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Esophageal adenocarcinoma (EAC) is a leading cause of cancer-related mortality. Sitravatinib is a novel multi-gene tyrosine kinase inhibitor (TKI) that targets tumor-associated macrophage (TAM) receptors, VEGF, PDGF and c-Kit. Currently, sitravatinib is actively being studied in clinical trials across solid tumors and other TKIs have shown efficacy in combination with immune checkpoint inhibitors (ICI) in cancer models. In this study, we investigated the anti-tumor activity of sitravatinib alone and in combination with PD-1 blockade in an EAC rat model. Treatment response was evaluated by mortality, pre- and post-treatment MRI, gene expression, immunofluorescence and immunohistochemistry. Our results demonstrated adequate safety and significant tumor shrinkage in animals treated with sitravatinib, and more profoundly, sitravatinib and PD-1 inhibitor, AUNP-12 (P  < 0.01). Suppression of TAM receptors resulted in increased gene expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines, enhanced infiltration of CD8+ T cells, and M2 to M1 macrophage phenotype repolarization in the tumor microenvironment of treated animals (P  < 0.01). Moreover, endpoint immunohistochemistry staining corroborated the anti-tumor activity by downregulation of Ki67 and upregulation of Caspase-3 in the treated animals. Additionally, pretreatment gene expression of TAM receptors and PD-L1 were significantly higher in major responders compared with the non-responders, in animals that received sitravatinib and AUNP-12 (P  < 0.02), confirming that TAM suppression enhances the efficacy of PD-1 blockade. In conclusion, this study proposes a promising immunomodulatory strategy using a multi-gene TKI to overcome developed resistance to an ICI in EAC, establishing rationale for future clinical development. [ABSTRACT FROM AUTHOR]

BACKGROUND. Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown. METHODS. To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n = 12) and without CIP (n = 6), prior to initiating first-line therapy for CIP (high-dose corticosteroids). We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis, and BAL supernatant cytokine measurements. RESULTS. We found increased BAL lymphocytosis, predominantly [CD4.sup.+] T cells, in patients with CIP. Specifically, we observed increased numbers of BAL central memory T cells, evidence of type I polarization, and decreased expression of cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 in BAL Tregs, suggesting both activation of proinflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1[beta] and decreased expression of counterregulatory interleukin-1 receptor antagonist. We observed increased levels of T-cell chemoattractants in the BAL supernatant, consistent with our proinflammatory, lymphocytic cellular landscape. CONCLUSION. We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune-related adverse event. FUNDING. NIH, Department of Defense, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy., Introduction With recent clinical trials demonstrating clear efficacy for immunotherapy in patients with locally advanced and advanced-stage non-small-cell lung cancer (NSCLC) as well as other tumors, the use of immune [...]

Simple Summary: Gastric and esophageal cancers represent a global health concern with considerable associated morbidity and mortality. The management of these malignancies was historically limited to chemotherapy, radiotherapy and surgery. More recently, immunotherapies, which can harness the immune system to treat cancer, have become an established treatment option in many cancer types. This article presents the existing evidence for the use of immunotherapies in gastric and esophageal cancers that are localized to one area or that have spread to other areas. It considers challenges in terms of the use of these agents and also discusses immune-based treatments that are currently under investigation in this area which may potentially change treatment practices in the future. Background: Gastroesophageal cancers (GECs) carry considerable morbidity and mortality, and demonstrate geographical histological variances in addition to molecular heterogeneity. Consequently, the immunogenicity of the different subtypes, which can predict the likelihood of immunotherapy response, can vary. Immune checkpoint inhibitor (ICI) therapy has transformed the treatment of many cancer types over the past decade but has been slower to gain a foothold in the treatment paradigm of GECs. Methods: This article reviews the existing evidence and use approvals for immunotherapies and immune-based treatments in GECs, in the neoadjuvant, adjuvant and metastatic disease settings. The challenges of and limitations to ICI application in current clinical practice are examined. Ongoing clinical trials and future directions of research are also considered. Conclusion: ICI therapy has become an established treatment option within GECs, both perioperatively and in advanced disease. However, nuances in terms of its use are not yet fully understood. Ongoing research proposes to broaden the application of immunotherapies in GECs with the potential to continue to improve outcomes. [ABSTRACT FROM AUTHOR]

