Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products

Shao, Lipei; Shi, Rongye; Zhao, Yingdong; Liu, Hui; Lu, Alexander; Ma, Jinxia; Cai, Yihua; Fuksenko, Tatyana; Pelayo, Alejandra; Shah, Nirali N.; Kochenderfer, James N.; Norberg, Scott M.; Hinrichs, Christian S.; Highfill, Steven L.; Somerville, Robert; Panch, Sandhya R.; Jin, Ping; Stroncek, David F.

doi:10.1186/s12967-022-03729-5

Cited by 15 publications

(6 citation statements)

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“…As the key to the preparation of CART cells, the design of gene transduction vectors is currently dominated by the use of RV and lentiviral vectors [18,19] , and the two BCMA CART currently on the market use lentivirus as a vector. However, compared with lentiviral vectors, RV showed the advantages of industrial production due to their ability to produce stable toxigenic cell lines, less plasmid dosage, lower impurity content, good transduction effect, and high viral vector titer.…”

Section: Discussionmentioning

confidence: 99%

The First Case of Multiple Myeloma Treated With ASCT followed by Anti-BCMA CART Cells using Retroviral Vector

zhi,

Liqiong,

wenxiang

et al. 2024

Preprint

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B- cell maturation antigen (BCMA) -targeted chimeric antigen receptor-T (CART) cell therapy has shown great promise in the treatment of relapsed/refractory multiple myeloma (MM). In this case, we reported a case of a 41-year-old male patient with MM who finally developed multi-line drug resistance, refractoriness and bone marrow suppression after multiple lines of high-intensity chemotherapy. After physician evaluation, this patient was recommended to receive autologous hematopoietic stem cell transplantation (ASCT) support followed by immunotherapy with autologous anti-BCMA CART cells. The CART product was a novel anti-BCMA CART based on retroviral vectors (RV). The patient achieved VGPR 1 month after anti-BCMA CART infusion and the remission has been ongoing for 3 months to date. Grade 3 cytokine release syndrome (CRS) was observed while no immune effector cell-associated neurotoxicity syndrome (ICANS) was found. This was the first clinical MM case report of anti-BCMA CART cells using retroviral vector, which demonstrated that the RV-based anti-BCMA CAR-T cells had good therapeutic effect and high safety in triple-refractory MM patients.

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Section: Discussionmentioning

confidence: 99%

The First Case of Multiple Myeloma Treated With ASCT followed by Anti-BCMA CART Cells using Retroviral Vector

zhi,

Liqiong,

wenxiang

et al. 2024

Preprint

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“…We have previously described the bulk RNA sequencing procedures in detail [ 18 ]. In brief, total mRNA from CAR T-cell products was isolated using the miRNeasy Mini Kit.…”

Section: Methodsmentioning

confidence: 99%

Deciphering the importance of culture pH on CD22 CAR T-cells characteristics

Prochazkova,

Dreyzin,

Shao

et al. 2024

J Transl Med

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Background Chimeric antigen receptor (CAR) T-cells have demonstrated significant efficacy in targeting hematological malignancies, and their use continues to expand. Despite substantial efforts spent on the optimization of protocols for CAR T-cell manufacturing, critical parameters of cell culture such as pH or oxygenation are rarely actively monitored during cGMP CAR T-cell generation. A comprehensive understanding of the role that these factors play in manufacturing may help in optimizing patient-specific CAR T-cell therapy with maximum benefits and minimal toxicity. Methods This retrospective study examined cell culture supernatants from the manufacture of CAR T-cells for 20 patients with B-cell malignancies enrolled in a phase 1/2 clinical trial of anti-CD22 CAR T-cells. MetaFLEX was used to measure supernatant pH, oxygenation, and metabolites, and a Bio-Plex assay was used to assess protein levels. Correlations were assessed between the pH of cell culture media throughout manufacturing and cell proliferation as well as clinical outcomes. Next-generation sequencing was conducted to examine gene expression profiles of the final CAR T-cell products. Results A pH level at the lower range of normal at the beginning of the manufacturing process significantly correlated with measures of T-cell expansion and metabolism. Stable or rising pH during the manufacturing process was associated with clinical response, whereas a drop in pH was associated with non-response. Conclusions pH has potential to serve as an informative factor in predicting CAR T-cell quality and clinical outcomes. Thus, its active monitoring during manufacturing may ensure a more effective CAR T-cell product.

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“…Moreover, if necessary, adding suicide elements to CAR could eliminate the potential transform risk caused by γ-retrovirus integration. Nevertheless, owing to the drawbacks of γ-retroviruses, such as their inability to infect non-dividing cells and the greater influence on the host transcriptome [ 427 ], lentivirus vectors have gradually replaced them in clinical trials [ 428 ].…”

Section: Gene Transduction Strategies In Actmentioning

confidence: 99%

Challenges and new technologies in adoptive cell therapy

Zhang,

Wan

2023

J Hematol Oncol

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Adoptive cell therapies (ACTs) have existed for decades. From the initial infusion of tumor-infiltrating lymphocytes to the subsequent specific enhanced T cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T cell therapies, many novel strategies for cancer treatment have been developed. Owing to its promising outcomes, CAR-T cell therapy has revolutionized the field of ACTs, particularly for hematologic malignancies. Despite these advances, CAR-T cell therapy still has limitations in both autologous and allogeneic settings, including practicality and toxicity issues. To overcome these challenges, researchers have focused on the application of CAR engineering technology to other types of immune cell engineering. Consequently, several new cell therapies based on CAR technology have been developed, including CAR-NK, CAR-macrophage, CAR-γδT, and CAR-NKT. In this review, we describe the development, advantages, and possible challenges of the aforementioned ACTs and discuss current strategies aimed at maximizing the therapeutic potential of ACTs. We also provide an overview of the various gene transduction strategies employed in immunotherapy given their importance in immune cell engineering. Furthermore, we discuss the possibility that strategies capable of creating a positive feedback immune circuit, as healthy immune systems do, could address the flaw of a single type of ACT, and thus serve as key players in future cancer immunotherapy.

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Genome-wide profiling of retroviral DNA integration and its effect on clinical pre-infusion CAR T-cell products

Cited by 15 publications

References 50 publications

The First Case of Multiple Myeloma Treated With ASCT followed by Anti-BCMA CART Cells using Retroviral Vector

The First Case of Multiple Myeloma Treated With ASCT followed by Anti-BCMA CART Cells using Retroviral Vector

Deciphering the importance of culture pH on CD22 CAR T-cells characteristics

Challenges and new technologies in adoptive cell therapy

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