Targeting sinonasal undifferentiated carcinoma with a combinatory immunotherapy approach.

PURPOSE: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal cavity with poor prognosis and limited treatment options. To investigate the potential for SNUC sensitivity to combinatory immunotherapy, we performed in vitro studies with SNUC cell lines and used multi-spectral immunofluorescence to characterize the in vivo patient SNUC tumor immune microenvironment (TIME). EXPERIMENTAL DESIGN: Human-derived SNUC cell lines were used for in vitro studies of tumor cell susceptibility to natural killer (NK) cell-based immunotherapeutic strategies. Tumor samples from 14 treatment naïve SNUC patients were examined via multi-spectral immunofluorescence and clinical correlations assessed. RESULTS: Anti-PD-L1 blockade enhanced NK cell lysis of SNUC cell lines ∼5.4 fold (P ≤ 0.0001). This effect was blocked by a CD16 neutralizing antibody demonstrating activity through an antibody-dependent cellular cytotoxicity (ADCC) mediated pathway. ADCC-dependent lysis of SNUC cells was further enhanced by upregulation of PD-L1 on tumor cells by exogenous interferon-gamma (IFN-γ) administration or interleukin-15 (IL-15) stimulated IFN-γ release from NK cells. Combination treatment with anti-PD-L1 blockade and IL-15 superagonism enhanced NK-cell killing of SNUC cells 9.6-fold (P ≤ 0.0001). Untreated SNUC patient tumor samples were found to have an NK cell infiltrate and PD-L1+ tumor cells at a median of 5.4 cells per mm2. A striking 55.7-fold increase in CKlow tumor cell/NK cell interactions was observed in patients without disease recurrence after treatment (P = 0.022). Patients with higher CD3+CD8+ in the stroma had a significantly improved 5-year overall survival (P = 0.0029) and a significant increase in CKlow tumor cell/CD8+ cytotoxic T cell interactions was noted in long-term survivors (P = 0.0225). CONCLUSION: These data provide the pre-clinical rationale for ongoing investigation into combinatory immunotherapy approaches for SNUC.

Human Papillomavirus-Related Carcinomas of the Sinonasal Tract.

Purpose of review: The sinonasal tract is home to a uniquely heterogenous collection of malignant tumors. Human papillomavirus (HPV) has been detected in a number of these, but the virus' role as an oncogenic driver or coincidental finding remains unclear. We aim to highlight five sinonasal tumor types and synthesize the prevalence, etiologic role, and known clinicopathologic relevance of HPV in each. Recent findings: The last decade has seen an expansion of investigation into HPV's oncogenic and prognostic significance within sinonasal malignancies. The sinonasal tract poses challenges to HPV detection where p16 lacks value as an accurate surrogate. A growing body of data supports a potentially favorable clinical profile for certain sinonasal HPV-positive lesions. Summary: HPV represents a potential biologically and clinically relevant factor for some sinonasal malignancies. Definitive conclusions regarding HPV's role as a potential oncogenic agent require routine testing using validated methodologies, genomic interrogation, and large-scale prospective studies.

Postoperative Pain Management and Perceived Patient Outcomes following Endoscopic Pituitary Surgery.

Objectives Pain management remains a point of emphasis given the ongoing opioid crisis. There are no studies in the literature interrogating opioid prescribing and use following endoscopic pituitary surgery. This study investigates provider prescribing tendency, patient utilization of analgesics, and patient outcomes regarding pain management after endoscopic pituitary surgery. Methods We identified 100 patients undergoing endoscopic pituitary surgery at one institution from 2016 to 2018 in the electronic medical record (EMR) and state narcotic database to determine postoperative analgesic regimens. A telephone survey was used to characterize postoperative analgesic use and satisfaction with prescribed regimen. Results Fifty-two different pain control regimens were prescribed to the study patients. Also, 93% of study patients were prescribed an opioid postoperatively. The average quantity of opioids prescribed per patient in morphine milligram equivalents (MMEs) was 625 (equivalent 83 oxycodone 5-mg tablets) with an average MME/day of 59 (equivalent 8 oxycodone 5-mg tablets). A total of 71% survey respondents who used opioids reported using <25% of their prescription. The majority of prescription narcotic users consumed >50% of their postoperative opioid intake in the first 24 to 48 hours after discharge. There were no significant differences in pain outcome between opioid users and nonopioid users. Conclusion Vast heterogeneity exists in narcotic prescribing by providers at our institution following endoscopic pituitary surgery. Narcotic prescribing patterns exceeded most patients' analgesic needs. Opioid analgesics were not superior to nonopioids regimens in patient-reported pain outcomes in this study population.

Organoid and Spheroid Tumor Models: Techniques and Applications.

Techniques to develop three-dimensional cell culture models are rapidly expanding to bridge the gap between conventional cell culture and animal models. Organoid and spheroid cultures have distinct and overlapping purposes and differ in cellular sources and protocol for establishment. Spheroids are of lower complexity structurally but are simple and popular models for drug screening. Organoids histologically and genetically resemble the original tumor from which they were derived. Ease of generation, ability for long-term culture and cryopreservation make organoids suitable for a wide range of applications. Organoids-on-chip models combine organoid methods with powerful designing and fabrication of micro-chip technology. Organoid-chip models can emulate the dynamic microenvironment of tumor pathophysiology as well as tissue-tissue interactions. In this review, we outline different tumor spheroid and organoid models and techniques to establish them. We also discuss the recent advances and applications of tumor organoids with an emphasis on tumor modeling, drug screening, personalized medicine and immunotherapy.

Combinatorial Natural Killer Cell-based Immunotherapy Approaches Selectively Target Chordoma Cancer Stem Cells.

Chordoma is a rare tumor derived from notochord remnants that has a propensity to recur and metastasize despite conventional multimodal treatment. Cancer stem cells (CSC) are implicated in chordoma's resistant and recurrent behavior; thus strategies that target CSCs are of particular interest. Using in vitro cytotoxicity models, we demonstrated that anti-programmed death-ligand 1 (N-601) and anti-epidermal growth factor receptor (cetuximab) antibodies enhanced lysis of chordoma cells by healthy donor and chordoma patient NK cells through antibody-dependent cellular cytotoxicity (ADCC). Treatment of NK cells with an IL-15 superagonist complex (N-803) increased their cytotoxicity against chordoma cells, which was further enhanced by treatment with N-601 and/or cetuximab. PD-L1-targeted chimeric antigen receptor NK cells (PD-L1 t-haNKs) were also effective against chordoma cells. CSCs were preferentially vulnerable to NK cell killing in the presence of N-601 and N-803. Flow cytometric analysis of a chordoma CSC population showed that CSCs expressed significantly more NK activating ligand B7-H6 and PD-L1 than non-CSCs, thus explaining a potential mechanism of selective targeting. These data suggest that chordoma may be effectively targeted by combinatorial NK cell-mediated immunotherapeutic approaches and that the efficacy of these approaches in chordoma and other CSC-driven tumor types should be investigated further in clinical studies.