A detailed understanding of the molecular and immunological changes that occur longitudinally across tumors exposed to immune checkpoint inhibitors is a significant knowledge gap in oncology. To address this unmet need, we created a statewide biospecimen collection and clinical informatics system to enable longitudinal tumor and immune profiling and to enhance translational research. The Texas Immuno-Oncology Biorepository (TIOB) consents patients to collect, process, store, and analyze serial biospecimens of tissue, blood, urine, and stool from a diverse population of over 100,000 cancer patients treated each year across the Baylor Scott & White Health system. Here we sought to demonstrate that these samples were fit for purpose with regard to downstream multi-omic assays. Plasma, urine, peripheral blood mononuclear cells, and stool samples from 11 enrolled patients were collected from various cancer types. RNA isolated from extracellular vesicles derived from plasma and urine was sufficient for transcriptomics. Peripheral blood mononuclear cells demonstrated excellent yield and viability. Ten of 11 stool samples produced RNA quality to enable microbiome characterization. Sample acquisition and processing methods are known to impact sample quality and performance. We demonstrate that consistent acquisition methodology, sample preparation, and sample storage employed by the TIOB can produce high-quality specimens, suited for employment in a wide array of multi-omic platforms, enabling comprehensive immune and molecular profiling. [ABSTRACT FROM AUTHOR]

In the West, recent decades have demonstrated an epidemiological trend towards esophago-gastric adenocarcinomas (EGAC), with considerable associated mortality. Historically, chemotherapy has represented the sole systemic treatment option in the advanced EGAC setting, in addition to complementing the role of surgery and radiotherapy in the case of localized disease. Immune checkpoint inhibitors (ICIs) represent a novel systemic therapeutic choice and have revolutionized the management of other malignancies, including melanoma and renal cell carcinomas. This article considers the rationale for ICIs in EGAC, reviews the evidence supporting their role in the current standard of care in EGAC, and briefly considers ongoing trials and future directions for the ICI class in EGAC. [ABSTRACT FROM AUTHOR]

Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, a multi-gene tyrosine kinase inhibitor, through targeting colony-stimulating factor 1 (CSF-1) receptor (CSF-1R), down modulates macrophage-mediated pro-survival tumor signaling. Previously, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in solid tumors. In this study, we investigated the antitumor activity of pexidartinib alone or in combination with blockade of PD-1 in a de novo EAC rat model. Here, we showed limited toxicity with significant tumor shrinkage in pexidartinib treated animals compared to controls, single agent and in combination with a PD-1 inhibitor, AUNP-12. Suppression of CSF-1/CSF-1R axis resulted in enhanced infiltration of CD3 + CD8 + T cells with reduced M2 macrophage polarization, in the tumor microenvironment (TME). Endpoint tissue gene expression in pexidartinib treated animals demonstrated upregulation of BAX, Cas3, TNFα, IFNγ and IL6 and downregulation of Ki67, IL13, IL10, TGFβ and Arg1 (P  < 0.05). Additionally, among the pexidartinib treated animals responders compared to nonresponders demonstrated a significant upregulation of pretreatment CSF-1 gene, confirming that tumor-associated macrophage suppression directly translates to clinical benefit. Moreover, a posttreatment serum cytokine assay exhibited similar systemic trends as the gene expression in the TME, depicting increases in proinflammatory cytokines and decreases in anti-inflammatory cytokines. In conclusion, our study established a promising combinatorial strategy using a CSF-1R inhibitor to overcome resistance to PD-1/PD-L1 axis blockade in an EAC model, providing the rationale for future clinical strategies. [ABSTRACT FROM AUTHOR]

Background: Although frequently used in the early pandemic, data on the effectiveness of COVID-19 convalescent plasma (CCP) remain mixed. We investigated the effectiveness and safety of CCP in hospitalized COVID-19 patients in real-world practices during the first two waves of the pandemic in a multi-hospital healthcare system in Texas. Methods and findings: Among 11,322 hospitalized patients with confirmed COVID-19 infection from July 1, 2020 to April 15, 2021, we included patients who received CCP and matched them with those who did not receive CCP within ±2 days of the transfusion date across sites within strata of sex, age groups, days and use of dexamethasone from hospital admission to the match date, and oxygen requirements 4–12 hours prior to the match date. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for effectiveness outcomes in a propensity score 1:1 matched cohort. Pre-defined safety outcomes were described. We included 1,245 patients each in the CCP treated and untreated groups. Oxygen support was required by 93% of patients at the baseline. The pre-defined primary effectiveness outcome of 28-day in-hospital all-cause mortality (HR = 0.85; 95%CI: 0.66,1.10) were similar between treatment groups. Sensitivity and stratified analyses found similar null results. CCP-treated patients were less likely to be discharged alive (HR = 0.82; 95%CI: 0.74, 0.91), and more likely to receive mechanical ventilation (HR = 1.48; 95%CI: 1.12, 1.96). Safety outcomes were rare and similar between treatment groups. Conclusion: The findings in this large, matched cohort of patients hospitalized with COVID-19 and mostly requiring oxygen support at the time of treatment, do not support a clinical benefit in 28-day in-hospital all-cause mortality for CCP. Future studies should assess the potential benefits with specifically high-titer units in perhaps certain subgroups of patients (e.g. those with early disease or immunocompromised). [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett’s Esophagus (BE) to esophageal adenocarcinoma. Background: The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC. Methods: The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett’s Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry. Results: BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively. Conclusion: Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium [ABSTRACT FROM AUTHOR]

