Patterns of immunotherapy utilization for non-small cell lung cancer in Texas pre- and post-regulatory approval.

PURPOSE: Immunotherapy has shown remarkable benefits for non-small cell lung cancer (NSCLC) since approved by the US Food and Drug Administration (FDA). Texas, however, ranks below the national average in access to treatment for NSCLC. This retrospective cohort study assessed first-line immunotherapy treatment patterns and associated factors pre- and post-FDA approval in Texas. METHODS: Patients ≥18 years diagnosed with NSCLC from the Texas Cancer Registry database (2011-2018) and were stratified into pre- and post-FDA approval era. The rates of immunotherapy utilization were examined, and the average annual percent change (AAPC) in immunotherapy utilization across patient subgroups was compared. Multivariable logistic regression was used to identify associations of patient characteristics with immunotherapy utilization for patients with metastatic- and all-stage NSCLC. RESULTS: A total of 13,501 and 9509 patients with NSCLC were identified in pre-post-approval periods, respectively. Post-approval, immunotherapy utilization increased from 1.7 to 13.0%, and AAPC from 54.8 to 82.7%. Pre-approval, patients living in a county with ≥20% of households below the poverty level were less likely to receive immunotherapy (OR = 0.73, 95% CI = 0.61-0.94) while patients with private insurance were more likely to receive immunotherapy (OR = 1.56, 95% CI = 1.10-2.23). Post-approval, socioeconomic disparities were more prominent (10-19.9 and ≥20% of households below the poverty level: OR = 0.77, 95% CI = 0.66-0.90 and OR = 0.71, 95% CI = 0.60-0.86, respectively). Patients with metastatic NSCLC showed similar patterns of socioeconomic disparities pre- and post-approval. CONCLUSIONS: Our findings suggest that patients' socioeconomic status hinders immunotherapy utilization for NSCLC in Texas. This emphasizes the need for state health policy reforms such as Medicaid expansion and tailored cancer care strategies.

Survival of patients with unfavorable prognosis cutaneous melanoma with increased use of immunotherapy agents: a population-based study in Belgium.

BACKGROUND: Although metastatic cutaneous melanoma is associated with an unfavorable prognosis, innovative therapies including immunomodulating agents and targeted therapies have shown survival benefits in clinical trials. We assessed the impact of the introduction of innovative drugs into clinical practice on the survival of patients with metastatic cutaneous melanoma during the period 2004-2017, in Belgium. The evolution of associated expenses was also analyzed. METHODS: This is a retrospective population-based study using data from the national Belgian Cancer Registry, compulsory health insurance, and administrative survival data. The immunomodulating drugs were ipilimumab, nivolumab and pembrolizumab, while targeted therapies included vemurafenib, dabrafenib and trametinib. RESULTS: We did not identify a trend for improvement over time. Median survival (years) was 1.5 (95% CI: 1.1-1.8) in 2004-2008, 1.1 (95% CI: 0.8-1.5) in 2009-2013, and 1.6 (95% CI: 1.3-2.4) in 2014-2017, respectively. In contrast, survival improved in those with unknown primary tumor localization. In this group, median survival time was 2.0 (95% CI: 1.4-2.9) in the most recent period, while it was 1.1 (95% CI: 0.7-1.3) in 2009-2013, and 0.9 (95% CI: 0.6-1.2) in 2004-2008. The uptake of innovative drugs remained modest, with no drug being used by more than 30% of patients. Yearly expenditure was almost non-existent, and gradually increased, reaching several million euros in 2014-2017. CONCLUSION: Patients with metastatic cutaneous melanoma who were diagnosed between 2004 and 2017 showed no apparent improvement in survival. In contrast, increased survival was observed in the subgroup of patients with unknown primary tumor localization.

