Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med

Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
New England Journal of Medicine (Impact Factor: 55.87). 07/2008; 358(25):2698-703. DOI: 10.1056/NEJMoa0800251
Source: PubMed


We developed an in vitro method for isolating and expanding autologous CD4+ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1. We infused these cells into a patient with refractory metastatic melanoma who had not undergone any previous conditioning or cytokine treatment. We show that the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.

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    • "This trial was based on preclinical studies showing that this vaccine can induce CD8 and CD4 T cell responses [20]. Besides vaccination strategies, adoptive cell therapy with autologous T cells transduced with a T-cell receptor directed against NY-ESO-1 showed responses in previously treated patients with NY-ESO-1 bearing tumors; 4 out of 6 patients with advanced synovial cell sarcoma and 5 out of 11 patients with metastatic melanoma had an objective response, and this approach is now being studied in additional patients, using NY-ESO-1 tumor expression as a criterion for eligibility [19, 43]. "
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    ABSTRACT: Background: Novel immune therapies targeting tumor specific antigens are being developed. Our purpose was to determine expression of the cancer testes antigen NY-ESO-1 in renal cell carcinoma (RCC), as NY-ESO-1 targeting approaches, particularly adoptive cell therapy, have not been evaluated in this disease. Methods: We employed tissue microarrays containing >300 unique RCC cases and adjacent benign renal tissue to determine NY-ESO-1 expression using a quantitative immunofluorescence method. In addition, we studied NY-ESO-1 expression in 35 matched primary and metastatic RCC specimens to assess concordance between different tumor sites. Results: NY-ESO-1 was highly expressed in a subset of RCCs. Expression in primary RCC specimens was significantly higher than adjacent normal renal tissue (P<0.0001) and higher in clear cell carcinomas than papillary RCC (P<0.0001). Expression levels in metastatic specimens were higher than in matched primary samples (P=0.0018), and the correlation between the two sites was modest (χ2=3.5, p=0.06). Conclusions: Aberrant NY-ESO-1 expression seen in clear cell RCC suggests that NY-ESO-1 targeting approaches should be studied in this disease. Expression is higher in metastatic sites, and discordance between primary and metastatic sites in some patients suggests that patient selection for these therapies should be based on expression in metastatic rather than nephrectomy specimens.
    Oncotarget 06/2014; 5(14). DOI:10.18632/oncotarget.2101 · 6.36 Impact Factor
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    • "Several preclinical studies have described antitumor effect of ACT using CD4+ T cell population, and CD4+ T cells have cytolytic activity dependent on class II-restricted recognition of tumors [132–134]. In a recent early-phase dose escalation study of ACT for patient with metastatic melanoma using CD4+ T cell clones, the patients experienced partial responses including a case of a complete durable response [128, 135]. "
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    ABSTRACT: Immunotherapy emerged as a promising therapeutic approach to highly incurable malignant gliomas due to tumor-specific cytotoxicity, minimal side effect, and a durable antitumor effect by memory T cells. But, antitumor activities of endogenously activated T cells induced by immunotherapy such as vaccination are not sufficient to control tumors because tumor-specific antigens may be self-antigens and tumors have immune evasion mechanisms to avoid immune surveillance system of host. Although recent clinical results from vaccine strategy for malignant gliomas are encouraging, these trials have some limitations, particularly their failure to expand tumor antigen-specific T cells reproducibly and effectively. An alternative strategy to overcome these limitations is adoptive T cell transfer therapy, in which tumor-specific T cells are expanded ex vivo rapidly and then transferred to patients. Moreover, enhanced biologic functions of T cells generated by genetic engineering and modified immunosuppressive microenvironment of host by homeostatic T cell expansion and/or elimination of immunosuppressive cells and molecules can induce more potent antitumor T cell responses and make this strategy hold promise in promoting a patient response for malignant glioma treatment. Here we will review the past and current progresses and discuss a new hope in adoptive T cell therapy for malignant gliomas.
    Research Journal of Immunology 06/2014; 2014(3):326545. DOI:10.1155/2014/326545
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    • "This is not an isolated finding, as it is in line with earlier reports showing the importance of this T-cell subset in tumor eradication in mouse models [26]–[28]. There are also findings in humans suggesting that this T-cell population plays a relevant role in tumor regression, as clinical efficacy has been reported after passive transfer of CD4+ T cells specific for NY-ESO-1 isolated from a melanoma tumor site [29]. The involvement of CD4+ T cells is not illogical, given their known central role in orchestrating the different phases of the adaptive immune response and the cross-talk they establish with other immune cells, especially the antigen-presenting cells. "
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    ABSTRACT: MAGE-A3 is a potential target for immunotherapy due to its tumor-specific nature and expression in several tumor types. Clinical data on MAGE-A3 immunotherapy have raised many questions that can only be addressed by using animal models. In the present study, different aspects of the murine anti-tumor immune responses induced by a recombinant MAGE-A3 protein (recMAGE-A3) in combination with different immunostimulants (AS01, AS02, CpG7909 or AS15) were investigated. Based on cytokine profile analyses and protection against challenge with MAGE-A3-expressing tumor, the combination recMAGE-A3+AS15 was selected for further experimental work, in particular to study the mechanisms of anti-tumor responses. By using MHC class I-, MHC class II-, perforin-, B-cell- and IFN-γ- knock-out mice and CD4+ T cell-, CD8+ T cell- and NK cell- depleted mice, we demonstrated that CD4+ T cells and NK cells are the main anti-tumor effectors, and that IFN-γ is a major effector molecule. This mouse tumor model also established the need to repeat recMAGE-A3+AS15 injections to sustain efficient anti-tumor responses. Furthermore, our results indicated that the efficacy of tumor rejection by the elicited anti-MAGE-A3 responses depends on the proportion of tumor cells expressing MAGE-A3. The recMAGE-A3+AS15 cancer immunotherapy efficiently induced an antigen-specific, functional and long-lasting immune response able to recognize and eliminate MAGE-A3-expressing tumor cells up to several months after the last immunization in mice. The data highlighted the importance of the immunostimulant to induce a Th1-type immune response, as well as the key role played by IFN-γ, CD4+ T cells and NK cells in the anti-tumoral effect.
    PLoS ONE 05/2014; 9(5):e94883. DOI:10.1371/journal.pone.0094883 · 3.23 Impact Factor
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