Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma: A Phase 1 Nonrandomized Controlled Trial.

Importance: Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts. Objective: To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions. Design, Setting, and Participants: This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022. Interventions: Two doses of IT GLA-SE (5 µg and 10 µg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion. Main Outcomes and Measures: Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes. Results: Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype. Conclusions and Relevance: In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02180698.

Conditionally Active, pH-Sensitive Immunoregulatory Antibodies Targeting VISTA and CTLA-4 Lead an Emerging Class of Cancer Therapeutics.

Immune checkpoints and other immunoregulatory targets can be difficult to precisely target due to expression on non-tumor immune cells critical to maintaining immune homeostasis in healthy tissues. On-target/off-tumor binding of therapeutics results in significant pharmacokinetic and pharmacodynamic problems. Target-mediated drug disposition (TMDD) significantly limits effective intratumoral drug levels and adversely affects anti-tumor efficacy. Target engagement outside the tumor environment may lead to severe immune-related adverse events (irAEs), resulting in a narrowing of the therapeutic window, sub-optimal dosing, or cessation of drug development altogether. Overcoming these challenges has become tractable through recent advances in antibody engineering and screening approaches. Here, we review the discovery and development of conditionally active antibodies with minimal binding to target at physiologic pH but high-affinity target binding at the low pH of the tumor microenvironment by focusing on the discovery and improved properties of pH-dependent mAbs targeting two T cell checkpoints, VISTA and CTLA-4.

Effects of HLA single chain trimer design on peptide presentation and stability.

MHC class I "single-chain trimer" molecules, coupling MHC heavy chain, ß2-microglobulin, and a specific peptide into a single polypeptide chain, are widely used in research. To more fully understand caveats associated with this design that may affect its use for basic and translational studies, we evaluated a set of engineered single-chain trimers with combinations of stabilizing mutations across eight different classical and non-classical human class I alleles with 44 different peptides, including a novel human/murine chimeric design. While, overall, single-chain trimers accurately recapitulate native molecules, care was needed in selecting designs for studying peptides longer or shorter than 9-mers, as single-chain trimer design could affect peptide conformation. In the process, we observed that predictions of peptide binding were often discordant with experiment and that yields and stabilities varied widely with construct design. We also developed novel reagents to improve the crystallizability of these proteins and confirmed novel modes of peptide presentation.

Bugs, Bumps, and Bacteria: The Role of Virtual Collaborative Learning Network in Pediatric Dermatology.

Patients in rural and underserved areas face significant barriers in accessing specialty care due to unavailability of services, geographic isolation, travel burden, and other cultural and socioeconomic factors.1 Pediatric dermatology is among the top three subspecialties that provides routine care for pediatric patients, however, shortage and maldistribution of pediatric dermatologists have remained a major hurdle for those living in remote and isolated areas.2 Pediatric dermatologists cluster in urban areas with high-patient volume and estimated wait times for new patients that often exceed 13 weeks, making access one of the major drivers of inequity for rural patients.2-4.

Disparities in the use of telehealth at the onset of the COVID-19 public health emergency.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic resulted in an unprecedented expansion in telehealth, but little is known about differential use of telehealth according to demographics, rurality, or insurance status. METHODS: We performed a cross-sectional analysis of 7742 family medicine encounters at a single USA institution in the initial month of the COVID-19 public health emergency (PHE). We compared the demographics of those using telehealth during the PHE to those with face-to-face visits during the same time period; we also compared the demographics of those using full audio-video to those using audio-only. RESULTS: The likelihood of any telehealth visit in the first 30 days of telehealth expansion was higher for women, those age 65 years and older, self-pay patients, and those with Medicaid and Medicare as primary payers. The likelihood of a telehealth visit was reduced for rural residence and Black or other races. Among all telehealth visits, the likelihood of a full audio-video telehealth visit was reduced for patients who were older, Black, from urban areas, or who were self-pay, Medicaid, or Medicare payer status. DISCUSSION: Significant disparities exist in telehealth use during the COVID-19 PHE by age, race, residence and payer.

External proficiency testing improves inter-scorer reliability of polysomnography scoring.