Abstract Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) family that inhibits caspases and blocks cell death is highly expressed in cancer and is associated with a poorer clinical outcome. Functioning simultaneously during cell division and apoptosis inhibition, survivin plays a pivotal role in determining cell survival. Survivin has consistently been identified by molecular profiling analysis to be associated with higher tumor grade, more advanced disease, abbreviated survival, accelerated rates of recurrence, and chemotherapy and radiation resistance. Survivin's differential expression in cancer compared to normal tissue and its role as a nodal protein in a number of cellular pathways make it a highly flexible therapeutic target, suitable for small-molecule inhibitiors, molecular antagonists, and vaccination-based therapies. By targeting survivin it is hoped that multiple tumor signaling circuitries may be simultaneously disabled. This effect may be applicable to many tumor histologies irrespective of specific genetic makeup. To date, survivin inhibitors have shown modest activity as single agents, but it is anticipated that when given in combination with cytotoxic chemotherapy or monoclonal antibodies they may exhibit enhanced efficacy. This review discusses the complex circuitry of survivin in human cancers and highlights clinical trials involving novel agents that target this important protein.

Aim: Study first-line (1L) treatment patterns and economic outcomes among patients with advanced metastatic gastric cancer (GC) and esophageal cancer (EC). Materials & methods: Newly diagnosed patients with systemic GC and EC treatments were identified between 1 January 2011 and 31 July 2017; costs were presented as per patient per month (PPPM) basis. Results: Study included 392 GC and 436 EC patients. Most frequently used 1L regimens were: 5-fluorouracil (5-FU) + oxaliplatin (22.5%) and epirubicin + cisplatin + 5-FU (ECF)/ECF modifications (21.9%) in patients with GC; and carboplatin + paclitaxel (29.6%) and 5-FU + oxaliplatin (11.5%) in EC patients. Mean all-cause costs were US$16,242 PPPM for GC, and $18,384 PPPM for EC during 1L treatment. Conclusion: GC and EC were resource intensive and costly. High costs and short treatment durations underscored a gap in care in 1L treatment. [ABSTRACT FROM AUTHOR]

PURPOSE: With an increase in biomarker-directed therapies, tissue biopsy to identify targetable genomic and immunologic alterations has become the mainstay of managing patients with non–small-cell lung cancer (NSCLC); however, little is known about the associated economic impact and complication rate. This study assesses the frequency, complications, and costs of diagnostic and postprogression biopsy. METHODS: This retrospective, observational study was conducted using administrative claims data from more than 30 million commercially insured individuals in the United States (2006 to 2014). Data were analyzed for the overall population and by time of biopsy (diagnostic or postprogression biopsy). RESULTS: Of 20,013 eligible patients, 13,411 (67%) received a diagnostic biopsy, whereas only 2,056 (10%) received a postprogression biopsy (mean cost, $9,977 and $16,806, respectively). Complication rates were similar at diagnosis and after progression, on the day of biopsy (10% v 7%, respectively) and within 30 days (63% v 61%, respectively). Mean costs were higher among patients with a complication compared with those without a complication on the day of biopsy (diagnostic biopsy, $12,030 v $6,508, respectively; postprogression biopsy, $22,593 v $7,812, respectively), within 7 days of biopsy (diagnostic biopsy, $13,657 v $7,765, respectively; postprogression biopsy, $23,969 v $8,932, respectively), and within 30 days of biopsy (diagnostic biopsy, $24,968 v $15,988, respectively; postprogression biopsy, $30,293 v $12,494, respectively; P <.001 for all comparisons). CONCLUSION: From 2006 to 2014, postprogression biopsies were not common practice in NSCLC. Complication rates were similar at diagnosis and after progression, with mean costs higher among patients with a complication than those without a complication. With increasing demands for effective novel targeted therapies and safe testing methods, these data may be valuable in determining the budget impact and comparing complication rates with newer, less invasive molecular testing methods, including plasma circulating tumor DNA testing. [ABSTRACT FROM AUTHOR]