Knowledge mapping of immunotherapy for allergic rhinoconjunctivitis: a bibliometric study (2002–2021)

Background: Allergic rhinoconjunctivitis (ARC) is a common chronic inflammatory disease. Numerous studies on the treatment of ARC have been published. By contrast, there are few bibliometric studies on immunotherapy for ARC. The purpose of this article is to describe the current treatments for ARC and to identify the trends in immunotherapy for ARC. Methods: Publications were searched from the Web of Science (WOS) Core Collection on April 25, 2022. CiteSpace and Microsoft Excel software were used for further bibliometric analysis. Results: A total of 969 publications on immunotherapy for ARC in English were retrieved. The number of relevant publications has been continuously increasing over the past 20 years, with many of the publications coming from Germany and the United States of America. In terms of institutions, the ALK Company in Denmark, Imperial College London in United Kingdom, and Charite–Universitatsmedizin Berlin in Germany published the most articles on immunotherapy for ARC. Meanwhile, Allergy and Journal of Allergy and Clinical Immunology published the most number of studies, and Oliver Pfaar from Germany authored the most number of articles. “Subcutaneous immunotherapy,” “international consensus,” “allergen immunotherapy,” and “recommendation” were the most popular subjects. Thus, directions in research can be predicted as studies regarding mechanisms of ARC, clinical trials, and extracts have reported high-quality results. Conclusion: Over the past 20 years, the overall quality of research on immunotherapy for ARC has gradually improved, allowing the introduction of specific and targeted treatment. Currently, the main focus of ARC research is the novel routes of drug delivery and combined treatment with biological agents (AU)

High farnesoid X receptor expression predicts favorable clinical outcomes in PD­L1low/negative non­small cell lung cancer patients receiving anti­PD­1­based chemo­immunotherapy.

Anti­programmed death­1 (PD­1)/programmed death­ligand 1 (PD­L1)­directed immunotherapy has revolutionized the treatment of advanced non­small cell lung cancer (NSCLC). However, predictive biomarkers are still lacking, particularly in identifying PD­L1low/negative patients who will benefit from immunotherapy. It was previously reported that farnesoid X receptor (FXR) downregulated PD­L1 expression in NSCLC, and that FXRhighPD­L1low mouse Lewis lung carcinoma tumors showed an increased susceptibility to PD­1 blockade compared with mock tumors. At present, whether the FXRhighPD­L1low phenotype predicts clinical response to immunotherapy in patients with NSCLC remains unclear. Herein, a retrospective study was conducted to examine the expression levels of FXR, PD­L1 and CD8+ T cells by immunohistochemistry in a cohort of 149 patients with NSCLC receiving anti­PD­1­based chemo­immunotherapy. The results revealed that high FXR and PD­L1 expression levels were associated with higher objective response rates (ORR) in all patients. High PD­L1 expression also indicated superior progression­free survival (PFS). Interestingly, an inverse correlation was identified between FXR and PD­L1 expression in specimens with NSCLC. Subgroup analysis revealed that high FXR expression was associated with a higher ORR, as well as longer PFS and overall survival (OS) in PD­L1low patients. Cox multivariate analysis revealed that high FXR expression was an independent predictor for PFS and OS in PD­L1low patients. Tumor microenvironment evaluation revealed a statistically significant decrease of infiltrating CD8+ T cells in FXRhigh specimens with NSCLC. Overall, the present study proposed an FXRhighPD­L1low signature as a candidate predictor of response to anti­PD­1­based chemo­immunotherapy in PD­L1low/negative patients with NSCLC, providing evidence that could be used to broaden the patients benefitting from immunotherapy.

Spike Gene Evolution and Immune Escape Mutations in Patients with Mild or Moderate Forms of COVID-19 and Treated with Monoclonal Antibodies Therapies.

We explored the molecular evolution of the spike gene after the administration of anti-spike monoclonal antibodies in patients with mild or moderate forms of COVID-19. Four out of the 13 patients acquired a mutation during follow-up; two mutations (G1204E and E406G) appeared as a mixture without clinical impact, while the Q493R mutation emerged in two patients (one receiving bamlanivimab and one receiving bamlanivimab/etesevimab) with fatal outcomes. Careful virological monitoring of patients treated with mAbs should be performed, especially in immunosuppressed patients.

PD-1 targeted immunotherapy for advanced hepatocellular carcinoma: current utilization and outcomes in the USA.