PURPOSE: This study evaluated whether or not polysomnography (PSG) inter-scorer reliability (ISR) across sleep centres could be improved by external proficiency testing (EPT), or by EPT combined with method alignment training. METHODS: Experienced scorers form 15 sleep centres were randomised to the following: (1) a control group, (2) a group that received a self-directed intervention of EPT reports (EPTPassive) or (3) a group that received an active intervention of method alignment training and EPT reports (EPTActive). Respiratory, arousal and sleep scoring ISR from sixteen PSG fragments were compared between groups across time. RESULTS: Among 30 scorers, there were no ISR changes in controls between baseline (BL) and 6 months (6 m). Both EPT groups showed ISR improvement from BL to 6 m for respiratory, arousal and sleep scoring (p < 0.05). Respiratory scoring back-transformed mean (95CI) proportion of specific agreement (PSA) for the EPTPassive group improved from 0.78 (0.72-0.84) to 0.80 (0.74-0.86) and for the EPTActive group from 0.80 (0.74-0.85) to 0.82 (0.76-0.88). Arousal scoring PSA for the EPTPassive group improved from 0.72 (0.66-0.77) to 0.74 (0.69-0.79) and for the EPTActive group from 0.71 (0.65-0.76) to 0.77 (0.72-0.82). Sleep scoring kappa for the EPTPassive group improved from 0.64 (0.58-0.69) to 0.73 (0.68-0.77) and for the EPTActive group from = 0.75 (0.71-0.80) to 0.80 (0.76-0.85). Overall, poorer performers achieved greater improvement. CONCLUSION: External proficiency testing produced modest, statistically significant PSG inter-scorer reliability improvements among experienced scorers across sleep centres, with potential to improve clinical management of individual patients and increase research study statistical power.

Improving the User Experience with Discount Site-Specific User Testing.

OBJECTIVES: Poor electronic health record (EHR) usability is associated with patient safety concerns, user dissatisfaction, and provider burnout. EHR certification requires vendors to perform user testing. However, there are no such requirements for site-specific implementations. Health care organizations customize EHR implementations, potentially introducing usability problems. Site-specific usability evaluations may help to identify these concerns, and "discount" usability methods afford health systems a means of doing so even without dedicated usability specialists. This report characterizes a site-specific discount user testing program launched at an academic medical center. We describe lessons learned and highlight three of the EHR features in detail to demonstrate the impact of testing on implementation decisions and on users. METHODS: Thirteen new EHR features which had already undergone heuristic evaluation and iterative design were evaluated over the course of three user test events. Each event included five to six users. Participants used think aloud technique. Measures of user efficiency, effectiveness, and satisfaction were collected. Usability concerns were characterized by the type of usability heuristic violated and by correctability. RESULTS: Usability concerns occurred at a rate of 2.5 per feature tested. Seventy percent of the usability concerns were deemed correctable prior to implementation. The first highlighted feature was moved to production despite low single ease question (SEQ) scores which may have predicted its subsequent withdrawal from production based on post implementation feedback. Another feature was rebuilt based on usability findings, and a new version was retested and moved to production. A third feature highlights an easily correctable usability concern identified in user testing. Quantitative usability metrics generally reinforced qualitative findings. CONCLUSION: Simplified user testing with a limited number of participants identifies correctable usability concerns, even after heuristic evaluation. Our discount usability approach to site-specific usability has a role in implementations and may improve the usability of the EHR for the end user.

Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens. METHODS: A patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry. RESULTS: WES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγ when stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet. CONCLUSIONS: We identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy.

Diabetes Control in a Student-Run Free Clinic During the COVID-19 Pandemic.

Student run free health clinics (SRFCs) provide medical care to vulnerable populations in communities throughout the United States. The COVID-19 pandemic had a significant impact on the delivery of healthcare services and demanded a rapid adjustment in care delivery methods in both resource-rich and resource-poor settings. The aim of this study is to evaluate the impact of the pandemic on the management of chronic disease, specifically diabetes. Patients with diabetes who received care continuously throughout the pre-pandemic (face-to-face) and pandemic (telehealth) study periods at MedZou Community Health Center, a SRFC located in central Missouri, were evaluated. This sample of patients (n = 29) was evaluated on six quality measures including annual eye exams, blood pressure, hemoglobin A1c, chronic kidney disease monitoring, flu vaccination, and statin therapy. Overall diabetes care, as measured by the number of quality measures met per patient, decreased by 0.37 after the onset of the pandemic. The median COVID-era ranks were not statistically significantly different than the pre-pandemic ranks (z = 1.65, P = 0.099). Fewer patients received an influenza vaccination the year following the onset of the pandemic (10.3%) compared to the year before the pandemic (37.9%; difference in proportions 0.276, 95% CI 0.079, 0.473; p = 0.005). No other individual measures of diabetes care statistically differed significantly in the year after the pandemic began. Twenty-six (90%) patients received diabetes care using telehealth after the onset of the pandemic. Diabetes care using telehealth in a SRFC may be an acceptable alternative model when face-to-face visits are not feasible. Observed decreases in diabetes-related clinical quality measure performance warrant further study.

