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Constitutional Mismatch Repair Deficiency Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
In addition, CMMRD tumors often contain mutated microsatellites in gene-encoding regions, leading to frameshifts and subsequent production of truncated and functionally inactive proteins that may be further processed into mutanome-derived epitopes (so called neoantigens). Increased amounts of neoantigens in CMMRD tumors render them readily recognized by cytotoxic T lymphocytes. Development of neoantigen-loaded cell vaccinations therefore offers another valuable approach for countering CMMRD tumors [30–32].
Precision medicine in oncology: An overview
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Fazilet Yılmaz, Sultan Ciftci Yılmaz, Esra Gunduz, Mehmet Gunduz
A mutanome is used to describe total mutations in tumor cells and is also known as patient centered tumor vaccination. It is a new treatment approach using the body's own defense system to eliminate tumor cells and it is specifically designed for each patient's tumors (Kuhn et al., 2011).
Immunotherapy strategies for mesothelioma – the role of tumor specific neoantigens in a new era of precision medicine
Published in Expert Review of Respiratory Medicine, 2019
Linda Ye, Shaokang Ma, Bruce W. Robinson, Jenette Creaney
This is a novel treatment approach still in the very early phases of development. Translating this concept into clinical practice requires optimization of the various steps involved in neoantigen detection and prediction, and in the vaccine manufacturing process. As evidenced by recent studies, only a small fraction of tumor specific mutations is immunogenic and therefore refinement of the antigen selection process is critical to improve therapeutic efficacy and reduce unnecessary cost. More sensitive high throughput gene sequencing technologies are needed to allow comprehensive evaluation of a tumor’s mutanome. Also, better bioinformatic prediction tools are needed to prioritize neoantigens with higher accuracy and reduce the rate of ‘false positives’. In addition, lead times from sample acquisition for gene sequencing and neoantigen prediction to a ready-to-use vaccine must be achievable in a clinically relevant timescale and allow timely treatment of patients with an aggressive cancer.
Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models
Published in OncoImmunology, 2018
Vassilis Genoud, Eliana Marinari, Sergey I Nikolaev, John C. Castle, Valesca Bukur, Pierre-Yves Dietrich, Hideho Okada, Paul R. Walker
Further evidence for low immunogenicity could be reflected by low infiltration by immune cells, as we show for SB28 in this study. In comparison, T-cell infiltration in human GBM is highly variable and reported to be undetectable by immunohistochemistry in around 20% of patients.20 However, the overall importance of immune infiltration will likely depend upon localization and subset representation, for example, low CD8+/high CD4+ T-cell infiltration was associated with a worse prognosis.45 Moreover, the presence of immunosuppressive cells and molecules will undoubtedly play a role. Indeed, analysis of SB28 tumor ex vivo by RNA-sequencing revealed expression of multiple potentially immunosuppressive molecules (PDL1, CD80, B7H3, GAL9, CD155 and TGFβ), and flow cytometry analysis of infiltrating immune cells showed presence of Tregs (Supplementary Figure S3 and data not shown). The in vivo microenvironment did influence the expressed mutanome of SB28, since ex vivo profiling indicated a different number of mutations and neoepitopes from the line analyzed in vitro and that analyzed ex vivo (108 vs. 132 expressed mutations), with a common core of mutations found from the two analyses (data not shown). To fully understand whether this in vivo reshaping of the mutanome is due to immune pressure or other mechanisms would require further study.
Enhanced protection of C57 BL/6 vs Balb/c mice to melanoma liver metastasis is mediated by NK cells
Published in OncoImmunology, 2018
Friedrich Foerster, Sebastian Boegel, Rosario Heck, Geetha Pickert, Nina Rüssel, Sebastian Rosigkeit, Matthias Bros, Stephanie Strobl, Leonard Kaps, Misbah Aslam, Mustafa Diken, John Castle, Ugur Sahin, Andrea Tuettenberg, Ernesto Bockamp, Detlef Schuppan
One reason for the failure of checkpoint inhibitors in the treatment of some melanoma patients is a (strongly) reduced immunogenicity of the respective melanoma cells which prevents the induction of an effective adaptive immune response. Moreover, the immune system of the liver is usually primed for tolerance, e.g., towards neoantigens derived from nutrition.8 In order to better understand the insufficient immune response to low immunogenic melanoma liver metastasis, we have employed the B16F10 cell line which has been derived from the melanoma of a C57 BL/6 mouse and which displays a highly metastatic potential in immunocompetent syngeneic mice.9 This cell line has been used successfully for modeling human melanoma metastasis to skin and lung, and for anti-cancer drug development,10-13 whereas liver metastasis has been little studied.14,15 Since the B16F10 cell line has a very low expression of MHC class I molecules,16 it is predestined for studying the immunology of low immunogenic melanoma and cancer in general. An example is a recent analysis exploring a mutanome-based individualized peptide immunization which achieved in vivo tumor control in tumor transplant models.17