Objective: To evaluate the utilization and outcomes of PD-1-directed immunotherapy (PD-1 IMT) for advanced hepatocellular carcinoma. Methods: Patients with advanced hepatocellular carcinoma receiving systemic therapy and PD-1 IMT (nivolumab/pembrolizumab) were included from the Flatiron database. Overall survival (OS) was evaluated using multivariable Cox models with the following subgroup analyses: patients with data on clinical performance and liver function and patients receiving tyrosine kinase inhibitors. Results: n = 1770 patients were included (PD-1 IMT 19.3%). Overall, PD-1 IMT was associated with longer OS (hazard ratio [HR]: 0.57). This effect was robust across both subgroup analyses with HR: 0.72 (subgroup 1) and HR: 0.57 (subgroup 2). Conclusions: PD-1 IMT is increasingly used in clinical practice and associated with an OS benefit.

PD-1-directed immunotherapy (PD-1 IMT) is increasingly used for the treatment of advanced hepatocellular carcinoma in the USA. Patients receiving PD-1 IMT demonstrate a favorable overall survival compared with those without PD-1 IMT treatment.

Prognosis of patients with hepatocellular carcinoma treated with immunotherapy - development and validation of the CRAFITY score.

BACKGROUND & AIMS: Immunotherapy with atezolizumab plus bevacizumab represents the new standard of care in systemic front-line treatment of hepatocellular carcinoma (HCC). However, biomarkers that predict treatment success and survival remain an unmet need. METHODS: Patients with HCC put on PD-(L)1-based immunotherapy were included in a training set (n = 190; 6 European centers) and a validation set (n = 102; 8 European centers). We investigated the prognostic value of baseline variables on overall survival using a Cox model in the training set and developed the easily applicable CRAFITY (CRP and AFP in ImmunoTherapY) score. The score was validated in the independent, external cohort, and evaluated in a cohort of patients treated with sorafenib (n = 204). RESULTS: Baseline serum alpha-fetoprotein ≥100 ng/ml (hazard ratio [HR] 1.7; p = 0.007) and C-reactive protein ≥1 mg/dl (HR, 1.7; p = 0.007) were identified as independent prognostic factors in multivariable analysis and were used to develop the CRAFITY score. Patients who fulfilled no criterion (0 points; CRAFITY-low) had the longest median overall survival (27.6 (95% CI 19.5-35.8) months), followed by those fulfilling 1 criterion (1 point; CRAFITY-intermediate; 11.3 (95% CI 8.0-14.6) months), and patients meeting both criteria (2 points; CRAFITY-high; 6.4 (95% CI 4.8-8.1) months; p <0.001). Additionally, best radiological response (complete response/partial response/stable disease/progressive disease) was significantly better in patients with lower CRAFITY score (CRAFITY-low: 9%/20%/52%/20% vs. CRAFITY-intermediate: 3%/25%/36%/36% vs. CRAFITY-high: 2%/15%/22%/61%; p = 0.003). These results were confirmed in the independent validation set and in different subgroups, including Child-Pugh A and B, performance status 0 and ≥1, and first-line and later lines. In the sorafenib cohort, CRAFITY was associated with survival, but not radiological response. CONCLUSIONS: The CRAFITY score is associated with survival and radiological response in patients receiving PD-(L)1 immunotherapy. The score may help with patient counseling but requires prospective validation. LAY SUMMARY: The immunotherapy-based regimen of atezolizumab plus bevacizumab represents the new standard of care in systemic first-line therapy of hepatocellular carcinoma (HCC). Biomarkers to predict treatment outcome are an unmet need in patients undergoing immunotherapy for HCC. We developed and externally validated a score that predicts outcome in patients with HCC undergoing immunotherapy with immune checkpoint blockers.

Early prediction of clinical response to checkpoint inhibitor therapy in human solid tumors through mathematical modeling.

