Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming

Atanackovic, Djordje; Altorki, Nasser K.; Cao, Yanran; Ritter, Erika; Ferrara, Carmine; Ritter, Gerd; Hoffman, Eric W.; Bokemeyer, Carsten; Old, Lloyd J.; Gnjatic, Sacha

doi:10.1073/pnas.0707140104

Cited by 142 publications

(115 citation statements)

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“…Collectively, these findings indicate that T-cell-based immunotherapies might represent one therapeutic route for effective targeting of CT antigens. Importantly, immunization with MAGE-A3 protein has previously been performed in melanoma and lung cancer patients and has proven to be safe, to be capable of evoking specific humoral and T-cell responses, 47,48 and to have some clinical activity in patients in the adjuvant setting. 49 However, in addition to applying immunotherapy directed against MAGE-C1/CT7 or MAGE-A3 these genes might also be targeted by more "immediate" therapeutic modes such as small molecules, antisense oligonucleotides, or classical gene therapy.…”

Section: Discussionmentioning

confidence: 99%

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

Atanackovic¹,

Hildebrandt²,

Jadczak³

et al. 2009

Haematologica

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BackgroundMultiple myeloma is a life-threatening disease and despite the introduction of stem cell transplantation and novel agents such as thalidomide, lenalidomide, and bortezomib most patients will relapse and develop chemoresistant disease. Therefore, alternative therapeutic modes for myeloma are needed and cancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 have been suggested to represent a class of tumor-specific proteins particularly suited for targeted immunotherapies. Surprisingly, the biological role of cancer-testis genes in myeloma remains poorly understood. Design and MethodsWe performed the first investigation of the function of two cancer-testis antigens most commonly expressed in myeloma, MAGE-C1/CT7 and MAGE-A3, using an RNA interferencebased gene silencing model in myeloma cell lines. Functional assays were used to determine changes in proliferation, cell adhesion, chemosensitivity, colony formation, and apoptosis resulting from gene-specific silencing. ResultsWe show that the investigated genes are not involved in regulating cell proliferation or adhesion; however, they play an important role in promoting the survival of myeloma cells. Accordingly, knock-down of MAGE-C1/CT7 and MAGE-A3 led to the induction of apoptosis in the malignant plasma cells and, importantly, both genes were also essential for the survival of clonogenic myeloma precursors. Finally, silencing of cancer-testis genes further improved the response of myeloma cells to conventional therapies. ConclusionsCancer-testis antigens such as MAGE-C1/CT7 and MAGE-A3 play an important role in promoting the survival of myeloma cells and clonogenic precursors by reducing the rate of spontaneous and chemotherapy-induced apoptosis and might, therefore, represent attractive targets for novel myeloma-specific therapies.Key words: cancer-testis antigens, gene function, RNAi, apoptosis, tumor immunology, multiple myeloma, stem cell transplantation.Citation: Atanackovic D, Hildebrandt Y, Jadczak A, Cao Y, Luetkens T, Meyer S, Kobold S, Bartels K, Pabst C, Lajmi N, Gordic M, Stahl T, Zander AR, Bokemeyer C, promote the survival of multiple myeloma cells. Haematologica 2010;95:785-793. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

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Section: Discussionmentioning

confidence: 99%

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

Atanackovic¹,

Hildebrandt²,

Jadczak³

et al. 2009

Haematologica

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“…Accordingly, CT7-specific CD4 + T cells were able to specifically kill peptide-pulsed melanoma cell line in a chromium release assay. Perforin-secreting CD4 + T cells have been previously described for the in vitro expanded MAGE-A3-specific CD4 + T cells (14) and in vivo for viral antigen-specific CD4 + T cells (38). Recently, two murine studies showed that cytolytic tumor-specific CD4 + T cells can egress to the tumor site and efficiently eradicate melanoma lesions when combined with additional treatments (39,40).…”

