ICI Group Research Articles

Real-World Survival Outcomes of First-Line Therapies in Patients with Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Analysis from Two Centres in Saudi Arabia.

Background: Metastatic renal cell carcinoma (mRCC) represents a challenging condition characterised by poor prognosis and limited response to chemoradiotherapy. In this retrospective study, we compared the survival outcomes of first-line ICI regimens versus single-agent TKIs in patients with mRCC from two centres in Saudi Arabia. Methods: This study included 84 patients diagnosed with clear cell mRCC between January 2016 and December 2023. Patients were grouped based on treatment regimens. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and Cox proportional hazards regression. Results: The median first-line PFS was 9.7 months (95% CI: 5.3-14.1) for the overall cohort, with no significant difference between the single-agent tyrosine kinase inhibitor (TKI) group (9.4 months; 95% CI: 6.4-12.4), combination ICI group (9.0 months; 95% CI: 0.0-24.9), and single-agent ICI group (21.2 months; 95% CI: 2.6-39.8; p = 0.591). The median OS for the overall cohort was 42.0 months (95% CI: 14.9-69.2), with the single-agent TKI group having a median OS of 33.3 months (95% CI: 0.0-71.7), the combination ICI group, 42.0 months (95% CI: 0.06-84.0), and the single-agent ICI group, 23.0 months (95% CI: 19.2-26.7; p = 0.73). In comparison, the ICI-based combination therapy group exhibited a higher ORR of 41.0% (95% CI: 26.3-57.8%), while the single-agent ICI group had an ORR of 20.0% (95% CI: 3.5-55.8%). Cox regression identified liver metastasis as a significant independent predictor of PFS (HR = 1.8, p = 0.043), while a lower Karnofsky Performance Status was a significant independent predictor of OS (HR = 3.5, p < 0.001). Conclusions: In real-world practice from Saudi Arabia, first-line, single-agent ICI therapy offers promising anti-tumour activity and non-inferior survival outcomes compared to standard ICI-based combinations and single-agent TKIs.

The Clinicopathological Characteristics and Prognosis of 55 Patients With TFE3-Rearranged Renal Cell Carcinomas

ObjectiveTo explore the clinicopathological features and prognosis of TFE3-rearranged renal cell carcinomas (TFE3-rRCC). MethodsIn this retrospective observational study, the data of patients with TFE3-rRCC admitted to Xijing Hospital from January 2010 to October 2023 were collected, encompassing the general information, pathological diagnosis, immunohistochemistry, and the results of FISH detection. The treatment information and survival data of the patients were recorded during the follow-up. ResultsA total of 55 patients with TFE3-rRCC were enrolled, among whom 25 were males and 30 were females. TFE3 FISH assay suggested the disruption of the TFE3 gene. Fifty-four patients underwent surgical resection of kidney lesions, while 1 patient did not. By the end of follow-up in December 2023, 3 patients were lost to follow-up, 28 patients remained alive, and 24 patients had died. Among the 52 patients followed up, 31 developed metastases, involving lymph nodes, liver, bone, lung, peritoneum, pleura, adrenal gland, and brain. The 1-year and 5-year survival rates of the patients were 84.6% and 50.6%, respectively. In this study, there were 31 patients with TFE3-rRCC recurrence or metastasis. Median PFS was 7 and 13 months in the VEGFR-TKI and VEGFR-TKI+ ICI groups, respectively. The median OS was 12 months in the VEGFR-TKI treatment group. The median OS data of VEGFR-TKI+ ICI group has not been reached. The ORR and DCR was 25%, 66.7% in the VEGFR-TKI group. The ORR and DCR was 33.3%, 77.8% in the VEGFR-TKI+ ICI group. ConclusionTFE3-rRCC is a rare subtype of malignant renal tumor. The diagnosis mainly relies on pathological morphology, immunohistochemistry, and the detection of TFE3 gene disruption by FISH. In terms of treatment, surgery is the primary approach, and lymph nodes, liver, and bone are the main metastatic sites. VEGFR-TKI+ICI treatment might be an option of recurrent or metastatic TFE3-rRCC.

