Tumor Exome Analysis Reveals Neoantigen-Specific T-Cell Reactivity in an Ipilimumab-Responsive Melanoma
By Nienke van Rooij, Marit M. van Buuren, Daisy Philips, A. Velds, M. Toebes, B. Heemskerk, Laura J A van Dijk, Sam Behjati, H. Hilkmann, Dris el Atmioui and 7 more. Journal of Clinical Oncology, 2013
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The evidence for T-cell–mediated regression of human cancers such as non–small-cell lung carcinoma, renal cell carcinoma, and—in particular—melanoma after immunotherapy is strong. Anti-CTLA4 (ipilimumab) treatment has been approved for treatment of meta-static melanoma,1 and antibody-mediated blockade of PD-1, a second inhibitory receptor on T cells, has shown highly encouraging results in early clinical trials.2,3 Although the clinical activity of these treatments is apparent, it is still unknown which T-cell reactivities are involved in immunotherapy-induced cancer regression.4 T-cell reactivity against nonmutated tumor-associated self-antigens has been analyzed in patients treated with ipilimumab or with autologous tumor-infiltrating T cells, but the magnitude of the T-cell responses observed has been relatively modest.5,6 In part on the basis of such data, recognition of patient-specific mutant epitopes (hereafter referred to as neoantigens) has been suggested to be a potentially important component.7 A potential involvement of mutated epitopes in T-cell control would also fit well with the observation that the mutation load in sun-exposed melanomas is particularly high.8-10 Intriguingly, on the basis of animal model data, it has recently been suggested that (therapy-induced) analysis of T-cell reactivity against patient-specific neoantigens may be feasible through exploitation of cancer genome data.11,12 However, human data have thus far been lacking. Here we report a case of a patient with stage IV melanoma who exhibited a clinical response to ipilimumab treatment. Cancer exome–guided analysis of T-cell reactivity in this patient revealed reactivity against two neoantigens, including a dominant T-cell response against a mutant epitope of the ATR (ataxia telangiectasia and Rad3 related) gene product that increased strongly after ipilimumab treatment. These data provide the first demonstration (to our knowledge) of cancer exome–guided analysis to dissect the effects of melanoma immunotherapy.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/c8b699f838ae2a7b5a40b8e10aa33f41a070d76f
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Citations in the corpus
- Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, background): “Several pre-clinical and clinical reports have described neoantigen-specific T cell responses that direct anti-tumor immunity (Gubin et al., 2014; Hadrup et al., 2009; McGranahan et al., 2016; Tran et al., 2015; van Rooij et al., 2013).”
- Therapeutic cancer vaccines. (2010, background): “Likewise, in a clinical study of patients with metastatic melanoma, clinical benefit from treatment with anti–CTLA-4 was strongly associated with a high mutational load in the patients’ cancer, indicating that the responses to neoantigens that were unleashed by the anti– CTLA-4 treatment were clinic”
- Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis (2016, neutral): “…tumor-specific mutant antigens can be functionally rescued by checkpoint blockade (PD1, PD-L1, CTLA4) or expansion in vitro (Gubin et al., 2014; Lu et al., 2013; Rizvi et al., 2015; Robbins et al., 2013; Snyder et al., 2014; Tran et al., 2014; van Rooij et al., 2013; Wolchok and Chan, 2014).”
- Precision Cancer Medicine: Challenges and Opportunities (2019, methodology): “1975–1977: The first generation Sanger DNA sequencing method was invented [42, 43], which was further optimized and automated over the following decades [10, 12].”