Background: Checkpoint inhibitor therapy of cancer has led to markedly improved survival of a subset of patients in multiple solid malignant tumor types, yet the factors driving these clinical responses or lack thereof are not known. We have developed a mechanistic mathematical model for better understanding these factors and their relations in order to predict treatment outcome and optimize personal treatment strategies. Methods: Here, we present a translational mathematical model dependent on three key parameters for describing efficacy of checkpoint inhibitors in human cancer: tumor growth rate (α), tumor-immune infiltration (Λ), and immunotherapy-mediated amplification of anti-tumor response (µ). The model was calibrated by fitting it to a compiled clinical tumor response dataset (n = 189 patients) obtained from published anti-PD-1 and anti-PD-L1 clinical trials, and then validated on an additional validation cohort (n = 64 patients) obtained from our in-house clinical trials. Results: The derived parameters Λ and µ were both significantly different between responding versus nonresponding patients. Of note, our model appropriately classified response in 81.4% of patients by using only tumor volume measurements and within 2 months of treatment initiation in a retrospective analysis. The model reliably predicted clinical response to the PD-1/PD-L1 class of checkpoint inhibitors across multiple solid malignant tumor types. Comparison of model parameters to immunohistochemical measurement of PD-L1 and CD8+ T cells confirmed robust relationships between model parameters and their underlying biology. Conclusions: These results have demonstrated reliable methods to inform model parameters directly from biopsy samples, which are conveniently obtainable as early as the start of treatment. Together, these suggest that the model parameters may serve as early and robust biomarkers of the efficacy of checkpoint inhibitor therapy on an individualized per-patient basis. Funding: We gratefully acknowledge support from the Andrew Sabin Family Fellowship, Center for Radiation Oncology Research, Sheikh Ahmed Center for Pancreatic Cancer Research, GE Healthcare, Philips Healthcare, and institutional funds from the University of Texas M.D. Anderson Cancer Center. We have also received Cancer Center Support Grants from the National Cancer Institute (P30CA016672 to the University of Texas M.D. Anderson Cancer Center and P30CA072720 the Rutgers Cancer Institute of New Jersey). This research has also been supported in part by grants from the National Science Foundation Grant DMS-1930583 (ZW, VC), the National Institutes of Health (NIH) 1R01CA253865 (ZW, VC), 1U01CA196403 (ZW, VC), 1U01CA213759 (ZW, VC), 1R01CA226537 (ZW, RP, WA, VC), 1R01CA222007 (ZW, VC), U54CA210181 (ZW, VC), and the University of Texas System STARS Award (VC). BC acknowledges support through the SER Cymru II Programme, funded by the European Commission through the Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) COFUND scheme and the Welsh European Funding Office (WEFO) under the European Regional Development Fund (ERDF). EK has also received support from the Project Purple, NIH (U54CA210181, U01CA200468, and U01CA196403), and the Pancreatic Cancer Action Network (16-65-SING). MF was supported through NIH/NCI center grant U54CA210181, R01CA222959, DoD Breast Cancer Research Breakthrough Level IV Award W81XWH-17-1-0389, and the Ernest Cockrell Jr. Presidential Distinguished Chair at Houston Methodist Research Institute. RP and WA received serial research awards from AngelWorks, the Gillson-Longenbaugh Foundation, and the Marcus Foundation. This work was also supported in part by grants from the National Cancer Institute to SHC (R01CA109322, R01CA127483, R01CA208703, and U54CA210181 CITO pilot grant) and to PYP (R01CA140243, R01CA188610, and U54CA210181 CITO pilot grant). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Programmed cell death ligand - 1 expression in triple negative breast carcinoma and its prognostic significance in Indian population.

BACKGROUND: The programmed cell death protein - 1 (PD-1) - programmed cell death ligand - 1 (PD-L1) axis is emerging as a promising target for immunotherapy in triple-negative breast cancers (TNBC). AIMS: We analyzed the expression of PD-L1 in TNBC cases, with special emphasis on lymphocyte-predominant tumors along with correlation of the same with clinicopathological features and outcome. SETTINGS AND DESIGN: Tissue microarrays (TMA) were prepared from resection specimens of TNBC cases diagnosed from 2004 to 2008. SUBJECTS AND METHODS: Immunohistochemical staining was performed on the TMA using the ventana PD-L1 antibody (Clone SP 263). STATISTICAL ANALYSIS: Chi-square test was used for correlation of PD-L1 positivity in tumor and immune cells with clinicopathological features. Univariate and multivariate survival analyses were carried out using the Kaplan Meir and Cox Regression methods, respectively. RESULTS: Overall, PD-L1 staining was seen in 35.9% (66 out of 184) tumors. PD-L1 positivity of tumor cells was seen in 14.7% (27 out of 184 cases), whereas stromal immune cell expression was observed in 21.2% (39 out of 184) cases. Lymphocyte-predominant tumors showed statistically significant expression of PD-L1 in both tumor (P < 0.0001) and immune cells (P 0.036). On univariate analysis, PD-L1 in immune cells was associated with good overall survival (P 0.05) as well as disease-free survival (P 0.013). On multivariate analysis, the same was associated with a significantly decreased risk for recurrence (P 0.018). CONCLUSION: PD-L1 expression in stromal immune cells proved to be a significant prognostic factor for TNBC. This data can serve as a baseline to plan clinical trials with anti-PD-L1 drugs for TNBC in the Indian setting.