An In Vivo Model of Human Macrophages in Metastatic Melanoma.

Despite recent therapeutic progress, advanced melanoma remains lethal for many patients. The composition of the immune tumor microenvironment (TME) has decisive impacts on therapy response and disease outcome, and high-dimensional analyses of patient samples reveal the heterogeneity of the immune TME. Macrophages infiltrate TMEs and generally associate with tumor progression, but the underlying mechanisms are incompletely understood. Because experimental systems are needed to elucidate the functional properties of these cells, we developed a humanized mouse model reconstituted with human immune cells and human melanoma. We used two strains of recipient mice, supporting or not supporting the development of human myeloid cells. We found that human myeloid cells favored metastatic spread of the primary tumor, thereby recapitulating the cancer-supportive role of macrophages. We next analyzed the transcriptome of human immune cells infiltrating tumors versus other tissues. This analysis identified a cluster of myeloid cells present in the TME, but not in other tissues, which do not correspond to canonical M2 cells. The transcriptome of these cells is characterized by high expression of glycolytic enzymes and multiple chemokines and by low expression of gene sets associated with inflammation and adaptive immunity. Compared with humanized mouse results, we found transcriptionally similar myeloid cells in patient-derived samples of melanoma and other cancer types. The humanized mouse model described here thus complements patient sample analyses, enabling further elucidation of fundamental principles in melanoma biology beyond M1/M2 macrophage polarization. The model can also support the development and evaluation of candidate antitumor therapies.

Impact of a Vendor-Developed Opioid Clinical Decision Support Intervention on Adherence to Prescribing Guidelines, Opioid Prescribing, and Rates of Opioid-Related Encounters.

BACKGROUND: Provider prescribing practices contribute to an excess of opioid-related deaths in the United States. Clinical guidelines exist to assist providers with improving prescribing practices and promoting patient safety. Clinical decision support systems (CDSS) may promote adherence to these guidelines and improve prescribing practices. The aim of this project was to improve opioid guideline adherence, prescribing practices, and rates of opioid-related encounters through the implementation of an opioid CDSS. METHODS: A vendor-developed, provider-targeted CDSS package was implemented in a multi-location academic health center. An interrupted time-series analysis was performed, evaluating 30 weeks pre- and post-implementation time periods. Outcomes were derived from vendor-supplied key performance indicators and directly from the electronic health record (EHR) database. Opioid-prescribing outcomes included count of opioid prescriptions, morphine milligram equivalents per prescription, counts of opioids with concurrent benzodiazepines, and counts of short-acting opioids in opioid-naïve patients. Encounter outcomes included rates of encounters for opioid abuse and dependence and rates of encounters for opioid poisoning and overdose. Guideline adherence outcomes included rates of provision of naloxone and documentation of opioid treatment agreements. RESULTS: The opioid CDSS generated an average of 1,637 alerts per week. Rates of provision of naloxone and opioid treatment agreements improved after CDSS implementation. Vendor-supplied prescribing outcomes were consistent with prescribing outcomes derived directly from the EHR, but all prescribing and encounter outcomes were unchanged. CONCLUSION: A vendor-developed, provider-targeted opioid CDSS did not improve opioid-prescribing practices or rates of opioid-related encounters. The CDSS improved some measures of provider adherence to opioid-prescribing guidelines. Further work is needed to determine the optimal configuration of opioid CDSS so that opioid-prescribing patterns are appropriately modified and encounter outcomes are improved.

Immunologic Gene Signature Analysis Correlates Myeloid Cells and M2 Macrophages with Time to Trabectedin Failure in Sarcoma Patients.

