Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients

Meidenbauer, Norbert; Marienhagen, J.; Laumer, Monika; Vogl, Sandra; Heymann, Jana; Andreesen, Reinhard; Mackensen, Andréas

doi:10.4049/jimmunol.170.4.2161

Cited by 151 publications

(124 citation statements)

References 47 publications

(47 reference statements)

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“…Under selective pressure exerted by adoptively transferred T cells, various immune escape mechanisms like viral mutation or antigen loss are described to limit therapeutic efficiency [19][20][21][22]. These mechanisms are less likely to occur after infusion of T cell lines that are able to recognize multiple epitopes or proteins.…”

Section: Discussionmentioning

confidence: 99%

HLA type-independent generation of antigen-specific T cells for adoptive immunotherapy

Hammer

Meyer²,

Brestrich³

et al. 2005

Eur. J. Immunol.

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Adoptive immunotherapy with antigen-specific T cells has been successfully used to treat certain infectious diseases and cancers. Although more patients may profit from T cell therapy, its more frequent use is restricted by limitations in current T cell generation strategies. The most commonly applied peptide-based approaches rely on the knowledge of relevant epitopes. Therefore, T cells cannot be generated for diseases with unknown epitopes or for patients with unfavorable HLA types. We developed a peptide-based approach for HLA type-independent generation of specific T cells against various proteins. It is based on short-time stimulation with peptide libraries that cover most CD4 + and CD8 + T cell epitopes of given proteins. The procedure requires no prior knowledge of epitopes because libraries are synthesized solely on the basis of the protein's amino acid sequence. Stimulation is followed by immunomagnetic selection of activated IFN-c-secreting cells and nonspecific expansion. To evaluate the protocol, we generated autologous T cells specific for a well-characterized antigen, the human cytomegalovirus phosphoprotein 65 (pp65). Generated T cell lines consisted of pp65-specific CD4 + and CD8 + lymphocytes that displayed antigen-specific killing and proliferation. The protocol combines the biosafety of peptide-based approaches with HLA type independence and may help to advance adoptive immunotherapy in the future.

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Section: Discussionmentioning

confidence: 99%

HLA type-independent generation of antigen-specific T cells for adoptive immunotherapy

Hammer

Meyer²,

Brestrich³

et al. 2005

Eur. J. Immunol.

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“…Our data however, although preliminary, suggest that differential activities might be detectable at temporally distinct points during the different phases of the immune response. 10 IL-2 is typically used for T-cell expansion ''in vitro'', including in the preparation of cells for adoptive immunotherapy, 35,36 and ''in vivo'', alone or as a supplement to vaccination treatments. 3,37 However, its clinical effects appear to require the use of high dosages endowed with substantial toxicity.…”

Section: Discussionmentioning

confidence: 99%

Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐1_27–35targeted active specific immunotherapy

Holzen

Adamina

Bolli

et al. 2005

Intl Journal of Cancer

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We have comparatively evaluated the proliferative response of CTL induced in metastatic melanoma patients upon immunization against Melan‐A/MART‐127–35 tumor associated antigen (TAA) to IL‐2, IL‐7 or IL‐15 cytokines, sharing a receptor common γ‐chain (cγ‐c cytokines). Twenty‐eight CTL clones were generated from CD8+ T cells obtained from 3 patients during the contraction phase of immune response following a successful vaccine mediated expansion of specific effectors. All clones were able to kill tumor cell lines expressing HLA‐A0201 and Melan‐A/MART‐1, and displayed phenotypic characteristics of effector/memory (CD45RA−/CCR7−) or CD45RA+/CCR7− effector cells in intermediate to late developmental stage (CD28−/CD276±) CTL. Proliferative responses could be elicited or enhanced by IL‐2 and IL‐15, but not IL‐7, in the absence or in the presence of T‐cell receptor (TCR) triggering, respectively. Accordingly, only IL‐2 and IL‐15 were able to promote the survival of the CTL clones under investigation. While all clones expressed high amounts of receptor cγ‐c (CD132), lower, but detectable, expression of IL‐7 receptor alpha chain was also observed. CD8+ cells from one of the patients treated were obtained 6 months after the last vaccine boost and were cultured in the presence of Melan‐A/MART‐127–35 and each of the 3 cytokines under investigation. Consistent with data from CTL clones, expansion of Melan‐A/MART‐127–35 tetramer positive cells was only observed in the presence of IL‐2 or IL‐15 but not IL‐7. Instead, when CD8+ cells from the same patient were sampled shortly (14 days) after an additional vaccination only IL‐2 was able to promote the expansion of Melan‐A/MART‐127–35 tetramer positive cells. Taken together these data suggest a selective responsiveness of TAA‐specific CTL to different cγ‐c cytokines. © 2005 Wiley‐Liss, Inc.

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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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Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients

Cited by 151 publications

References 47 publications

HLA type-independent generation of antigen-specific T cells for adoptive immunotherapy

HLA type-independent generation of antigen-specific T cells for adoptive immunotherapy

Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐1_27–35targeted active specific immunotherapy

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

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Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients

Cited by 151 publications

References 47 publications

HLA type-independent generation of antigen-specific T cells for adoptive immunotherapy

HLA type-independent generation of antigen-specific T cells for adoptive immunotherapy

Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐127–35targeted active specific immunotherapy

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

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Selective responsiveness to common gamma chain cytokines in peripheral blood‐derived cytotoxic T lymphocytes induced by Melan‐A/MART‐1_27–35targeted active specific immunotherapy