Use of Second-line Immunotherapy in Control Arms of Randomized Clinical Trials in Kidney Cancer: A Systematic Review.

Importance: Immunotherapy (anti-programmed death ligand 1 antibodies) is associated with improved survival rates in advanced kidney cell carcinoma (KCC) after progression on first-line tyrosine kinase inhibitor (TKI) treatment. It is unknown whether and to what degree patients in the control arm receive postprotocol immunotherapy in trials comparing combination immunotherapy regimens with TKI in first-line advanced KCC. Objective: To characterize the proportion of patients in the control arm who received postprotocol immunotherapy in trials comparing combination immunotherapy regimens with TKI in first-line advanced KCC. Evidence Review: A search of PubMed was conducted to identify randomized clinical trials of combination immunotherapy compared with TKI in first-line advanced KCC between January 1, 2015, and February 28, 2021. Combination immunotherapy was defined as an anti-programmed death ligand 1 agent and an additional agent. Search terms included renal cell cancer and first-line and were filtered by the type clinical trial. All English-language trials of combination immunotherapy compared with a TKI were included. The trials and their protocols and supplements were analyzed to determine the proportion of patients in the control arm receiving postprotocol immunotherapy. Findings: A total of 106 articles met search criteria and were screened. A total of 6 trials and 3 published updates of trial results were included in the systematic review. Of 2565 patients assigned to control arm groups, 2069 (81%) were no longer on TKI at last data cutoff. Of patients in the control arm who discontinued TKI, 932 (45%) received postprotocol immunotherapy. Of patients in the control arm receiving any type of postprotocol therapy, 66.4% received immunotherapy. Conclusions and Relevance: This systematic review found that the proportion of patients in the control arm receiving postprotocol immunotherapy is low in randomized clinical trials of first-line combination immunotherapy regimens for advanced KCC. Appropriate use of postprotocol therapy is essential to answering the question of whether a combination or sequential treatment strategy with immunotherapy is superior.

Comparison of Survival Outcomes With/Without Adjuvant Radiation Therapy in Desmoplastic Melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare variant of cutaneous melanoma with a high rate of local recurrence. Recent studies have indicated a potential benefit in local control with the addition of adjuvant radiotherapy (RT). OBJECTIVE: This study sought to evaluate the outcomes of adjuvant RT for patients with DM. MATERIALS AND METHODS: The National Cancer Database was queried (2004-2015) for patients with newly diagnosed, nonmetastatic DM. Patients were divided into 2 groups based on the adjuvant therapy they received: RT or observation. Statistics included multivariable logistic regression to determine factors predictive of receiving adjuvant RT, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: There was no difference in median OS between patients treated with RT when compared with patients observed (111.4 months vs 133.9 months, p = .1312). On multivariable analysis, older age, T stage ≥2, N stage ≥1, and no receipt of immunotherapy were associated with worse OS. CONCLUSION: In this large study evaluating efficacy of adjuvant RT in DM, no overall survival benefit was observed among patients receiving adjuvant RT.

T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model.

BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aimed to use a mouse model to elucidate the molecular mechanisms of immune-related hepatitis, one of the common irAEs associated with ICIs. METHODS: Immune phenotyping and molecular profiling were performed on Pdcd1-/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor epacadostat or a 4-1BB agonistic antibody. RESULTS: ICI combination-induced hepatitis and 4-1BB agonist-mediated hepatitis share similar features yet maintain distinct immune signatures. Both were characterized by an expansion of periportal infiltrates and pan-zonal inflammation albeit with different morphologic characteristics. In both cases, infiltrates were predominantly CD4+ and CD8+ T cells with upregulated T-cell activation markers, ICOS and CD44. Depletion of CD8+ T cells abolished ICI-mediated hepatitis. Single-cell transcriptomics revealed that the hepatitis induced by combination ICIs is associated with a robust immune activation signature in all subtypes of T cells and T helper 1 skewing. Expression profiling revealed a central role for IFNγ and liver monocyte-derived macrophages in promoting a pro-inflammatory T-cell response to ICI combination and 4-1BB agonism. CONCLUSION: We developed a novel mouse model which offers significant value in yielding deeper mechanistic insight into immune-mediated liver toxicity associated with various immunotherapies. LAY SUMMARY: Hepatitis is one of the common immune-related adverse events in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. The mechanisms of ICI-induced hepatitis are not well understood. In this paper, we identify key molecular mechanisms mediating immune intracellular crosstalk between liver T cells and macrophages in response to ICI in a mouse model.

Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Herein, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis. METHODS: We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled in interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA. RESULTS: Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer. CONCLUSIONS: Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy. LAY SUMMARY: Intratumor molecular heterogeneity is a key feature of tumorigenesis that is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.

COVID-19 in immunocompromised populations: implications for prognosis and repurposing of immunotherapies.

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. COVID-19 has highly variable disease severity and a bimodal course characterized by acute respiratory viral infection followed by hyperinflammation in a subset of patients with severe disease. This immune dysregulation is characterized by lymphocytopenia, elevated levels of plasma cytokines and proliferative and exhausted T cells, among other dysfunctional cell types. Immunocompromised persons often fare worse in the context of acute respiratory infections, but preliminary data suggest this may not hold true for COVID-19. In this review, we explore the effect of SARS-CoV-2 infection on mortality in four populations with distinct forms of immunocompromise: (1) persons with hematological malignancies (HM) and hematopoietic stem cell transplant (HCT) recipients; (2) solid organ transplant recipients (SOTRs); (3) persons with rheumatological diseases; and (4) persons living with HIV (PLWH). For each population, key immunological defects are described and how these relate to the immune dysregulation in COVID-19. Next, outcomes including mortality after SARS-CoV-2 infection are described for each population, giving comparisons to the general population of age-matched and comorbidity-matched controls. In these four populations, iatrogenic or disease-related immunosuppression is not clearly associated with poor prognosis in HM, HCT, SOTR, rheumatological diseases, or HIV. However, certain individual immunosuppressants or disease states may be associated with harmful or beneficial effects, including harm from severe CD4 lymphocytopenia in PLWH and possible benefit to the calcineurin inhibitor ciclosporin in SOTRs, or tumor necrosis factor-α inhibitors in persons with rheumatic diseases. Lastly, insights gained from clinical and translational studies are explored as to the relevance for repurposing of immunosuppressive host-directed therapies for the treatment of hyperinflammation in COVID-19 in the general population.

Real-World Survival Outcomes Associated With First-Line Immunotherapy, Targeted Therapy, and Combination Therapy for Metastatic Clear Cell Renal Cell Carcinoma.

Importance: Clinical trials have shown an overall survival (OS) benefit associated with first-line immunotherapy (IT) and combination targeted therapy (TT) and IT regimens compared with TT among patients with metastatic clear cell renal cell carcinoma (RCC). Generalizability of these findings in a real-world cohort outside of a clinical trial setting is unclear. Objective: To assess the association of first-line TT, IT, and combination TT and IT regimens with OS in a real-world cohort of patients with metastatic clear cell RCC. Design, Setting, and Participants: This retrospective propensity-matched cohort study identified 5872 patients with metastatic clear cell RCC in the National Cancer Database from January 1, 2015, to December 31, 2017, who received first-line TT, IT, or combination TT and IT and were not treated on a clinical trial protocol. Patients were stratified by first-line systemic treatment. Statistical analysis was conducted from October 1 to December 1, 2020. Main Outcomes and Measures: The primary outcome was OS from the date of diagnosis to death or censoring at last follow-up. After 1:1:1 nearest-neighbor caliper matching of propensity scores, survival analyses were conducted using Cox proportional hazards regression and Kaplan-Meier estimates. Results: The final study population included 5872 patients (TT group: n = 4755 [81%]; 3332 men [70%]; median age, 64 years [interquartile range, 57-71 years]; IT group: n = 638 [11%]; 475 men [74%]; median age, 61 years [interquartile range, 54-69 years]; and combination TT and IT group: n = 479 [8%]; 321 men [67%]; median age, 62 years [interquartile range, 55-69 years]), and the matched cohort included 1437 patients (479 per treatment group). Patients in the IT and combination TT and IT groups were younger than those in the TT group, had fewer comorbid conditions (Charlson-Deyo score of 0, 480 of 638 [75%] in the TT group, 356 of 479 [74%] in the IT group, and 3273 of 4755 [69%] in the combination TT and IT group), and were more often treated at academic centers (315 of 638 [49%], 216 of 479 [45%], and 1935 of 4755 [41%], respectively). Both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC (IT group: hazard ratio [HR], 0.60 [95% CI, 0.48-0.75]; P < .001; combination TT and IT group: HR, 0.74 [95% CI, 0.60-0.91]; P = .005). No survival difference was seen between the IT and combination TT and IT groups (combination TT and IT: HR, 1.24 [95% CI, 0.98-1.56]; P = .08). Conclusions and Relevance: This study suggests that both first-line IT and combination TT and IT were associated with improved OS compared with first-line TT for patients with metastatic clear cell RCC. These findings are similar to those identified in recently reported clinical trials, lending confidence to the broader applicability of these findings outside of a clinical trial setting.