Impact of cognitive impairment on driving behaviour and route choices of older drivers: a real-world driving study

Maintaining driving independence is important for older adults. However, cognitive decline, a common issue in older populations, can impair older adults’ driving abilities and overall safety on the roads. This study explores how cognitive impairment influences driving patterns and driving choices among older adults. We analyzed real-world driving patterns of 246 older adults using GPS dataloggers. Our sample included 230 cognitively normal older adults (CN; Clinical Dementia RatingR\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^R$$\\end{document} [CDR] = 0) and 16 older adults with incident cognitive impairment (ICI; CDR = 0.5). The CN group had an average age of 68.2 years, with 46% females and an average of 16.5 years of education, while the ICI group’s average age was 69.2 years, with 36% females and an average of 16.0 years of education. We employed spatial clustering and hashing algorithms to evaluate driving behaviours. Significant differences emerged: The ICI group used fewer distinct routes to their most common destination. These differences can be leveraged to develop driving as a digital biomarker for the early detection and continuous monitoring of cognitive impairment.

Real-world outcomes of third-line immune checkpoint inhibitors versus irinotecan-based chemotherapy in patients with advanced gastric cancer: a Korean, multicenter study (KCSG ST22-06)

BackgroundImmune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy is frequently used after failure of second-line paclitaxel plus ramucirumab treatment for patients with locally advanced unresectable or metastatic advanced gastric cancer (AGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with AGC.MethodsWe retrospectively reviewed patients with AGC, whose third-line treatment started between July 2019 and June 2021 at 17 institutions in Korea. The ICI group included patients who received nivolumab or pembrolizumab, and the irinotecan-based chemotherapy group included patients who received irinotecan or FOLFIRI (5-fluorouracil, leucovorin and irinotecan).ResultsA total of 363 patients [n = 129 (ICI) and n = 234 (irinotecan-based chemotherapy)] were analyzed. The median progression-free survival was 2.3 and 2.9 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.802). The median overall survival (OS) was 5.5 and 6.0 months in ICI and irinotecan-based chemotherapy groups, respectively (p = 0.786). For all patients included in this study, multivariable analysis showed that weight loss, peritoneal metastasis, low serum sodium or albumin, and short duration of second-line treatment were associated with inferior OS (p < 0.05). ICI showed significantly longer OS than irinotecan-based chemotherapy in patients without peritoneal metastasis. Whereas ICI showed significantly shorter OS in patients without PD-L1 expression than irinotecan-based chemotherapy.ConclusionsNo significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for AGC patients. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression.Trial registrationThis study was registered in the Clinical Trial Registry of Korea (https://cris.nih.go.kr: KCT 0007732).

Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study

PurposeImmune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC.MethodsWe analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003).ResultsA total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046).ConclusionICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.

Immune checkpoint inhibitors in cancer: the increased risk of atherosclerotic cardiovascular disease events and progression of coronary artery calcium

