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Introduction Thyroid dysfunction is the most frequent endocrine immune related adverse event (irAE) in non-small cell lung cancer (NSCLC), typically arising 3–6 months into immune checkpoint inhibitor (ICI) therapy, but arising after ICI cessation, in some cases. Due to limited post-treatment adverse event reporting requirements on ICI trials, the incidence of ICI-induced thyroid dysfunction arising after therapy is unclear. We investigated ICI-induced thyroid dysfunction in a cohort of 294 NSCLC patients, with a specific focus on the post-treatment setting. Methods Retrospective analysis of ICI-induced thyroid dysfunction (clinically acted upon or laboratory only) was performed in 294 UCLA NSCLC patients treated 2012–2018. Clinically acted upon thyroid dysfunction was defined as thyroid diagnosis documentation and/or thyroid medication administration. Laboratory only dysfunction was defined as abnormal thyroid labs in the absence of clinical action. Timing of thyroid dysfunction relative to ICI treatment and thyroid monitoring patterns were also assessed. Results 82% (241/294) of ICI treated NSCLC patients had thyroid labs during treatment. Of these 241 patients, 13% (31/241) had clinically acted upon thyroid dysfunction prior to, 8% (18/241) during, and 4% (9/241) after ICI. Most patients, 66% (159/241), did not have thyroid labs after ICI, but in the 53 patients with labs and no prior clinical dysfunction, 17% (9/53) developed clinical dysfunction after ICI. In these 9 patients, median time from ICI initiation to dysfunction was 253 days. Two patients with post-treatment laboratory only dysfunction were observed. Conclusions ICI-induced thyroid dysfunction arising post-treatment appears more common than previously appreciated, warranting additional evaluation.

Aim: There is an unmet need for predictive biomarkers for immune checkpoint blockade in ovarian cancer. Homologous recombination deficiency (HRD) and immunoreactive molecular subtype may be associated with determinants of immunogenicity. Materials & methods: Neoantigen load, tumor inflammation signature (TIS), immune cell infiltrates and individual immune checkpoints were assessed based on HRD status and molecular subtype. Results: Tumors with HRD demonstrated significantly higher expression of neoantigens and multiple immune check points, but not higher TIS scores or increased immune cell infiltrates. Immunoreactive tumors had significantly higher neoantigen expression, TIS scores, immune cell infiltrate and immune checkpoint expression compared with other subtypes. Conclusion: HRD and the immunoreactive molecular subtype signature were associated with multiple determinants of immunogenicity and deserve further exploration as predictive biomarkers.

Immune check point blockade (ICB) has recently transformed the treatment of non-small cell lung (NSCLC). However, the majority of patients do not respond to ICB. For ICB to be effective, tumor neoantigens need to be presented in a human leukocyte antigen (HLA) class I-restricted manner. Recent studies by our group and others have shown that HLA-B44 supertype is associated with extended survival in patients treated with ICB. Herein, we hypothesize that HLA-B44-specific motif neoepitopes generate an active tumor immune microenvironment and a favorable ICB response in NSCLC. Utilizing the TCGA database, we found that nearly half of the NSCLC patients have at least one HLA-B44 allele, of whom 36.8% and 37.3% of patients harbor at least one B44 motif neoepitope in lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC), respectively. In a pooled analysis of patients with LUAD and LUSC, gene expression of PD-L1, CTLA-4, LAG-3, CXCL9, CXCL10, CXCL13, CD8A and cytolytic gene signature (includes GZMA and PRF1) is elevated in patients with B44 motif neoepitopes compared to those without motif neoepitopes. Immune cell component analysis showed increased infiltration of Th1, Th2 and CD8 T cells in LUAD and regulatory and CD8 T cells in LUSC. Although a linear regression model revealed a positive correlation between tumor mutational burden (TMB) and number of B44 motif neoepitopes, pooled analysis of LUAD and LUSC with similar TMB showed significant elevation of CTLA-4, LAG3, CXCL10 and a trend of increased expression of CXCL9 in motif patients. Upon investigation of possible immune editing, we found a significantly higher proportion of genes containing B44 neoepitope downregulated at the RNA level both in LUAD and LUSC. Lastly, we showed that combining B44 motif with either PD-L1 or TMB improved prediction of progression-free survival in NSCLC patients treated with ICB. In summary, we demonstrate that HLA-B44 motif neoepitopes are associated with a favorable tumor immune microenvironment and can serve as a potential biomarker for ICB benefit in NSCLC patients. Citation Format: Rui Li, Charlene M. Fares, Tristan R. Grogan, Tianhao Zhang, Debory Li, Matthew Theisen, Maria A. Velez, Paige M. Brodrick, Jackson P. Lind-Lebuffe, Yazeed Radwan, Gregory A. Ayzenberg, David Elashoff, Bin Liu, Aaron E. Lisberg, Amy L. Cumming, Edward B. Garon. HLA-B44 motif neoepitope is associated with a favorable tumor immune microenvironment and predicts ICB response in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4340.

