Neoadjuvant Treatment of Regional Stage IIIB Melanoma With High-Dose Interferon Alfa-2b Induces Objective Tumor Regression in Association With Modulation of Tumor Infiltrating Host Cellular Immune Responses

Moschos, Stergios J.; Edington, Howard; Land, Stephanie R.; Rao, Uma; Jukic, D.M.; Shipe-Spotloe, Janice; Kirkwood, John M.

doi:10.1200/jco.2005.05.2498

Cited by 229 publications

(156 citation statements)

References 25 publications

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“…This process is generally referred to as cancer immune surveillance (1) and cancer immunoediting (2). Several studies found a correlation between the degree of tumor infiltration by CD8 + T cells and longer disease-free survival in cancer patients (3,4), which supports the concept of immune surveillance. Furthermore, spontaneous cellular and humoral tumor-specific immune responses can be detected in cancer patients (5).…”

mentioning

confidence: 86%

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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mentioning

confidence: 86%

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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“…Likewise, patients with tumors showing naturally immunogenic mutations and associated TIL are potential candidates for treatment with immune modulators such as CTLA4-or PDCD1-targeted antibodies. There is evidence that such therapies are most effective against tumors infiltrated by T cells (Moschos et al 2006;Hamid et al 2009). Our results indicate that tumors bearing predicted immunogenic mutations have not only Each ring represents one patient, and the intersection with the axis represents that patient's value for that axis.…”

Section: à3mentioning

confidence: 99%

Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

et al. 2014

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Somatic missense mutations can initiate tumorogenesis and, conversely, anti-tumor cytotoxic T cell (CTL) responses. Tumor genome analysis has revealed extreme heterogeneity among tumor missense mutation profiles, but their relevance to tumor immunology and patient outcomes has awaited comprehensive evaluation. Here, for 515 patients from six tumor sites, we used RNA-seq data from The Cancer Genome Atlas to identify mutations that are predicted to be immunogenic in that they yielded mutational epitopes presented by the MHC proteins encoded by each patient’s autologous HLA-A alleles. Mutational epitopes were associated with increased patient survival. Moreover, the corresponding tumors had higher CTL content, inferred from CD8A gene expression, and elevated expression of the CTL exhaustion markers PDCD1 and CTLA4. Mutational epitopes were very scarce in tumors without evidence of CTL infiltration. These findings suggest that the abundance of predicted immunogenic mutations may be useful for identifying patients likely to benefit from checkpoint blockade and related immunotherapies.

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“…(i) It is not clear which population most benefits from the adjuvant treatment (ii) The benefit is only clear for disease-free survival, with no consistent information referring to global survival (iii) The toxicity is considerable (iv) The ideal duration and dose for the treatment are unknown STAT3 being observed and related to cell proliferation; high dose interferon-2b would reduce this protein and increase STAT1 This enables opening a new approach to adjuvant treatment in high risk patients which should be more widely explored [52]. Low and intermediate doses have not shown any real benefits in the adjuvant treatment of high risk melanomas (Table 12) [53].…”

Section: Adjuvant Treatment Withmentioning

confidence: 99%

Adjuvant Treatment of Melanoma

Nogueira¹,

Valero²,

Moreno³

2011

Current Management of Malignant Melanoma

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Melanomas represent 4% of all malignant tumors of the skin, yet account for 80% of deaths from skin cancer.While in the early stages patients can be successfully treated with surgical resection, metastatic melanoma prognosis is dismal. Several oncogenes have been identified in melanoma as BRAF, NRAS, c-Kit, and GNA11 GNAQ, each capable of activating MAPK pathway that increases cell proliferation and promotes angiogenesis, although NRAS and c-Kit also activate PI3 kinase pathway, including being more commonly BRAF activated oncogene. The treatment of choice for localised primary cutaneous melanoma is surgery plus lymphadenectomy if regional lymph nodes are involved. The justification for treatment in addition to surgery is based on the poor prognosis for high risk melanomas with a relapse index of 50-80%. Patients included in the high risk group should be assessed for adjuvant treatment with high doses of Interferon-2b, as it is the only treatment shown to significantly improve disease free and possibly global survival. In the future we will have to analyze all these therapeutic possibilities on specific targets, probably associated with chemotherapy and/or interferon in the adjuvant treatment, if we want to change the natural history of melanomas.

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Neoadjuvant Treatment of Regional Stage IIIB Melanoma With High-Dose Interferon Alfa-2b Induces Objective Tumor Regression in Association With Modulation of Tumor Infiltrating Host Cellular Immune Responses

Abstract: Neoadjuvant HDI is highly effective for the treatment of palpable stage IIIB-C melanoma, and the findings of this study implicate an indirect immunomodulatory mechanism rather than a direct antitumor mechanism.

Cited by 229 publications

References 25 publications

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

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

Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival

Adjuvant Treatment of Melanoma

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