Patients with metastatic soft tissue sarcoma (STS) have a poor prognosis and few available systemic treatment options. Trabectedin is currently being investigated as a potential adjunct to immunotherapy as it has been previously shown to kill tumor-associated macrophages. In this retrospective study, we sought to identify biomarkers that would be relevant to trials combining trabectedin with immunotherapy. We performed a single-center retrospective study of sarcoma patients treated with trabectedin with long-term follow-up. Multiplex gene expression analysis using the NanoString platform was assessed, and an exploratory analysis using the lasso-penalized Cox regression and kernel association test for survival (MiRKAT-S) methods investigated tumor-associated immune cells and correlated their gene signatures to patient survival. In total, 147 sarcoma patients treated with trabectedin were analyzed, with a mean follow-up time of 5 years. Patients with fewer prior chemotherapy regimens were more likely to stay on trabectedin longer (pairwise correlation = -0.17, p = 0.04). At 5 years, increased PD-L1 expression corresponded to worse outcomes (HR = 1.87, p = 0.04, q = 0.199). Additionally, six immunologic gene signatures were associated with up to 7-year survival by MiRKAT-S, notably myeloid-derived suppressor cells (p = 0.023, q = 0.058) and M2 macrophages (p = 0.03, q = 0.058). We found that the number of chemotherapy regimens prior to trabectedin negatively correlated with the number of trabectedin cycles received, suggesting that patients may benefit from receiving trabectedin earlier in their therapy course. The correlation of trabectedin outcomes with immune cell infiltrates supports the hypothesis that trabectedin may function as an immune modulator and supports ongoing efforts to study trabectedin in combination with immunotherapy. Furthermore, tumors with an immunosuppressive microenvironment characterized by macrophage infiltration and high PD-L1 expression were less likely to benefit from trabectedin, which could guide clinicians in future treatment decisions.

Impact of HPV status on immune responses in head and neck squamous cell carcinoma.

The main objective of our study was to understand the impact of immune cell composition and the tumor-reactivity of tumor infiltrating lymphocytes (TIL) in HPV-positive (HPV+) and HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC). TIL cultures were established from primary HNSCC tumors, the T cell subsets were phenotypically characterized using flow cytometry, and Interferon (IFN)-γ ELISA assay was used to determine TIL function. NanoString Immune Profiler was used to determine an immune signature by HPV-status, and multiplex immunohistochemistry (MIHC) was used to quantify immune cell distributions and their spatial relationships. Results showed that HPV+ and HPV- HNSCC had similar capacity to expand IFN-γ reactive TIL populations, and these TIL populations had similar characteristics. NanoString analysis revealed increased differential expression of genes related to B cell functions in HPV+ HNSCC, which were significant at a Benjamini-Yekutieli adjusted p-value of < 0.001. MIHC also displayed increased CD8+ T cell and CD19/CD20+ B cell densities in the tumor region of HPV+ HNSCC as opposed to HPV- HNSCC (p < 0.01). Increases in a combined metric of tumor B cell content and stromal plasma cell content was associated with increased progression-free survival in HPV- HNSCC patients treated with immune checkpoint inhibitor therapy (p = 0.03). In summary, TIL populations expanded from HPV+ and HPV- HNSCC displayed similar IFN-γ reactivity. However, we identified a strong B-cell signature present within HPV+ HNSCC, and higher B and plasma cell content associated with improved PFS in HPV- HNSCC patients treated with immune checkpoint inhibitors.

Targeting an alternate Wilms' tumor antigen 1 peptide bypasses immunoproteasome dependency.

Designing effective antileukemic immunotherapy will require understanding mechanisms underlying tumor control or resistance. Here, we report a mechanism of escape from immunologic targeting in an acute myeloid leukemia (AML) patient, who relapsed 1 year after immunotherapy with engineered T cells expressing a human leukocyte antigen A*02 (HLA-A2)-restricted T cell receptor (TCR) specific for a Wilms' tumor antigen 1 epitope, WT1126-134 (TTCR-C4). Resistance occurred despite persistence of functional therapeutic T cells and continuous expression of WT1 and HLA-A2 by the patient's AML cells. Analysis of the recurrent AML revealed expression of the standard proteasome, but limited expression of the immunoproteasome, specifically the beta subunit 1i (ß1i), which is required for presentation of WT1126-134. An analysis of a second patient treated with TTCR-C4 demonstrated specific loss of AML cells coexpressing ß1i and WT1. To determine whether the WT1 protein continued to be processed and presented in the absence of immunoproteasome processing, we identified and tested a TCR targeting an alternative, HLA-A2-restricted WT137-45 epitope that was generated by immunoproteasome-deficient cells, including WT1-expressing solid tumor lines. T cells expressing this TCR (TTCR37-45) killed the first patients' relapsed AML resistant to WT1126-134 targeting, as well as other primary AML, in vitro. TTCR37-45 controlled solid tumor lines lacking immunoproteasome subunits both in vitro and in an NSG mouse model. As proteasome composition can vary in AML, defining and preferentially targeting these proteasome-independent epitopes may maximize therapeutic efficacy and potentially circumvent AML immune evasion by proteasome-related immunoediting.

