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Original Article Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma Alexandra Snyder, M.D., Vladimir Makarov, M.D. Microsoft Office 2007 Pro Torrent France more. , Taha Merghoub, Ph.D., Jianda Yuan, M.D., Ph.D., Jesse M. Zaretsky, B.S., Alexis Desrichard, Ph.D., Logan A.

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Chan, M.D., Ph.D. N Engl J Med 2014; 371:2189-2199 DOI: 10.1056/NEJMoa1406498. Results Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing.

A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti–CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab. Immune checkpoint blockade has led to durable antitumor effects in patients with metastatic melanoma, non–small-cell lung cancer, and other tumor types, but the factors determining whether a patient will have a response remain elusive.

The fully human monoclonal antibodies ipilimumab and tremelimumab block cytotoxic T-lymphocyte antigen 4 (CTLA-4), resulting in T-cell activation. Some studies have established correlations between outcomes with ipilimumab and peripheral-blood lymphocyte count, markers of T-cell activation, an “inflammatory” microenvironment, and maintenance of high-frequency T-cell receptor clonotypes. The relationship among the genomic landscape of the tumor, the mutational load, and the benefit from treatment remains obscure. The immunogenicity resulting from nonsynonymous melanoma mutations has been shown in a mouse model, and the antigenic diversity of human melanoma tumors has been modeled in silico and in melanoma-specific CD8 T-cell responses after treatment with ipilimumab. Effector and helper T-cell function and regulatory T-cell depletion are necessary for the efficacy of CTLA-4 blockade, but there is not an association between a specific HLA type and a clinical benefit. Melanomas have very high mutational burdens (0.5 to >100 mutations per megabase) as compared with other solid tumors. Elegant studies have shown that somatic mutations can give rise to neoepitopes and that these may serve as neoantigens.

We conducted a study to determine whether the genetic landscape of a tumor affects the clinical benefit provided by CTLA-4 blocking agents. Tierra Nueva Font Free Download on this page. Sample Acquisition and DNA Preparation For the discovery set, we conducted whole-exome sequencing of DNA from tumors and matched normal blood from 25 ipilimumab-treated patients. A validation set included an additional 39 patients, of whom 5 were treated with tremelimumab.

Primary tumor samples and matched normal peripheral-blood specimens were obtained after the patients had provided written informed consent. DNA was extracted, and exon capture was performed with the use of the SureSelect Human All Exon 50-Mb kit (Agilent Technologies).

Foxconn Lan Driver Windows Xp more. Enriched exome libraries were sequenced on the HiSeq 2000 platform (Illumina) to provide a mean exome coverage of more than 100× (Memorial Sloan Kettering Cancer Center Genomics Core and Broad Institute). Mutational Landscape of Melanomas from the Study Patients Baseline patient characteristics are shown in Table 1 Clinical Characteristics of the Patients in the Discovery and Validation Sets, According to Clinical Benefit from Therapy. (for more detailed information, see Tables S1 and S2 in the ).