Phase I Study of Adoptive T-Cell Therapy Using Antigen-Specific CD8<sup>+</sup> T Cells for the Treatment of Patients With Metastatic Melanoma

Mackensen, Andréas; Meidenbauer, Norbert; Vogl, Sandra; Laumer, Monika; Berger, Jana; Andreesen, Reinhard

doi:10.1200/jco.2006.07.1100

Cited by 289 publications

(209 citation statements)

References 25 publications

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“…Although T cell clones can be expanded over two weeks to achieve numbers >10 10 , there are additional weeks needed to generate the clones first and the cloning process is laborious (Yee et al, 2002). Mackensen and his colleagues (Mackensen et al, 2006) established a protocol to generate M27L-specific T cells by stimulating CD8+ lymphocytes (selected by beads) with dendritic cells weekly for 4 weeks. Of 11 patients treated, there were a total of 52 infusions, with an average of 2x10 8 M27L-specific T cells in each infusion.…”

Section: Discussionmentioning

confidence: 99%

In vitro methods for generating highly purified EBV associated tumor antigen-specific T cells by using solid phase T cell selection system for immunotherapy

Mookerjee

Wagner

et al. 2007

Journal of Immunological Methods

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Section: Discussionmentioning

confidence: 99%

In vitro methods for generating highly purified EBV associated tumor antigen-specific T cells by using solid phase T cell selection system for immunotherapy

Mookerjee

Wagner

et al. 2007

Journal of Immunological Methods

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“…Although the immunogenicity of a number of TAA has been documented in clinical trials, their therapeutic potential has not been clearly assessed, with the exception of the Melan-A/MART-1 antigen. Indeed, the therapeutic usefulness of the Melan-A antigen in melanoma is supported by the analysis of several active [2,3] and passive [4][5][6][7][8][9] immunotherapy protocols targeting this antigen.…”

Section: Introductionmentioning

confidence: 99%

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

et al. 2010

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We recently showed that the infusion of tumor infiltrating lymphocytes specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 1 melanoma patients who received tumor infiltrating lymphocytes therapy. Here, we characterized the MELOE-1/A2-specific T-cell repertoire in healthy donors and melanoma patients to further support an immunotherapy targeting this epitope. Using tetramer enrichment followed by multicolor staining, we found that MELOE-1-specific T cells were present in the blood of healthy donors and patients at similar frequencies (around 1 in 1 Â 10 5 CD8 1 cells). These cells mainly displayed a naïve phenotype in 4/6 healthy donors and 3/6 patients, whereas high proportions of memory cells were observed in the remaining individuals of both groups. There was a recurrent usage of the Va12.1 chain for 17/18 MELOE-1-specific T-cell clones derived from healthy donors or patients, associated with diverse Vb chains and V(D)J junctional sequences. All clones derived from melanoma patients (9/9) were reactive against the MELOE-1 36-44 peptide and against HLA-A2 1 melanoma cell lines. This study documents the existence of a large TCR repertoire specific for the MELOE-1/A2 epitope and its capacity to give rise to antitumor CTL that supports the development of immunotherapies targeting this epitope.Key words: Immunotherapy . Melanoma . MELOE-1 . T-cell repertoire . TCR Introduction A key advance in tumor immunology in the past 15 years has been the elucidation of the antigenic basis of tumor cell recognition and destruction, which has opened the way to development of antigen-based immunotherapy in cancer patients. Tumor-associated antigens (TAA) have been grouped into categories according to their expression pattern in neoplastic and normal tissues. TAA can be roughly subdivided into two main classes: proteins expressed specifically by tumor cells, and proteins that are expressed by both tumor cells and by normal cells to a significant level. The first category includes cancergermline antigens, proteins expressed by unconventional gene expression and mutated antigens (see [1] for review). TAA belonging to the second category are the differentiation antigens, mainly expressed in the melanocytic lineage, and the antigens overexpressed by various tumor tissues. Although the immunogenicity of a number of TAA has been documented in clinical Ã These authors contributed equally to this work. We recently showed a correlation between the infusion of T cells reactive against an HLA-A2 epitope derived from another melanoma antigen, MELOE-1, and time to progression of patients treated with autologous tumor infiltrating lymphocytes (TIL) [10]. This antigen is encoded by the meloe gene, overexpressed in human melanoma cell lines, when compared to normal melanocytes, and dramatically underexpressed in other cancer cell lines (colon, renal, breast and lung carcinoma cell lines) and in a variety of normal tissues [10]. This expression profile and the potential involvement of MELOE-1-specific...

