Process validation and clinical evaluation of a protocol to generate gene-modified T lymphocytes for imunogene therapy for metastatic renal cell carcinoma: GMP-controlled transduction and expansion of patient's T lymphocytes using a carboxy anhydrase IX-specific scFv transgene

Lamers, Cor H.J.; Elzakker, Pascal van; Langeveld, Sabine C. L.; Sleijfer, Stefan; Gratama, Jan-Willem

doi:10.1080/14653240601056396

Cited by 32 publications

(27 citation statements)

References 25 publications

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“…When batches of clinical-grade FCS became available, we further used the latter reagent because of its superior performance to supplement the RTV production medium and used FCS-supplemented RTV production medium to generate our clinical lot of RTVsup. 3 Optimization of conditions to produce and preserve stability of retroviral vectors is crucial for clinical gene therapy applications. First, the choice of the producer cell line is of utmost importance to obtain a high-level producer cell line.…”

Section: Discussionmentioning

confidence: 99%

“…15 Two production media were used, that is, RPMI-1640 supplemented with 2% human serum albumin ( Retroviral transduction of primary human T lymphocytes PBMC were activated as described, 3 followed by two cycles of transduction at days 2 and 3 postactivation. Over a period of B10 years our (laboratory-scale) transduction protocols have been significantly optimized.…”

Section: Retroviral Supernatantmentioning

confidence: 99%

“…Tests were performed according to our standardized protocol and using clinical-grade components, 3 and resulted in highly reproducible transduction efficiencies, with very limited inter-donor and inter-test variations (Figure 4). Only donor 5 performed slightly less than the other donors (all t-tests Pp0.02) (Figure 4, left panel).…”

Section: Stable Transduction Potency Of Clinical Batch Of Phoenix Clomentioning

confidence: 99%

“…1,2 We have described procedures for the production of high-titer clinical-grade retroviruscontaining culture supernatant (RTVsup) and clinicalscale retroviral transduction that yield clinically relevant numbers of stably transduced human T cells for patient treatment. 3 However, it has been recognized that retroviral vectors, in particular murine leukemia virus (MLV)-derived vectors furnished with an amphotropic envelope, are relatively labile. 4,5 Among the factors that influence retroviral vector stability are physicochemical properties of the viral lipid shell such as the cholesterol:phospholipid ratio.…”

Section: Introductionmentioning

confidence: 99%

“…3,16 From day 4 postactivation onwards, the transduced T cells were expanded until day 14 as described. 3 …”

mentioning

confidence: 99%

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Retroviral vectors for clinical immunogene therapy are stable for up to 9 years

et al. 2008

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Recombinant retroviruses are one of the most commonly used gene transfer vehicles for therapeutic gene delivery. The stability of viral vectors upon long-term storage, anticipated to be short lived, is expected to impact timeline and financial course of clinical immunogene therapy. However, to date little is known about vector stability. Therefore, we analyzed the stability of retroviral vectors produced in culture supernatants (RTVsup) for ex vivo gene therapy upon long-term storage. We have generated RTVsups derived from two packaging cell lines, PG13 and Phoenix(Ampho). Both lines produced murine leukemia virus-derived SFG-scFv(G250)-CD4g vector, which were pseudotyped with the gibbon ape leukemia virus envelope and amphotropic envelope, respectively. The supernatants were stored at À80 or À196 1C. To date, the PG13-derived RTVsups have been evaluated over a period of 9 years (1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007). In addition, a clinical batch of Phoenix(Ampho)-derived RTVsup has been evaluated over a period of 5 years (2002)(2003)(2004)(2005)(2006)(2007). Here, we show that both RTVsups, when stored up to 9 and 5 years, respectively, do not show any sign of decay in their capacity to functionally transduce primary human T cells. These data provide evidence that in terms of 'life expectancy' the production and storage of clinical batches of RTVsup for gene therapy warrants the corresponding professional and financial risks.

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Section: Discussionmentioning

confidence: 99%

Section: Retroviral Supernatantmentioning

confidence: 99%

Section: Stable Transduction Potency Of Clinical Batch Of Phoenix Clomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…3,16 From day 4 postactivation onwards, the transduced T cells were expanded until day 14 as described. 3 …”

mentioning

confidence: 99%

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Retroviral vectors for clinical immunogene therapy are stable for up to 9 years

et al. 2008

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Adoptive Transfer of T-Bodies: Toward an Effective Cancer Immunotherapy

Friedmann‐Morvinski¹,

Eshhar

2009

Targeted Cancer Immune Therapy

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The T-Body Approach: Redirecting T Cells with Antibody Specificity

Eshhar¹

2008

Therapeutic Antibodies

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"T-bodies" are genetically engineered T cells armed with chimeric receptors whose extracellular recognition unit is comprised of an antibody-derived recognition domain and whose intracellular region is derived from lymphocyte stimulating moiety(ies). The structure of the prototypic chimeric receptor, also known as a chimeric immune receptor, is modular, designed to accomodate various functional domains and thereby to enable choice of specificity and controlled activation of T cells. The preferred antibody-derived recognition unit is a single chain variable fragment (scFv) that combines the specificity and binding residues of both the heavy and light chain variable regions of a monoclonal antibody. The most common lymphocyte activation moieties include a T-cell costimulatory (e.g. CD28) domain in tandem with a T-cell triggering (e.g. CD3zeta) moiety. By arming effector lymphocytes (such as T cells and natural killer cells) with such chimeric receptors, the engineered cell is redirected with a predefined specificity to any desired target antigen, in a non-HLA restricted manner. Chimeric receptor (CR) constructs are introduced ex vivo into T cells from peripheral lymphocytes of a given patient using retroviral vectors. Following infusion of the resulting T-bodies back into the patient, they traffic, reach their target site, and upon interaction with their target cell or tissue, they undergo activation and perform their predefined effector function. Therapeutic targets for the T-body approach include cancer and HIV-infected cells, or autoimmune effector cells. To date, the most investigated area is cancer therapy. Here, the T-bodies are advantageous because their tumor recognition is not HLA-specific and, therefore, the same constructs can be used for a wide spectrum of patients and cancers.

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Process validation and clinical evaluation of a protocol to generate gene-modified T lymphocytes for imunogene therapy for metastatic renal cell carcinoma: GMP-controlled transduction and expansion of patient's T lymphocytes using a carboxy anhydrase IX-specific scFv transgene

Cited by 32 publications

References 25 publications

Retroviral vectors for clinical immunogene therapy are stable for up to 9 years

Retroviral vectors for clinical immunogene therapy are stable for up to 9 years

Adoptive Transfer of T-Bodies: Toward an Effective Cancer Immunotherapy

The T-Body Approach: Redirecting T Cells with Antibody Specificity

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