Cellular Therapy Updates in B-Cell Lymphoma: The State of the CAR-T

Crees, Zachary; Ghobadi, Armin

doi:10.3390/cancers13205181

Cited by 16 publications

(10 citation statements)

References 69 publications

(108 reference statements)

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“…[87][88][89] Notwithstanding these biosafety concerns, more than a thousand patients with incurable oncologic diseases have been successfully treated with CAR-T cells. [90,91] To date, not a single clinical report has described proliferative abnormalities that could be attributed to the inadvertent contamination of therapeutic T-cells with VL30 genomes. [38,40,91] Theoretically, it is remotely possible that in contrast to the PG13 producer cells characterized in this study, specific vector producer cell clones that were individually isolated for specific clinical applications did not secrete VL30 genomes-comprising g-retroviral particles.…”

Section: Discussionmentioning

confidence: 99%

Inadvertent Transfer of Murine VL30 Retrotransposons to CAR-T Cells

Lee

Gui

Dotti

et al. 2022

Preprint

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For more than a decade genetically engineered autologous T-cells have been successfully employed as immunotherapy drugs for patients with incurable blood cancers. The active component in some of these game-changing medicines are autologous T-cells that express viral vector- delivered chimeric antigen receptors (CARs), which specifically target proteins that are preferentially expressed on cancer cells. Some of these therapeutic CAR expressing T-cells (CAR-Ts) are engineered via transduction with γ-retroviral vectors (γ-RVVs) produced in a stable producer cell line that was derived from murine PG13 packaging cells (ATCC CRL-10686). Earlier studies reported on the co-packaging of murine virus-like 30S RNA (VL30) genomes with γ- retroviral vectors generated in murine stable packaging cells. In an earlier study VL30 mRNA was found to enhance the metastatic potential of human melanoma cells. These findings raise biosafety concerns regarding the possibility that therapeutic CAR-Ts have been inadvertently contaminated with potentially oncogenic VL30 retrotransposons. In this study, we demonstrated the presence of infectious VL30 particles in PG13 cells conditioned media and observed the ability of these particles to deliver transcriptionally active VL30 genomes to human cells. Notably, VL30 genomes packaged by HIV-1-based vector particles transduced naïve human cells in culture. Furthermore, we detected transfer and expression of VL30 genomes in clinical-grade CAR-Ts generated by transduction with PG13 cells-derived γ-retroviral vectors. Our findings raise biosafety concerns regarding the use of murine packaging cell lines in ongoing clinical applications.

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Section: Discussionmentioning

confidence: 99%

Inadvertent Transfer of Murine VL30 Retrotransposons to CAR-T Cells

Lee

Gui

Dotti

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Notwithstanding these biosafety concerns, more than a thousand patients with incurable oncologic diseases have been successfully treated with CAR-T cells [ 94 , 95 ]. To date, not a single clinical report has described proliferative abnormalities that could be attributed to the inadvertent contamination of therapeutic T-cells with VL30 genomes [ 42 , 44 , 95 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, there is a possibility that CAR-T cell activation (via the CAR CD28-costimulatory domain) may be altered following binding/sequestration of nuclear PFS by VL30 mRNA [91][92][93]. Notwithstanding these biosafety concerns, more than a thousand patients with incurable oncologic diseases have been successfully treated with CAR-T cells [94,95]. To date, not a single clinical report has described proliferative abnormalities that could be attributed to the inadvertent contamination of therapeutic T-cells with VL30 genomes [42,44,95].…”

Section: Discussionmentioning

confidence: 99%

Inadvertent Transfer of Murine VL30 Retrotransposons to CAR-T Cells

Lee

Gui

Dotti

et al. 2022

Advances in Cell and Gene Therapy

View full text Add to dashboard Cite

For more than a decade, genetically engineered autologous T-cells have been successfully employed as immunotherapy drugs for patients with incurable blood cancers. The active components in some of these game-changing medicines are autologous T-cells that express viral vector-delivered chimeric antigen receptors (CARs), which specifically target proteins that are preferentially expressed on cancer cells. Some of these therapeutic CAR expressing T-cells (CAR-Ts) are engineered via transduction with γ -retroviral vectors ( γ -RVVs) produced in a stable producer cell line that was derived from murine PG13 packaging cells (ATCC CRL-10686). Earlier studies reported on the copackaging of murine virus-like 30S RNA (VL30) genomes with γ -retroviral vectors generated in murine stable packaging cells. In an earlier study, VL30 mRNA was found to enhance the metastatic potential of human melanoma cells. These findings raise biosafety concerns regarding the possibility that therapeutic CAR-Ts have been inadvertently contaminated with potentially oncogenic VL30 retrotransposons. In this study, we demonstrated the presence of infectious VL30 particles in PG13 cell-conditioned media and observed the ability of these particles to deliver transcriptionally active VL30 genomes to human cells. Notably, VL30 genomes packaged by HIV-1-based vector particles transduced naïve human cells in culture. Furthermore, we detected the transfer and expression of VL30 genomes in clinical-grade CAR-T cells generated by transduction with PG13 cell-derived γ -retroviral vectors. Our findings raise biosafety concerns regarding the use of murine packaging cell lines in ongoing clinical applications.

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“…The advent of CAR-T cell therapies has dramatically improved outcomes in the relapsed/refractory setting of several lymphoma subtypes. However, refractoriness to CAR-T treatment, relapse after initial response, therapy-related toxicities, and treatment costs represent relevant hurdles to overcome (34). Therefore, several research fields are being developed towards different aims: to identify strategies to increase CD-19 CAR-T activity and persistence, to target new antigens in B-cell neoplasms, and to identify alternative platforms for CAR engineering.…”

Section: Future Of Car Technologymentioning

confidence: 99%