Personalized Immunotherapy Targeting the Cancer Mutanome

Nielsen, Julie S.; Martin, Spencer D.; Nelson, Brad H.

doi:10.1016/b978-0-12-374279-7.17006-7

Cited by 1 publication

(1 citation statement)

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“…Encouragingly, our findings suggest that a higher proportion of mutations can be recognized by autologous T cells than previously thought based on analyses of pre-existing T-cell responses alone (37). For example, in anecdotal studies of melanoma patients who responded well to TIL therapy or ipilimumab, TIL were shown to recognize only about 2% of mutations identified by whole exome sequencing (8,9,38).…”

Section: Discussionmentioning

confidence: 72%

Toward Personalized Lymphoma Immunotherapy: Identification of Common Driver Mutations Recognized by Patient CD8+ T Cells

Nielsen

Sedgwick

Shahid

et al. 2016

Clinical Cancer Research

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Purpose: A fundamental challenge in the era of next-generation sequencing (NGS) is to design effective treatments tailored to the mutational profiles of tumors. Many newly discovered cancer mutations are difficult to target pharmacologically; however, T-cell-based therapies may provide a valuable alternative owing to the exquisite sensitivity and specificity of antigen recognition. To explore this concept, we assessed the immunogenicity of a panel of genes that are common sites of driver mutations in follicular lymphoma, an immunologically sensitive yet currently incurable disease.Experimental Design: Exon capture and NGS were used to interrogate tumor samples from 53 patients with follicular lymphoma for mutations in 10 frequently mutated genes. For 13 patients, predicted mutant peptides and proteins were evaluated for recognition by autologous peripheral blood T cells after in vitro priming.Results: Mutations were identified in 1-5 genes in 81% (43/53) of tumor samples. Autologous, mutation-specific CD8 þ T cells were identified in 23% (3/13) of evaluated cases.T-cell responses were directed toward putative driver mutations in CREBBP and MEF2B. Responding T cells showed exquisite specificity for mutant versus wild-type proteins and recognized lymphoma cells expressing the appropriate mutations.Responding T cells appeared to be from the na€ ve repertoire, as they were found at low frequencies and only at single time points in each patient. Conclusions: Patients with follicular lymphoma harbor rare yet functionally competent CD8 þ T cells specific for recurrent mutations. Our results support the concept of using NGS to design individualized immunotherapies targeting common driver mutations in follicular lymphoma and other malignancies. Clin CancerRes; 22(9); 2226-36. Ó2015 AACR.

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