Identifying patients who respond to immune checkpoint blockade (ICB) is a significant challenge in oncology. While PD-L1 expression by immunohistochemistry (IHC) is the current diagnostic gold standard for patient selection, it nevertheless does not capture all patients who may respond to ICB. Recent gene expression studies in high-grade serous ovarian carcinoma have defined an immunoreactive molecular subtype that has a measurable difference in patient survival compared with non-immunoreactive subtypes, but no studies have yet demonstrated its impact on predicting response to ICB. As a step toward establishing the predictive value of gene expression classifiers in ICB, we assessed the relationship between PD-L1 IHC and molecular subtypes of ovarian epithelial cancer. This was done by analyzing a total of 93 tissue specimens from patients with stage III and IV disease, and comparing PD-L1 IHC with gene expression by Agilent microarrays using TCGA-defined subtypes. We showed that ovarian tumors with elevated IHC PD-L1 expression are most strongly associated with immunoreactive subtype as compared with other molecular subtypes, reaching statistical significance against differentiated (Dunn’s test, 33.39, p = 0.0003) and mesenchymal (39.63, p

The emergence of immune checkpoint blockade therapies over the last decade has transformed cancer treatment in a wide range of tumor types. Unprecedented and durable clinical responses in difficult-to-treat cancer histologies have been observed. However, despite these promising long-term responses, the majority of patients fail to respond to immune checkpoint blockade, demonstrating primary resistance. Additionally, many of those who initially respond to treatment eventually experience relapse secondary to acquired resistance. Both primary and acquired resistance are a result of complex and constantly evolving interactions between cancer cells and the immune system. Many mechanisms of resistance have been characterized to date, and more continue to be uncovered. By elucidating and targeting mechanisms of resistance, treatments can be tailored to improve clinical outcomes. This review will discuss the landscape of immune checkpoint blockade response data, different resistance mechanisms, and potential therapeutic strategies to overcome resistance.

Introduction Tyrosine kinase inhibitors (TKI) targeting epidermal growth factor receptor (EGFR) are approved for use in metastatic non-small cell lung cancer (NSCLC). Case presentation Here we present a case of a African American patient with stage IIIA NSCLC treated with osimertinib in the neoadjuvant setting with concurrent radiation, followed by resection. The patient remains disease-free 4 months after surgery. Conclusion This case report suggests that osimertinib may be effective as neoadjuvant therapy in resectable stage III disease. Additionally, we provide a summary of previous case reports and ongoing clinical trials for neoadjuvant EGFR inhibition in stage III NSCLC patients.

Human leukocyte antigen (HLA)-B has been recognized as a major determinant of discrepancies in disease outcomes, and recent evidence indicates a role in immune checkpoint blockade (ICB) efficacy. The B44 supertype, which features an electropositive binding pocket that preferentially displays peptides with negatively charged amino acid anchors, is associated with improved survival in ICB-treated melanoma. Yet this effect was not seen in ICB-treated non-small-cell lung cancer (NSCLC). Here we show that mutations leading to glutamic acid substitutions occur more often in melanoma than NSCLC based on mutational landscape. We additionally show stratifying B44 based on the presence of somatic mutations that lead to negatively charged glutamic acid anchors identifies patients with NSCLC with an ICB benefit similar to that seen in melanoma. We anticipate these findings could improve assessment of HLA-related outcomes and prediction of ICB benefit in those with B44, representing approximately half of the world’s population. Garon and colleagues demonstrate that the association of HLA supertype B44 with response to immune checkpoint blockade in melanoma but not NSCLC is related to differential mutational features that influence HLA binding of neoepitopes.

Purpose of review Immune checkpoint blockade (ICB) is a promising area of cancer therapeutic research. Therapies targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) mechanism of tumor immune evasion have resulted in durable responses in many difficult-to-treat tumor types. While these inhibitors are being actively investigated in clinical trials for ovarian cancer, most patients fail to respond to initial treatment with immune therapy. This review focuses on biomarkers for predicting response to treatment, and discusses clinical trials using ICB for recurrent ovarian cancer. Recent findings While PD-L1 detection by immunohistochemistry (IHC) is approved as a companion or complementary diagnostic in some cancers, there are many limitations with its use as a predictive marker. Recent research has explored biomarkers beyond PD-L1 that assess for somatic mutations, immune cell infiltrate, and gene signatures. Summary With improved understanding of the tumor microenvironment and genomic classifications of ovarian tumors, new diagnostics and biomarkers that supplement conventional IHC may help predict response to therapy.