Importance of Margins, Radiotherapy, and Systemic Therapy in Mucosal Melanoma of the Head and Neck.

OBJECTIVES/HYPOTHESIS: The ideal strategy in the treatment of mucosal melanoma of the head and neck (MMHN) remains unclear. Our objective was to evaluate the importance of surgical margins, radiotherapy, and systemic therapy in MMHN. STUDY DESIGN: Retrospective Single Institutional Review. METHODS: Retrospective review of patients with MMHN treated at a tertiary care oncology center between 1999 and 2016. RESULTS: Seventy-six patients were included, 60 of whom were treated with curative intent. Negative or close margins compared with positive margins were associated with higher 3-year overall survival (OS) (62% vs. 29% vs. 13% P = .012), disease-free survival (33% vs. 29% vs. 4% P = .003), and distant control (48% vs. 29% vs. 22% P = .039). Cases with pre-/postoperative radiotherapy had a marginally higher locoregional control versus without (69% vs. 59%, P = .117). Immunotherapy for recurrent and/or metastatic disease was associated with an increase in 3-year OS (15% vs. 3% P = .01). CONCLUSION: Achieving negative surgical margins is relevant in disease control. Despite small sample size, our data suggest that radiotherapy may enhance surgical outcomes. Immunotherapy has therapeutic benefit. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2269-2276, 2021.

Treatment patterns in patients with metastatic non-small-cell lung cancer in the era of immunotherapy.

Background: Chemotherapy (CT) alone was previously standard first-line (1L) therapy for metastatic non-small-cell lung cancer (NSCLC) but alternative treatments, including immunotherapy (I-O), are now available. Patients & methods: In this retrospective study, adults with stage IV NSCLC who initiated 1L treatment between 1 August 2018 and 31 December 2019 and had ≥2 visits were identified in the Flatiron database. Patients were followed up until 30 June 2020. Baseline characteristics and treatment patterns were described by treatment group: CT, I-O + CT, I-O monotherapy and other. Results: Approximately 20% of patients received 1L CT in the 2018-2019 timeframe studied; these patients tended to have squamous histology and low (≤49%) programmed death ligand-1 expression. Conclusion: A proportion of patients with metastatic NSCLC still receive 1L CT despite the availability and widespread use of I-O therapies.

Finding an easy way to harmonize: a review of advances in clinical research and combination strategies of EZH2 inhibitors.

Enhancer of zeste homolog 2 inhibitors (EZH2i) have garnered increased attention owing to their anticancer activity by targeting EZH2, a well-known cancer-promoting factor. However, some lymphomas are resistant to EZH2i, and EZH2i treatment alone is ineffective in case of EZH2-overexpressing solid tumors. The anti-cancer efficacy of EZH2i may be improved through safe and effective combinations of these drugs with other treatment modalities. Preclinical evidence indicates that combining EZH2i with other therapies, such as immunotherapy, chemotherapy, targeted therapy, and endocrine therapy, has complementary or synergistic antitumor effects. Therefore, elucidating the underlying mechanisms of the individual constituents of the combination therapies is fundamental for their clinical application. In this review, we have summarized notable clinical trials and preclinical studies using EZH2i, their progress, and combinations of EZH2i with different therapeutic modalities, aiming to provide new insights for tumor treatment.