Neoadjuvant Therapy Induces a Potent Immune Response to Sarcoma, Dominated by Myeloid and B Cells.

PURPOSE: To characterize changes in the soft-tissue sarcoma (STS) tumor immune microenvironment induced by standard neoadjuvant therapy with the goal of informing neoadjuvant immunotherapy trial design. EXPERIMENTAL DESIGN: Paired pre- and postneoadjuvant therapy specimens were retrospectively identified for 32 patients with STSs and analyzed by three modalities: multiplexed IHC, NanoString, and RNA sequencing with ImmunoPrism analysis. RESULTS: All 32 patients, representing a variety of STS histologic subtypes, received neoadjuvant radiotherapy and 21 (66%) received chemotherapy prior to radiotherapy. The most prevalent immune cells in the tumor before neoadjuvant therapy were myeloid cells (45% of all immune cells) and B cells (37%), with T (13%) and natural killer (NK) cells (5%) also present. Neoadjuvant therapy significantly increased the total immune cells infiltrating the tumors across all histologic subtypes for patients receiving neoadjuvant radiotherapy with or without chemotherapy. An increase in the percentage of monocytes and macrophages, particularly M2 macrophages, B cells, and CD4+ T cells was observed postneoadjuvant therapy. Upregulation of genes and cytokines associated with antigen presentation was also observed, and a favorable pathologic response (≥90% necrosis postneoadjuvant therapy) was associated with an increase in monocytic infiltrate. Upregulation of the T-cell checkpoint TIM3 and downregulation of OX40 were observed posttreatment. CONCLUSIONS: Standard neoadjuvant therapy induces both immunostimulatory and immunosuppressive effects within a complex sarcoma microenvironment dominated by myeloid and B cells. This work informs ongoing efforts to incorporate immune checkpoint inhibitors and novel immunotherapies into the neoadjuvant setting for STSs.

Impact of the COVID-19 Pandemic & Telehealth Implementation in a Student Run Free Clinic.

Student run free clinics (SRFCs) fill a void in healthcare access for many communities and have been subject to unprecedented shifts in care delivery brought about by the coronavirus disease 2019 (COVID-19) pandemic. Our single-center institution serving uninsured patients in central Missouri switched from in-person visits to strictly telehealth visits with the onset of the pandemic. This study investigated the impact of the pandemic and the switch to telehealth on the clinic return rates by ethnicity, race, gender, rurality, and age. The pandemic led to a 47.4% reduction in the number of monthly patient encounters. Of the established SRFC population (N = 309), only 87 patients (28.2%) returned for a telehealth visit during the COVID-19 pandemic. Older patients (≥ 45 years old) were more likely to return (OR 1.71, 95% CI 1.02-2.85) for care via telehealth after the onset of the pandemic than younger patients (< 45 years old). No differences in the likelihood of returning for a telehealth visit were identified by race, ethnicity, gender, or rurality. Telehealth offers an effective solution to the complex problems faced by SRFCs during the COVID-19 pandemic and has not added barriers to care with regards to race, ethnicity, gender, or rurality at our SRFC.

Mavorixafor, an Orally Bioavailable CXCR4 Antagonist, Increases Immune Cell Infiltration and Inflammatory Status of Tumor Microenvironment in Patients with Melanoma.