Section: Ct7-specific Cd4 + T-cell Clones Recognize Naturally Processmentioning

confidence: 99%

“…Spontaneous immunity to CT antigens was found in melanoma patients, which illustrates their immunogenicity (8,9). Boosting the tumor-specific immune response is considered a promising therapeutic modality with minimal toxicity, and promising results have been achieved with this approach (10)(11)(12)(13)(14). Ideally, an effective antitumor vaccine consists of immunogenic tumor-specific antigens, such as NY-ESO-1 (15).…”

mentioning

confidence: 99%

Fine analysis of spontaneous MAGE-C1/CT7–specific immunity in melanoma patients

Nuber

Curioni-Fontecedro

Matter

et al. 2010

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

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Cancer/testis (CT) antigens represent prime candidates for immunotherapy in cancer patients, because their expression is restricted to cancer cells and germ cells of the testis. MAGE-C1/CT7 is a CT antigen that is highly expressed in several types of cancers. Spontaneous occurrence of CT7-specific antibodies was previously detected by SEREX screen in a melanoma patient. However, naturally occurring CT7-specific T-cell responses have thus far not been detected. Peripheral blood mononuclear cells (PBMCs) from 26 metastatic melanoma patients expressing CT7 in their tumor lesions (CT7 + ) were analyzed for CT7-specific T-cell responses using overlapping peptides. CT7-specific CD4 + T-cell responses were detected in three patients (11.5%). These CT7-specific CD4 + T-cell responses were detectable in melanoma patients' PBMCs exclusively from preexisting CD45RA − memory CD4 + T-cell pool. Additional CT7-specific memory CD4 + T-cell responses were detected in CT7 + melanoma patients after depletion of CD4 + CD25high Treg cells showing that Treg cells impact on CT7-specific CD4 + T cells in melanoma patients. CT7-specific CD4 + T-cell clones were generated and used to define minimal epitopes, restriction elements, and confirm the recognition of naturally processed antigen. Surprisingly, these clones were able to secrete perforin and exert cytotoxicity. This study shows that CT7 can induce specific cellular immunity in melanoma patients. Based on these findings, CT7 will be further explored as a potential vaccine for melanoma immunotherapy.cancer/testis antigens | T-cell response

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“…In vitro stimulation (presensitization) of T cells from ovarian cancer patients, who had spontaneous Ab against NY-ESO-1, was performed as described (29). Briefly, CD8…”

Section: Presensitizationmentioning

confidence: 99%

Antibody-Targeted NY-ESO-1 to Mannose Receptor or DEC-205 In Vitro Elicits Dual Human CD8+ and CD4+ T Cell Responses with Broad Antigen Specificity

Tsuji

Matsuzaki

Kelly

et al. 2011

The Journal of Immunology

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105

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Immunization of cancer patients with vaccines containing full-length tumor Ags aims to elicit specific Abs and both CD4+ and CD8+ T cells. Vaccination with protein Ags, however, often elicits only CD4+ T cell responses without inducing Ag-specific CD8+ T cells, as exogenous protein is primarily presented to CD4+ T cells. Recent data revealed that Ab-mediated targeting of protein Ags to cell surface receptors on dendritic cells could enhance the induction of both CD4+ and CD8+ T cells. We investigated in this study if these observations were applicable to NY-ESO-1, a cancer-testis Ag widely used in clinical cancer vaccine trials. We generated two novel targeting proteins consisting of the full-length NY-ESO-1 fused to the C terminus of two human mAbs against the human mannose receptor and DEC-205, both internalizing molecules expressed on APC. These targeting proteins were evaluated for their ability to activate NY-ESO-1–specific human CD4+ and CD8+ T cells in vitro. Both targeted NY-ESO-1 proteins rapidly bound to their respective targets on APC. Whereas nontargeted and Ab-targeted NY-ESO-1 proteins similarly activated CD4+ T cells, cross-presentation to CD8+ T cells was only efficiently induced by targeted NY-ESO-1. In addition, both mannose receptor and DEC-205 targeting elicited specific CD4+ and CD8+ T cells from PBLs of cancer patients. Receptor-specific delivery of NY-ESO-1 to APC appears to be a promising vaccination strategy to efficiently generate integrated and broad Ag-specific immune responses against NY-ESO-1 in cancer patients.

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Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming

Cited by 142 publications

References 54 publications

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

Cancer-testis antigens MAGE-C1/CT7 and MAGE-A3 promote the survival of multiple myeloma cells

Fine analysis of spontaneous MAGE-C1/CT7–specific immunity in melanoma patients

Antibody-Targeted NY-ESO-1 to Mannose Receptor or DEC-205 In Vitro Elicits Dual Human CD8+ and CD4+ T Cell Responses with Broad Antigen Specificity

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