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We reviewed response to immune checkpoint inhibitors (ICI) of 207 patients with diagnoses of lung or head and neck cancer treated with chemotherapy/ICI combination therapy and ICI monotherapy between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine (Houston, TX). Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority populations and provide equal access to care regardless of means. 174 patients had a diagnosis of lung cancer (non–small cell or small cell) and 33 had a diagnosis of head and neck squamous cell carcinoma (HNSCC). 38% self-identified as Black, 45% as non-Hispanic White, and 18% as Hispanic. The objective response rate (ORR) was similar for patients with lung cancer (35.057%) and HNSCC (30.3%; P = 0.894). The ORR for Hispanic and Black patients was lower compared with non-Hispanic White patients (H 27.0%, B 32.5%, W 38.7%; H vs. W P = 0.209; B vs. W P = 0.398). When considering only patients treated with ICI monotherapy, the ORR for Hispanic patients dropped further to 20.7% while the ORR of Black and non-Hispanic White patients remained about the same (B 29.3% and W 35.9%, H vs. W P = 0.133; B vs. W P = 0.419). Immune-related adverse events were the lowest in the Hispanic population occurring in only 30% of patients compared with 40% of patients in the Black cohort and 50% of the non-Hispanic White cohorts. Significance: To our knowledge, this report is the first to compare ICI effectiveness within a diverse patient population with a substantial Black and Hispanic NSCLC and HNSCC patient population treated in the context of equal access to care. The data presented in this article suggests reduced effectiveness of ICI monotherapy in Hispanic patients and thereby underscores the need for improved access and representation of racial/ethnic minority patients in ICI clinical trials.

Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.

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We reviewed response to immune checkpoint inhibitors (ICI) of 207 patients with diagnoses of lung or head and neck cancer treated with chemotherapy/ICI combination therapy and ICI monotherapy between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine (Houston, TX). Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority populations and provide equal access to care regardless of means. 174 patients had a diagnosis of lung cancer (non–small cell or small cell) and 33 had a diagnosis of head and neck squamous cell carcinoma (HNSCC). 38% self-identified as Black, 45% as non-Hispanic White, and 18% as Hispanic. The objective response rate (ORR) was similar for patients with lung cancer (35.057%) and HNSCC (30.3%; P = 0.894). The ORR for Hispanic and Black patients was lower compared with non-Hispanic White patients (H 27.0%, B 32.5%, W 38.7%; H vs. W P = 0.209; B vs. W P = 0.398). When considering only patients treated with ICI monotherapy, the ORR for Hispanic patients dropped further to 20.7% while the ORR of Black and non-Hispanic White patients remained about the same (B 29.3% and W 35.9%, H vs. W P = 0.133; B vs. W P = 0.419). Immune-related adverse events were the lowest in the Hispanic population occurring in only 30% of patients compared with 40% of patients in the Black cohort and 50% of the non-Hispanic White cohorts.Significance:To our knowledge, this report is the first to compare ICI effectiveness within a diverse patient population with a substantial Black and Hispanic NSCLC and HNSCC patient population treated in the context of equal access to care. The data presented in this article suggests reduced effectiveness of ICI monotherapy in Hispanic patients and thereby underscores the need for improved access and representation of racial/ethnic minority patients in ICI clinical trials.

Background The purpose of this study is to describe human epidermal growth factor 2 (HER2) overexpression in head and neck squamous cell carcinoma (HNSCC) and re-evaluate its potential as a target for HER2-directed immunotherapies. Methods A retrospective cohort of patients with HNSCC receiving curative treatment was identified, and HER2 expression evaluated in archival tissue by immunohistochemistry and correlated with clinicopathological characteristics. HER2 expression data were also determined for HNSCC patients in The Cancer Genome Atlas. Results Nineteen percent of HNSCC and 39% of oropharyngeal HNSCC (OPSCC) were HER2 positive. HER2 expression positively correlated with nodal metastasis (p = 0.035). Patients with HER2-positive tumors had decreased overall survival (p = 0.012), including within the human papilloma virus-positive OPSCC subgroup (p = 0.007). Conclusions A substantial fraction of HNSCC overexpresses HER2 protein, suggesting it may be a suitable target for antigen-directed immunotherapy. HER2 expression and its correlation with survival vary across HNSCC subsites, making it unsuitable as a prognostic marker.