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“…However, considerable research has shown that the persistence of transferred T cells in vivo is both central to therapeutic success and elusive to current technology (6,7). The efficacy of adoptive immunotherapy in humans is often limited by the failure of transferred T cells to survive in the host (8,9).…”

mentioning

confidence: 99%

Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems

Chen

Jensen

Smolke

2010

Proc. Natl. Acad. Sci. U.S.A.

242

245

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RNA molecules perform diverse regulatory functions in natural biological systems, and numerous synthetic RNA-based control devices that integrate sensing and gene-regulatory functions have been demonstrated, predominantly in bacteria and yeast. Despite potential advantages of RNA-based genetic control strategies in clinical applications, there has been limited success in extending engineered RNA devices to mammalian gene-expression control and no example of their application to functional response regulation in mammalian systems. Here we describe a synthetic RNA-based regulatory system and its application in advancing cellular therapies by linking rationally designed, drug-responsive, ribozymebased regulatory devices to growth cytokine targets to control mouse and primary human T-cell proliferation. We further demonstrate the ability of our synthetic controllers to effectively modulate T-cell growth rate in response to drug input in vivo. Our RNAbased regulatory system exhibits unique properties critical for translation to therapeutic applications, including adaptability to diverse ligand inputs and regulatory targets, tunable regulatory stringency, and rapid response to input availability. By providing tight gene-expression control with customizable ligand inputs, RNA-based regulatory systems can greatly improve cellular therapies and advance broad applications in health and medicine. T he ability to control functional responses in mammalian cells with customizable and compact regulatory systems in vivo addresses a critical need in diverse clinical applications, particularly in cellular therapies (1). As an example, adoptive T-cell therapy seeks to harness the precision and efficacy of the immune system against diseases that escape the body's natural surveillance. The adoptive transfer of antigen-specific T cells can reconstitute immunity to viruses and mediate tumor regression (2-4). T cells engineered to express tumor-specific T-cell antigen receptors can achieve highly refined target recognition (5), thus minimizing toxic off-target effects associated with conventional chemotherapy. However, considerable research has shown that the persistence of transferred T cells in vivo is both central to therapeutic success and elusive to current technology (6, 7). The efficacy of adoptive immunotherapy in humans is often limited by the failure of transferred T cells to survive in the host (8, 9).Clonal expansion of T cells is a critical component of T-cell activation mediated by cytokines such as IL-2 and IL-15, which activate JAK-STAT signaling pathways and lead to the expression of genes involved in growth modulation (10) (Fig. 1A). Sustaining the survival and proliferation of Tcells following adoptive transfer is challenging because of the limited availability of homeostatic cytokines (IL-15/IL-7) and stimulatory antigen presenting cells. State-of-the-art strategies for improving the persistence of adoptively transferred lymphocytes require that patients be subjected to myeloablative total body irradiation/chemother...

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Phase I Study of Adoptive T-Cell Therapy Using Antigen-Specific CD8⁺ T Cells for the Treatment of Patients With Metastatic Melanoma

Abstract: Our data indicate that the adoptive transfer of antigen-specific T cells in melanoma patients can induce clinical tumor-specific immune responses without major adverse effects.

Cited by 289 publications

References 25 publications

In vitro methods for generating highly purified EBV associated tumor antigen-specific T cells by using solid phase T cell selection system for immunotherapy

In vitro methods for generating highly purified EBV associated tumor antigen-specific T cells by using solid phase T cell selection system for immunotherapy

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems

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Phase I Study of Adoptive T-Cell Therapy Using Antigen-Specific CD8+ T Cells for the Treatment of Patients With Metastatic Melanoma

Abstract: Our data indicate that the adoptive transfer of antigen-specific T cells in melanoma patients can induce clinical tumor-specific immune responses without major adverse effects.

Cited by 289 publications

References 25 publications

In vitro methods for generating highly purified EBV associated tumor antigen-specific T cells by using solid phase T cell selection system for immunotherapy

In vitro methods for generating highly purified EBV associated tumor antigen-specific T cells by using solid phase T cell selection system for immunotherapy

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems

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Product

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Phase I Study of Adoptive T-Cell Therapy Using Antigen-Specific CD8⁺ T Cells for the Treatment of Patients With Metastatic Melanoma