BackgroundImmune checkpoint inhibitors (ICIs) have contributed to a significant advancement in the treatment of cancer, leading to improved clinical outcomes in many individuals with advanced disease. Both preclinical and clinical investigations have shown that ICIs are associated with atherosclerosis and other cardiovascular events; however, the exact mechanism underlying this relationship has not been clarified.MethodsPatients diagnosed with stages III or IV non-small cell lung cancer (NSCLC) at the Wuhan Union Hospital from March 1, 2020, to April 30, 2022, were included in this retrospective study. Coronary artery calcium (CAC) volume and score were assessed in a subset of patients during non-ECG-gated chest CT scans at baseline and 3, 6, and 12 months after treatment. Propensity score matching (PSM) was performed in a 1:1 ratio to balance the baseline characteristics between the two groups.ResultsOverall, 1458 patients (487 with ICI therapy and 971 without ICI therapy) were enrolled in this cardiovascular cohort study. After PSM, 446 patients were included in each group. During the entire period of follow-up (median follow-up 23.1 months), 24 atherosclerotic cardiovascular disease (ASCVD) events (4.9%) occurred in the ICI group, and 14 ASCVD events (1.4%) in the non-ICI group, before PSM; 24 ASCVD events (5.4%) occurred in the ICI group and 5 ASCVD events (1.1%) in the non-ICI group after PSM. The CAC imaging study group comprised 113 patients with ICI therapy and 133 patients without ICI therapy. After PSM, each group consisted of 75 patients. In the ICI group, the CAC volume/score increased from 93.4 mm3/96.9 (baseline) to 125.1 mm3/132.8 (at 12 months). In the non-ICI group, the CAC volume/score was increased from 70.1 mm3/68.8 (baseline) to 84.4 mm3/87.9 (at 12 months). After PSM, the CAC volume/score was increased from 85.1 mm3/76.4 (baseline) to 111.8 mm3/121.1 (12 months) in the ICI group and was increased from 74.9 mm3/76.8 (baseline) to 109.3 mm3/98.7 (12 months) in the non-ICI group. Both cardiovascular events and CAC progression were increased after the initiation of ICIs.ConclusionsTreatment with ICIs was associated with a higher rate of ASCVD events and a noticeable increase in CAC progression.

Intrathoracic Progression Is Still the Most Dominant Failure Pattern after First-Line Chemo-immunotherapy in Extensive-Stage Small-Cell Lung Cancer: Implications for Thoracic Radiotherapy.

This study aimed to compare the failure patterns before and after the introduction of immunotherapy and to determine the role of thoracic radiotherapy (TRT) in extensive-stage small-cell lung cancer (ES-SCLC) treatment. We retrospectively reviewed 294 patients with ES-SCLC, of which 62.2% underwent chemotherapy alone, 13.3% underwent chemotherapy followed by consolidative TRT (TRT group), and 24.5% underwent chemotherapy with immune checkpoint inhibitor (ICI group). We performed propensity-score matching (PSM) to compare each treatment group. The median follow-up duration was 10.4 months. At the first relapse, in the cohort showing objective response, the proportion of cases showing intrathoracic progression was significantly lower in the TRT group (37.8%) than in the chemotherapy-alone (77.2%, p < 0.001) and the ICI (60.3%, p=0.03) groups. Furthermore, in the subgroup analysis, TRT showed benefits related to intrathoracic progression-free survival (PFS) in comparison with ICI in patients with less than two involved extrathoracic sites (p=0.008) or without liver metastasis (p=0.02) or pleural metastasis (p=0.005) at diagnosis. After PSM, the TRT group showed significantly better intrathoracic PFS than both chemotherapy-alone and ICI groups (p < 0.001 and p=0.04, respectively), but showed no significant benefit in terms of PFS and overall survival in comparison with the ICI group (p=0.17 and p=0.31, respectively). In ES-SCLC, intrathoracic progression was the most dominant failure pattern after immunotherapy. In the era of chemoimmunotherapy, consolidative TRT can still be considered a useful treatment strategy for locoregional control.

Single-cell mass cytometric analysis of peripheral immunity and multiplex plasma marker profiling of non-small cell lung cancer patients receiving PD-1 targeting immune checkpoint inhibitors in comparison with platinum-based chemotherapy.