5536 Background: Immune checkpoint blockade (ICB) is being explored as a treatment option in ovarian cancer, but objective response rates for single agent ICB are modest at around 10-15%. Validated biomarkers are needed to predict which patients will respond to ICB. BRCA mutations and homologous recombination deficiency (HRD) status are the only validated integral biomarkers in ovarian cancer. HRD tumors exhibit defective DNA repair mechanisms that promote increased mutational burden, which we postulate may correlate with higher neoantigen load and increased expression of targetable immune checkpoints. Methods: The Cancer Genome Atlas (TCGA) ovarian cancer dataset was evaluated and previously published, well annotated samples were obtained for HRD status. HLA type was determined with OptiType. Nonsynonymous mutations were annotated with Ensembl VEP. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 amino acids in length for MHC class I, reporting only those with a predicted IC50 less than 500 nM. Immune checkpoint gene expression counts were normalized with TCGAbiolinks. Correlation between HRD status and neoantigen load was assessed by Wilcoxon test. After log2 transformation, Wilcoxon tests evaluated for association between HRD status and expression of immune checkpoints. The relationship between HRD status and PD-L1 protein abundance with reverse phase protein array was measured. Results: Data from 154 HRD positive and 198 HRD negative tumors were analyzed. HRD positive status correlated with higher neoantigen load (p = 0.038) and increased expression of the immune checkpoints CTLA4 (p = 0.024), TIGIT (p = 0.027), and PVR (p = 0.002), but not PD-L1 (p = 0.238), LAG3 (p = 0.583), HVEM (p = 0.805), GAL9 (p = 0.750), NECTIN2 (p = 0.874), VSIG3 (p = 0.438), PSGL1 (p = 0.205) or VISTA (p = 0.531). TIM3 (p = 0.064) and B7H3 (p = 0.052) both demonstrated a trend towards increased expression in HRD tumors. Interestingly, HRD status showed a negative association with PVRIG (p = 0.028). There was no association between PD-L1 protein abundance and HRD status. Conclusions: HRD positive ovarian tumors demonstrate higher neoantigen load than HRD negative tumors, as well as increased expression of certain immune checkpoints. This supports the hypothesis that increased neoantigen load leads to compensatory induction of immune checkpoints, and suggests that HRD status may predict response to ICB, particularly to drugs that target CTLA4, TIGIT, PVR, TIM3 and B7H4.

Purpose Health care research increasingly relies on assessment of data extracted from electronic medical records (EMRs). Clinical trial adverse event (AE) logs and patient-reported outcomes (PROs) are sources of data often available in the context of specific research projects. The aim of this study was to evaluate the extent of data concordance from these sources. Patients and Methods Patients enrolled in clinical trials or receiving standard treatment for lung cancer (n = 62) completed validated questionnaires on physical and psychological symptoms at up to three assessment points. Temporally matched documentation was extracted from EMR notes and, for clinical trial participants (n = 41), AE logs. Evaluated data included symptom assessment, vital signs, medication logs, and laboratory values. Agreement (positive, negative) and Cohen’s κ coefficients were calculated to assess concordance of symptoms among sources, with PROs considered the gold standard. Results Patient-reported weight loss correlated significantly with clinical measurements ( t = 2.90; P = .02), and average number of PROs correlated negatively with albumin concentration, supporting PROs as the gold standard. Comparisons of PROs versus EMR yielded poor concordance across 11 physical symptoms, anxiety, and depressive symptoms (all κ < 0.40). Providers under-reported the presence of each symptom in the EMR compared with PROs. AE logs showed similarly poor concordance with PROs (all κ < 0.40, except shortness of breath). Negative agreement among sources was higher than positive agreement for all symptoms except pain. Conclusion There was poor concordance between EMR notes and AE logs with PROs. Findings suggest that EMR notes and AE logs may not be reliable sources for capturing physical and psychological symptoms experienced by patients with lung cancer, supporting use of PRO assessments in oncology practices.

