Tumor-specific mutations can generate neoantigens that drive CD8 T cell responses against cancer. Next-generation sequencing and computational methods have been successfully applied to identify mutations and predict neoantigens. However, only a small fraction of predicted neoantigens are immunogenic. Currently, predicted peptide binding affinity for MHC-I is often the major criterion for prioritizing neoantigens, although little progress has been made toward understanding the precise functional relationship between affinity and immunogenicity. We therefore systematically assessed the immunogenicity of peptides containing single amino acid mutations in mouse tumor models and divided them into two classes of immunogenic mutations. The first comprises mutations at a nonanchor residue, for which we find that the predicted absolute binding affinity is predictive of immunogenicity. The second involves mutations at an anchor residue; here, predicted relative affinity (compared with the WT counterpart) is a better predictor. Incorporating these features into an immunogenicity model significantly improves neoantigen ranking. Importantly, these properties of neoantigens are also predictive in human datasets, suggesting that they can be used to prioritize neoantigens for individualized neoantigen-specific immunotherapies.

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BACKGROUND Diffuse low-grade gliomas (DLGGs, WHO Grade II gliomas) comprise 13-16% of all primary brain tumors. Although there has been a paradigmatic shift toward upfront maximal safe resection (MSR) for these heterogeneous tumors, it is important to consider the health economic perspective of this approach, compared with the traditional watch-and-wait approach, as well. OBJECTIVE To conduct a systematic review of the health economic literature on the range of DLGG management options. METHODS Following the PRISMA guidelines, Medline, EMBASE, The Central Registration Depository (CRD), EconPapers, and EconLit were searched for ‘cost-effectiveness’, ‘health economics’ and ‘Low-grade glioma’. Grade I tumors were excluded. Pre-specified variables were extracted. All currencies were converted to USD. RESULTS Among 258 abstracts, 28 were selected for full-text screening, and 3 were selected for this review. A European study evaluated the role of intraoperative electrical stimulation (IES). Although IES was associated with higher direct costs upfront ($38,662.70 vs $32,116.10), this was offset by less long-term indirect costs ($12,222.30 vs $31,927.10; p=0.023), greater QALY (4.8 vs 2.9; p=0.001), and an incremental cost-effectiveness ratio (ICER) of $1,842.50. Another study evaluated the cost-effectiveness of adjuvant PCV+RT vs RT alone, finding greater QALY for the former (9.94 vs 5.17) and an ICER of $10,186 per QALY gained. A third study evaluated the cost-effectiveness of adding 18F-fluoroethyl-L-tyrosine (FET) PET to MRI, compared to preoperative MRI alone. This resulted in an ICER of $7,193.58 for the baseline scenario (lowest reimbursement) and $10,236.12 for the morbidity-adjusted reimbursement rate scenario (highest reimbursement). There were no studies evaluating the health economics of maximal upfront surgical resection to the watch-and-wait approach. CONCLUSION We found a limited number of studies reporting on the health economics of DLGGs. Given the paradigmatic transition toward more aggressive upfront surgical resection, DLGG-specific health economic analyses are underway.

In 2015, an estimated 59,340 people will develop head and neck cancer and an estimated 12,290 deaths will occur. Recent evidence has demonstrated that the immune system plays a key role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). Here, we conduct comprehensive immune profiling to better understand the immunophenotype of HNSCC patients, assess the applicability of immune-modulatory drugs, and identify prognostic biomarkers of response to cetuximab treatment. Our systems immunology approach is composed of three complimentary, high-dimensional technologies: time-of-flight mass cytometry (CyTOF), luminex, and the HIMChip microarray platform. Mass cytometry quantifies protein expression on a single-cell basis by utilizing transition element, isotope-tagged antibodies. The Luminex immunoassay measures plasma cytokine levels. The “HIMChip” microarray is a custom Agilent SurePrint HD 8×15k format array containing over 7,000 unique probes for over 4,274 human immune-related genes. We employed these technologies to study the global immune status of thirty HNSCC patients receiving treatment with cetuximab, an IgG1 monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR). Patients were consented to participate on the Phase 0 biomarker-focused clinical trial (NCT01114256) and peripheral blood was obtained before and after cetuximab treatment. Peripheral blood mononuclear cells and plasma were isolated from each time point and utilized in downstream analysis. Via manual gating, our CyTOF-based phenotyping measured 24 distinct populations and the expression of 5 activation markers and 5 checkpoint receptors. The results of manual gating were confirmed with an automated, unsupervised algorithmic analysis combining stochastic neighbor embedding and k-means clustering. The resulting 2D representation of our single-cell data preserved global geometries and facilitated exploration of unique subsets within the natural killer (NK) compartment. To assess the prognostic value of these NK cell subsets, we applied a lasso-regularized logistic regression model to stratify patients based on their clinical response to cetuximab therapy. We identified an NK cell subset that is associated with clinical benefit to therapy. Luminex analysis revealed a cetuximab-induced cytokine signature composed of VCAM1, IP-10, and VEGFD that may play a role in increasing NK cell trafficking to tumor (T-statistics of 1.77, 2.17, and 1.55 respectively). The HIMChip microarray results support our proteomic findings. These results provide the first known comprehensive immune profiling of HNSCC patients as they undergo treatment with cetuximab. Validation in a large cohort of patients is needed and future mechanistic studies will investigate the efficacy of our novel NK cell population in disease control. Citation Format: Cariad Chester, Ajay Fernandez, Atsushi Yonezawa, Xing Zhao, Naren Rajasekaran, Holbrook Kohrt. A systems immunology analysis to detect prognostic biomarkers in patients with squamous cell carcinomas of the head and neck. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1401.