Monitoring CAR T cell generation with a CD8-targeted lentiviral vector by single-cell transcriptomics

Charitidis, Filippos T; Adabi, Elham; Thalheimer, Frederic B.; Clarke, Colin; Buchholz, Christian J.

doi:10.1016/j.omtm.2022.01.010

Cited by 3 publications

(1 citation statement)

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“…An example is SAMHD1, which blocks early reverse transcription of LVs, especially in monocytes (41,42). While further studies on 62L-LV-mediated transduction of myeloid cells and more importantly CD62L-positive tumor cells will be required, it appears well conceivable that the previously described LVs targeted to the Tcell markers CD8, CD4, or CD3 are more suited for in vivo gene therapy applications than 62L-LV (13,14,16,29,43,44). Even if CD62L-positive non-T cells will be protected from transduction, they could function as a sink for 62L-LV particles, thereby limiting their availability for on-target transduction.…”

Section: Discussionmentioning

confidence: 99%

CD62L as target receptor for specific gene delivery into less differentiated human T lymphocytes

Kapitza,

Ho,

Kerzel

et al. 2023

Front. Immunol.

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Chimeric antigen receptor (CAR)-expressing T cells are a complex and heterogeneous gene therapy product with variable phenotype compositions. A higher proportion of less differentiated CAR T cells is usually associated with improved antitumoral function and persistence. We describe in this study a novel receptor-targeted lentiviral vector (LV) named 62L-LV that preferentially transduces less differentiated T cells marked by the L-selectin receptor CD62L, with transduction rates of up to 70% of CD4+ and 50% of CD8+ primary T cells. Remarkably, higher amounts of less differentiated T cells are transduced and preserved upon long-term cultivation using 62L-LV compared to VSV-LV. Interestingly, shed CD62L neither altered the binding of 62L-LV particles to T cells nor impacted their transduction. The incubation of 2 days of activated T lymphocytes with 62L-LV or VSV-LV for only 24 hours was sufficient to generate CAR T cells that controlled tumor growth in a leukemia tumor mouse model. The data proved that potent CAR T cells can be generated by short-term ex vivo exposure of primary cells to LVs. As a first vector type that preferentially transduces less differentiated T lymphocytes, 62L-LV has the potential to circumvent cumbersome selections of T cell subtypes and offers substantial shortening of the CAR T cell manufacturing process.

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Section: Discussionmentioning

confidence: 99%

CD62L as target receptor for specific gene delivery into less differentiated human T lymphocytes

Kapitza,

Ho,

Kerzel

et al. 2023

Front. Immunol.

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Immunotherapy in hematologic malignancies: achievements, challenges and future prospects

Tang,

Huang,

Mei

et al. 2023

Sig Transduct Target Ther

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The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape, which has accelerated the progress of immunotherapy. Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers, including stem cell transplantation, immune checkpoint inhibitors, antigen-targeted antibodies, antibody-drug conjugates, tumor vaccines, and adoptive cell therapies. These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success. Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed. To provide clinicians with timely information on these revolutionary therapeutic approaches, the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy. Here, we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies. We further discuss the specific mechanisms of action, summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies, as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.

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Insights gained from single-cell analysis of chimeric antigen receptor T-cell immunotherapy in cancer

Tang,

Huang,

Mei

et al. 2023

Military Med Res

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Advances in chimeric antigen receptor (CAR)-T cell therapy have significantly improved clinical outcomes of patients with relapsed or refractory hematologic malignancies. However, progress is still hindered as clinical benefit is only available for a fraction of patients. A lack of understanding of CAR-T cell behaviors in vivo at the single-cell level impedes their more extensive application in clinical practice. Mounting evidence suggests that single-cell sequencing techniques can help perfect the receptor design, guide gene-based T cell modification, and optimize the CAR-T manufacturing conditions, and all of them are essential for long-term immunosurveillance and more favorable clinical outcomes. The information generated by employing these methods also potentially informs our understanding of the numerous complex factors that dictate therapeutic efficacy and toxicities. In this review, we discuss the reasons why CAR-T immunotherapy fails in clinical practice and what this field has learned since the milestone of single-cell sequencing technologies. We further outline recent advances in the application of single-cell analyses in CAR-T immunotherapy. Specifically, we provide an overview of single-cell studies focusing on target antigens, CAR-transgene integration, and preclinical research and clinical applications, and then discuss how it will affect the future of CAR-T cell therapy.

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Monitoring CAR T cell generation with a CD8-targeted lentiviral vector by single-cell transcriptomics

Cited by 3 publications

References 0 publications

CD62L as target receptor for specific gene delivery into less differentiated human T lymphocytes

CD62L as target receptor for specific gene delivery into less differentiated human T lymphocytes

Immunotherapy in hematologic malignancies: achievements, challenges and future prospects

Insights gained from single-cell analysis of chimeric antigen receptor T-cell immunotherapy in cancer

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