Purpose: Mavorixafor is an oral, selective inhibitor of the CXCR4 chemokine receptor that modulates immune cell trafficking. A biomarker-driven phase Ib study (NCT02823405) was conducted in 16 patients with melanoma to investigate the hypothesis that mavorixafor favorably modulates immune cell profiles in the tumor microenvironment (TME) and to evaluate the safety of mavorixafor alone and in combination with pembrolizumab. Experimental Design: Serial biopsies of melanoma lesions were assessed after 3 weeks of mavorixafor monotherapy and after 6 weeks of combination treatment for immune cell markers by NanoString analysis for gene expression and by multiplexed immunofluorescent staining for in situ protein expression. Serum samples taken at biopsy timepoints were evaluated for key chemokine and cytokine alterations using the Myriad Rules Based Medicine multiplex immunoassays. Results: Within the TME, mavorixafor alone increased CD8+ T-cell infiltration, granzyme B signal, antigen presentation machinery, and both tumor inflammatory signature (TIS) and IFNγ gene expression signature scores. Increases in the key serum cytokines CXCL9 and CXCL10 were further enhanced when mavorixafor was combined with pembrolizumab. Adverse events (AE), as assessed by the investigator according to NCI Common Terminology Criteria for Adverse Events (v4.03), related to either mavorixafor or pembrolizumab (≥15%) were diarrhea, fatigue, maculopapular rash, and dry eye. Reported AEs were all ≤ grade 3. Conclusion/Discussion: Treatment with single-agent mavorixafor resulted in enhanced immune cell infiltration and activation in the TME, leading to increases in TIS and IFNγ gene signatures. Mavorixafor as a single agent, and in combination with pembrolizumab, has an acceptable safety profile. These data support further investigation of the use of mavorixafor for patients unresponsive to checkpoint inhibitors. Significance: Despite survival improvements in patients with melanoma treated with checkpoint inhibitor therapy, a significant unmet medical need exists for therapies that enhance effectiveness. We propose that mavorixafor sensitizes the melanoma tumor microenvironment and enhances the activity of checkpoint inhibitors, and thereby may translate to a promising treatment for broader patient populations.

The Liver-Immunity Nexus and Cancer Immunotherapy.

The impact of liver metastases on immune checkpoint-inhibitor effectiveness in patients with solid-tumor malignancies has been the focus of several recent clinical and translational studies. We review the literature describing the immune functions of the liver and particularly the mechanistic observations in these studies. The initial clinical observation was that pembrolizumab appeared to be much less effective in melanoma and non-small cell lung cancer (NSCLC) patients with liver metastasis. Subsequently other clinical studies have extended and reported similar findings with programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors in many cancers. Two recent translational studies in animal models have dissected the mechanism of this systemic immune suppression. In both studies CD11b+ suppressive macrophages generated by liver metastasis in a two-site MC38 model appear to delete CD8+ T cells in a FasL-dependent manner. In addition, regulatory T-cell (Treg) activation was observed and contributed to the distal immunosuppression. Finally, we discuss some of the interventions reported to address liver immune suppression, such as radiation therapy, combination checkpoint blockade, and Treg depletion.

A Comparison of Models Predicting One-Year Mortality at Time of Admission.

CONTEXT: Hospitalization provides an opportunity to address end-of-life care (EoLC) preferences if patients at risk of death can be accurately identified while in the hospital. The modified Hospital One-Year Mortality Risk (mHOMR) uses demographic and admission data in a logistic regression algorithm to identify patients at risk of death one year from admission. OBJECTIVES: This project sought to validate mHOMR and identify superior models. METHODS: The mHOMR model was validated using historical data from an academic health system. Alternative logistic regression and random forest (RF) models were developed using the same variables. Receiver operating characteristic (ROC) and precision recall curves were developed, and sensitivity, specificity, and positive and negative predictive values were compared over a range of model thresholds. RESULTS: The RF model demonstrated higher area under the ROC curve (0.950, 95% CI 0.947 - 0.954) as compared to the logistic regression models (0.818 [95% CI 0.812 - 0.825] and 0.841 [95% CI 0.836 - 0.847]). Area under the precision recall curve was higher with the random forest model compared to the logistic regression models (0.863 vs. 0.458 and 0.494, respectively). Across a range of thresholds, the RF model demonstrated superior sensitivity, equivalent specificity, and higher positive and negative predictive values. CONCLUSION: A machine learning RF model, using common demographic and utilization data available on hospital admission, identified inpatients at risk of death more effectively than logistic regression models using the same variables. Machine learning models have promise for identifying admitted patients with elevated one-year mortality risk, increasing opportunities to prompt discussion of EoLC preferences.