Purpose: Immune checkpoint blockade (ICB) has revolutionized treatment of melanoma and lung cancer. Recent evidence suggests that human leukocyte antigen (HLA) B supertype influences efficacy of ICB. HLA-B27 and B44 supertypes have electronegative and electropositive binding pockets, respectively, and preferentially bind and display oppositely charged neoepitopes. We sought to evaluate the relationship between baseline immune activation and charged neoepitopes in the context of oppositely charged HLA-B binding pockets. Methods: Datasets from a total of 466 MEL and 513 LUAD patients included in the TCGA were used. HLA type was obtained with OptiType. Nonsynonymous mutations were annotated with SnpEff, Ensembl VEP, and VAtools. Only transcribed variants were filtered for analysis. pVAC-Seq using NetMHCpan algorithm predicted nonamer neoepitopes. Favorable B27 neoepitopes were defined as having new positively charged amino acid (AA) substitutions (H/K/R) from oppositely charged or uncharged wildtype AA, while neoepitopes with new negatively charged AAs (D/E) were considered favorable for B44. Three gene signatures were evaluated with normalized RNA expression values from 14 antigen presentation, 15 immunostimulator, and 11 immunoinhibitor genes. Linear regression tests were performed between gene expression values and fraction of nonsynonymous mutations resulting in neoepitopes with new positively and negatively charged AAs. Paired t-tests were performed between the mean of Pearson's r for fraction of new positively versus negatively charged AAs compared to gene expression values, and subsetted to B27/B44. Heterozygotes for B27/B44 were excluded from analysis to avoid competing charges. Results: 26.4% and 48.7% of MEL patients had B27 and B44, respectively. In LUAD, 28.6% had B27 and 47.2% had B44. Of new charged AAs resulting from nonsynonymous mutations, 72.6% in MEL and 75.0% in LUAD were positively charged (p=0.0053). In MEL, difference in Pearson's r values between fraction of new positively and negatively charged AAs as compared to immunostimulator (B27 p=.016; B44 p Conclusion: Immune gene signatures showed association with neoepitopes that have oppositely charged AAs than their HLA-B binding pocket in both MEL and LUAD, indicating that presentation of favorable neoepitopes stimulates an immune response. The association was limited to B27 in LUAD and strongest for B44 in MEL. Citation Format: Charlene M. Fares, Amy L. Cummings, Matthew K. Theisen, Nicholas Hornstein, Jaklin Gukasyan, Wisdom Akingbemi, Debory Li, Paige Brodrick, Aaron Lisberg, Edward B. Garon. Association between immune gene signatures and neoepitopes with electrostatic charge opposite to their HLA-B binding pocket in melanoma (MEL) and lung adenocarcinoma (LUAD) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6614.

3083 Background: Recent evidence suggests efficacy of immune checkpoint blockade may be influenced by human leukocyte antigen (HLA)-B. HLA-B27 supertype has an electronegative binding pocket which favorably binds and displays neoepitopes harboring positively charged amino acids (AAs). Based on immune surveillance, we postulate that B27 tumors that have favorable neoepitopes should face negative selective pressure, and B27 tumors with favorable neoepitopes that develop could be more likely to upregulate immune escape mechanisms. Here we evaluate the relationship between prevalence of B27 and positively charged neoepitopes and assess association between positively charged neoepitopes and expression of PD-L1. Methods: TCGA datasets from head and neck squamous cell (HNSC), lung squamous cell (LUSC), and melanoma (SKCM) patients were evaluated. HLA alleles were determined with OptiType and supertype was based on 2008 criteria. Nonsynonymous mutations were annotated with Ensembl VEP and VAtools. pVAC-Seq using NetMHCpan algorithm predicted neoepitopes 9 AAs in length. Favorable B27 neoepitopes were defined as those having new positively charged AA substitutions (H/K/R) from negative or uncharged wildtype AAs. RNA-seq data for the PD-L1 gene were normalized on transcripts per million and log2 transformed. Linear regression tests were performed between PD-L1 gene expression values and fraction of nonsynonymous mutations resulting in neoepitopes with new positively charged AAs in patients with B27. Results: Data from 497 HNSC, 494 LUSC, and 468 SKCM patients were analyzed. B27 was observed in 20.1%, 23.2%, and 26.5% of HNSC, LUSC, and SKCM patients, respectively, with a significant difference seen between HNSC and SKCM by chi-square test (χ² = 5.14, p = .023). Of new charged AAs resulting from nonsynonymous mutations, 76.3% in HNSC, 74.0% in LUSC, and 72.0% in SKCM were positively charged (p < .05 between all histologies, paired t-tests). In B27 patients, association between PD-L1 gene expression and fraction of neoepitopes with new positively charged AAs was seen in HNSC (r = 0.25 p = .036) and SKCM (r = 0.30 p = .007), but not LUSC (r = -0.12 p = .296). Conclusions: With increasing fraction of positively charged neoepitopes, a decrease in prevalence of B27 was observed, suggesting improved binding and immune elimination of tumors with favorable neoepitopes. In B27 tumors that develop despite having favorable neoepitopes, upregulation of PD-L1 could be a putative mechanism to evade immune detection.