Preservation of cell-based immunotherapies for clinical trials

Li, R. U.I.; Johnson, Ross G.; Yu, Guanglin; McKenna, David H.; Hubel, Allison

doi:10.1016/j.jcyt.2019.07.004

Cited by 80 publications

(45 citation statements)

References 120 publications

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“…However, NK cells represent large granular lymphocytes which are more sensitive to cryopreservation than T cells, usually displaying impaired viability and long lag phases after thawing (181). While efforts are made to improve cryopreservation of NK cells, and some NK-92 cell products under commercial development are provided in cryopreserved form (154, 182, 183), we decided to use fresh NK-92/5.28.z cells in exponential growth phase for application in glioblastoma patients.…”

Section: Manufacturing Of Car-nk-92 Cells For Clinical Applicationmentioning

confidence: 99%

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

et al. 2019

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Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with ex vivo activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.

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Section: Manufacturing Of Car-nk-92 Cells For Clinical Applicationmentioning

confidence: 99%

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

et al. 2019

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“…Cryopreservation of CAR-NK cells is a necessity, but also allows to use NK cells as “off-the-shelf” products. This measure should guarantee the recipient always receives a similar quality of CAR-NK cells, thus disregarding the natural variety in NK cell donors [ 190 ]. Numerous groups are trying to optimize the ingredients of the freezing medium and procedures for expanded CAR-NK cells and have achieved encouraging outcomes [ 162 , 190 , 191 ].…”

Section: Prospective and Outlookmentioning

confidence: 99%

“…This measure should guarantee the recipient always receives a similar quality of CAR-NK cells, thus disregarding the natural variety in NK cell donors [ 190 ]. Numerous groups are trying to optimize the ingredients of the freezing medium and procedures for expanded CAR-NK cells and have achieved encouraging outcomes [ 162 , 190 , 191 ]. A recent approach uses nanoparticle-mediated intracellular protection of NK cells which can avoid cryoinjury and maintain the killing potential of NK-92 cells, which could completely replace DMSO as a freezing protector [ 192 ].…”

Section: Prospective and Outlookmentioning

confidence: 99%

Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy

et al. 2021

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Due to their efficient recognition and lysis of malignant cells, natural killer (NK) cells are considered as specialized immune cells that can be genetically modified to obtain capable effector cells for adoptive cellular treatment of cancer patients. However, biological and technical hurdles related to gene delivery into NK cells have dramatically restrained progress. Recent technological advancements, including improved cell expansion techniques, chimeric antigen receptors (CAR), CRISPR/Cas9 gene editing and enhanced viral transduction and electroporation, have endowed comprehensive generation and characterization of genetically modified NK cells. These promising developments assist scientists and physicians to design better applications of NK cells in clinical therapy. Notably, redirecting NK cells using CARs holds important promise for cancer immunotherapy. Various preclinical and a limited number of clinical studies using CAR-NK cells show promising results: efficient elimination of target cells without side effects, such as cytokine release syndrome and neurotoxicity which are seen in CAR-T therapies. In this review, we focus on the details of CAR-NK technology, including the design of efficient and safe CAR constructs and associated NK cell engineering techniques: the vehicles to deliver the CAR-containing transgene, detection methods for CARs, as well as NK cell sources and NK cell expansion. We summarize the current CAR-NK cell literature and include valuable lessons learned from the CAR-T cell field. This review also provides an outlook on how these approaches may transform current clinical products and protocols for cancer treatment.

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“…The formulations and shelf-lives of fresh and frozen CBMPs in clinical development present a similar picture. 12 Frozen T-cell products are predominantly formulated in 5e10% DMSO, HSA (5e20%) and an isotonic multi-electrolyte solution, such as Plas-maLyte A. Dendritic cell (DC) and natural killer (NK) cell formulations stored under frozen conditions are comparably complex. Some products contain CryoStor CS5 or CS10, a proprietary, 'ready to use', complex medium of more than fifteen excipients containing 5% and 10% DMSO, respectively (see Table 1).…”

Section: Formulation Of Cbmpsmentioning

confidence: 99%

“…All EU marketed frozen CBMPs (Table 1) and a lot of frozen CBMPs in clinical development contain 5e10% DMSO as intracellular CPA. 12,13 While needed to protect the cells against freezing stress, DMSO in these concentrations is toxic to cells in the nonfrozen state. This implies that pre-freeze and post-thaw CBMP stabilities in the presence of DMSO are short.…”

Section: Cbmps and Dmso: A Love-hate Relationshipmentioning

confidence: 99%

Formulation of Cell-Based Medicinal Products: A Question of Life or Death?

Hoogendoorn

Crommelin

Jiskoot

2021

Journal of Pharmaceutical Sciences

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The formulation of cell-based medicinal products (CBMPs) poses major challenges because of their complexity, heterogeneity, interaction with their environment (e.g., the formulation buffer, interfaces), and susceptibility to degradation. These challenges can be quality, safety, and efficacy related. In this commentary we discuss the current status in formulation strategies of off-the-shelf and non-off-the-shelf (patient-specific) CBMPs and highlight advantages and disadvantages of each strategy. Analytical tools for the characterization and stability assessment of CBMP formulations are addressed as well. Finally, we discuss unmet needs and make some recommendations regarding the formulation of CBMPs.

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Preservation of cell-based immunotherapies for clinical trials

Cited by 80 publications

References 120 publications

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

CAR-Engineered NK Cells for the Treatment of Glioblastoma: Turning Innate Effectors Into Precision Tools for Cancer Immunotherapy

Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy

Formulation of Cell-Based Medicinal Products: A Question of Life or Death?

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