BackgroundMetformin is a commonly used antidiabetic medication which has demonstrated promise as an anticancer agent alone and in combination with conventional treatment regimens. There is increasing evidence that metformin can also generate immunomodulatory effects in solid tumors and is currently being investigated as an adjunct to immune checkpoint inhibitors (ICIs). We hypothesized that metformin would generate a shift in immunity unfavorable to tumor growth and tested this hypothesis in a preclinical model of head and neck cancer.MethodsUsing a syngeneic mouse model of human papillomavirus-associated head and neck cancer (mEER/MTEC), we tested the impact of metformin on systemic and local immunity and tumor growth velocity. We compared the effects of acute and chronic treatment regimens on immunocyte presence and activation using a combination of flow cytometry and targeted transcriptomic analysis.ResultsAcute metformin exposure generated measurable shifts in systemic myeloid and T-cell populations in non-tumor-bearing mice and decreased myeloid derived suppressor cell (MDSC) levels in tumor draining lymph nodes of tumor-bearing mice. Although metformin decreased regulatory T-cell (T-reg) and MDSC levels and increased CD8+ levels in murine tumors when combined with ICIs, acute metformin exposure was insufficient to generate substantial antitumor activity. Conversely, long-term metformin treatment significantly reduced tumor growth velocity, increased the CD8+/T-reg ratio, increased tumor infiltrating lymphocyte levels and upregulated component genes of the previously validated T-cell inflamed expression profile.ConclusionsMetformin generates complex systemic and local immune effects which vary as a function of treatment duration. Combinatorial strategies with ICIs must take into account both the complexity and variability of these effects in order to generate maximal antitumor activity in future clinical trials.

PURPOSE: High-risk oropharyngeal squamous cell carcinoma (OPSCC) associated with tobacco exposure remains difficult to treat due to high rates of locoregional recurrence similar to oral cavity squamous cell carcinoma (OCSCC). Current NCCN guidelines allow for surgical management of this disease, but oncologic and functional data in the modern era remain scarce. We sought to compare and contrast oncologic and functional considerations for surgical management of OPSCC and OCSCC in a cohort of Veterans. MATERIALS AND METHODS: We conducted a retrospective review of patients treated at the Michael E. DeBakey Veterans Affairs Medical Center between 2017 and 2020, treated using a homogenous, multi-modality algorithm. RESULTS: OPSCC tumors presented with a higher rate of perineural invasion (p < 0.05) and extranodal extension (p = 0.02) compared to OCSCC tumors. Compliance with NCCN guidelines for adjuvant treatment were lower for OPSCC patients primarily due to a higher rate of previous irradiation; re-irradiation could be delivered in 75% of patients when recommended by NCCN guidelines. Total glossectomy was accompanied by concomitant total laryngectomy in 100% of OPSCC patients and 0% of OCSCC. CONCLUSION: Surgical resection and free flap reconstruction of high-risk OPSCC generates oncologic outcomes comparable to OCSCC with comparable complication rates but a lower overall functional status. Reconstruction focused on rapid healing allows for high-rates of re-irradiation and minimal treatment delays. Level of evidence: level 4.

Background: Mutational neo-antigens (MuNeoAgs) are attractive targets for cancer vaccines because they are unique to tumors. However, limited epitope potential of point mutations, inherent difficulties predicting immunogenicity, and lack of shared mutations across patient tumors has hindered vaccine development. Alternatively, we elected to identify non-mutated, expression-based tumor-specific neo-antigens (EbNeoAgs) defined by their overexpression in tumors and negligible expression in healthy tissue. EbNeoAgs have a low probability of cross-reactivity, while allowing epitope creation across the entire protein. Additionally, they should be present in a higher proportion of patients and could be used to make modular off-the-shelf vaccines. Methods: RNAseq data from the NIH Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) projects, previously harmonized with a common calling/ mapping algorithm and available from the University of California Santa Cruz TOIL RNAseq recompute project, were used to calculate upper quartile FPKM gene expression values for all samples based on protein coding RNAs. RNAseq data from 27 normal tissue types (excluding testis) from GTEx and TCGA normal tissue was analyzed to identify genes with negligible expression across all healthy tissue. Genes with negligible expression were then analyzed to determine if they were elevated (i.e. expressed at intermediate or higher levels) in samples across 32 different cancer types (excluding testicular tumors). Thresholds for intermediate expression were calculated individually for each tumor type based upon the median FPKM expression values for all protein coding genes with 95% confidence intervals. Results: 1296 genes were expressed below threshold in all healthy tissues, and 107 of these genes were elevated in 5% or more of samples in at least one cancer. 40/107 EbNeoAgs (37%) are known Cancer Testis Antigens (CTAs), with the remaining 67 representing potentially novel EbNeoAgs. If the threshold for elevated expression is lowered to just 1% of samples for at least one cancer, 58 of the known 276 CTAs are detected. The remaining CTAs are overexpressed in at least one healthy tissue or were not elevated in cancer. In melanoma (cancer with the most EbNeoAgs), 53 (52.0%), 69 (67.6%), and 88 (86.3%) samples expressed at least 5, 3, or 1 EbNeoAg respectively. Comparatively, in lung adenocarcinoma, 81 (15.8%), 97 (18.9%), and 228 (44.4%) samples expressed at least 5, 3, or 1 EbNeoAg respectively. Conclusion: We leveraged publicly available tumor and normal RNAseq datasets to comprehensively identify EbNeoAgs in an unbiased fashion across 32 tumor types. Many of the EbNeoAgs were known CTAs, but a significant number of EbNeoAgs were novel. Approximately half the cancers exhibited EbNeoAg expression in a large proportion of patients making them broad targets for cancer vaccine development. Citation Format: Jan O. Kemnade, Maria Cardenas, David Wheeler, Andrew G. Sikora, Mitchell J. Frederick. Comparative mining of normal and tumor tissue RNAseq gene expression datasets to define expression-based neo-antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 567.