treatment-related death.

    An analysis of the risk of severe immune-mediated toxicity following CAR T-cell therapy in the study participants revealed that patients with severe cytokine release syndrome (CRS) exhibited elevated peak norepinephrine levels. Receptor-expressing bone marrow cells and regulatory T cells may play a significant role in the pathogenesis of severe NT and CRS, and a model has been proposed in which the severity of CAR T toxicity is driven by interactions between the infused CAR T cells and these receptor-expressing cells. The role of receptor-expressing regulatory T cells in CAR T-treated LBCL patients, as well as their relationship to immune-mediated toxicity and clinical response, has not yet been clearly defined. Reducing systemic inflammation and polarizing the TME toward a T-cell-infiltrated phenotype are potential strategies for reducing toxicity. However, the impact of regulatory T cells in the tumor microenvironment on therapeutic efficacy has not been fully elucidated and requires further study.

03

    Most patients with relapsed or refractory mantle cell lymphoma have a poor prognosis. KTE-X19 is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy; in a one-year follow-up study by Wang et al., it was found that CAR T-cell therapy may be beneficial for patients with relapsed or refractory mantle cell lymphoma.

    In a Phase 2 clinical trial, the research team evaluated KTE-X19 in patients with relapsed or refractory mantle cell lymphoma. Patients had relapsed or refractory disease after receiving up to five prior treatments; all patients were required to have previously received treatment with a BTK inhibitor. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2 × 10^6 CAR T cells per kilogram of body weight. Results showed that among a total of 74 patients, 93% responded to the CAR-T cell therapy KTE-X19, with 67% achieving a complete response. At a median follow-up of one year, 57% of patients were in complete remission, with estimated progression-free survival and overall survival rates of 61% and 83%, respectively. This study demonstrates that a CAR-T cell therapy called KTE-X19 has been developed and used to treat the majority of patients with relapsed or refractory mantle cell lymphoma.

Figure 2: Objective response (A), duration of response (B), progression-free survival (C), and overall survival (D) in patients who received treatment during follow-up

[1] Wiebking V ,  Patterson J O ,  Martin R , et al. Metabolic engineering generates a transgene-free safety switch for cell therapy[J]. Nature Biotechnology, 2020:1-10.

[2] Faramand R G ,  Jain M D ,  Staedtke V , et al. Tumor Microenvironment Composition and Severe Cytokine Release Syndrome (CRS) Influence Toxicity in Patients with Large B-Cell Lymphoma Treated with Axicabtagene Ciloleucel[J]. Clinical Cancer Research, 2020, 26(18):clincanres.1434.2020.

[3] Wang M ,  Munoz J ,  Goy A , et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma[J]. New England Journal of Medicine, 2020, 382(14):1331-1342.