The effect of platinum-based chemotherapy (Chem.) and second- or multiple- line immune checkpoint PD-1 blocking therapy by Nivolumab or Pembrolizumab (ICI) was assayed in the peripheral blood of non-small cell lung cancer (NSCLC) patients. Flow cytometry was used to detect NSCLC-related antigen binding IgG antibodies. The Luminex MagPix multiplex bead-based cytokine/chemokine detecting system was used to quantitatively measure 17 soluble markers in the plasma samples. Single-cell mass cytometry was applied for the immunophenotyping of peripheral leukocytes. The incubation of patient derived plasma with human NSCLC tumor cell lines, such as A549, H1975, and H1650, detected NSCLC-specific antibodies reaching a maximum of up to 32% reactive IgG-positive NSCLC cells. The following markers were detected in significantly higher concentration in the plasma of Chem. group versus healthy non-smoker and smoker controls: BTLA, CD27, CD28, CD40, CD80, CD86, GITRL, ICOS, LAG-3, PD-1, PD-L1, and TLR-2. The following markers were detected in significantly higher concentration in the plasma of ICI group versus healthy non-smoker and smoker controls: CD27, CD28, CD40, GITRL, LAG-3, PD-1, PD-L1, and TLR-2. We showed the induction of CD69 and IL-2R on CD4+ CD25+ T-cells upon chemotherapy; the exhaustion of one CD8+ T-cell population was detected by the loss of CD127 and a decrease in CD27. CD19+CD20+, CD79B+, or activated B-cell subtypes showed CD69 increase and downregulation of BTLA, CD27, and IL-2R in NSCLC patients following chemotherapy or ICI. Peripheral immunophenotype caused by chemotherapy or PD-1 blocking was shown in the context of advanced NSCLC.

Systematic comparison with autoimmune liver disease identifies specific histological features of immune checkpoint inhibitor-related adverse events

BackgroundImmune checkpoint inhibitors (ICIs) have become a mainstay of cancer treatment. Their immune-boosting quality has one major drawback, their proclivity to induce a broad array of immune-related adverse events (irAEs)...

Increased risk of incident diabetes after therapy with immune checkpoint inhibitor compared with conventional chemotherapy: A longitudinal trajectory analysis using a tertiary care hospital database

Aims/hypothesisImmune checkpoint inhibitor (ICI) has been emerged as a promising cancer treatment. However, ICI use induces immune-related adverse events, including diabetes mellitus. We compared the risk of new-onset diabetes between patients receiving an ICI and those receiving conventional chemotherapy (CC). MethodsUsing a tertiary care hospital database, we included cancer patients without a previous history of diabetes who were treated with either CC or an ICI. One-to-five nearest neighbor propensity matching was applied, and the risk of diabetes was estimated using a Cox proportional hazards model. Latent class growth modeling was performed with a trajectory approach to determine distinct clusters that followed similar glucose trajectory patterns over time. ResultsAmong 1326 subjects, 1105 received CC, and 221 received an ICI. The risk of new-onset diabetes was significantly higher in the ICI group than the CC group (adjusted hazard ratio 2.454, 95 % confidence interval 1.528–3.940; p < 0.001). The ICI group had a higher proportion of subjects in the trajectory cluster with an increasing glucose pattern than the CC group (10.4 % and 7.4 %, respectively). Within the ICI group, the subjects with an increasing glucose pattern were predominantly male and associated with enhanced lymphocytosis after ICI administration. ConclusionsICI therapy is associated with an increased risk of incident diabetes compared with CC. The glucose levels of patients treated with an ICI, especially males and those with prominent lymphocytosis after ICI treatment, need to be monitored regularly to detect ICI-associated diabetes as early as possible.

TNF-α inhibitor ameliorates immune-related arthritis and pneumonitis in humanized mice

ObjectivesThis study aimed at establishing a mouse model of immune-related adverse in humanized BALB/c-hPD1/hCTLA4 mice to investigate their potential pathogenesis and explore therapeutic targets for immune-related arthritis and pneumonitis.MethodsHumanized BALB/c-hPD1/hCTLA4 mice were injected with vehicle or collagen-specific antibodies (CA) and immune checkpoint inhibitors (ICI, ipilimumab, anti-human CTLA-4; and nivolumab, anti-human PD-1), and some mice were treated with anti-TNF-α antibody, leading to the control, collagen antibody-induced arthritis (CAIA), CAIA+ICI and treatment groups. The severity of clinical arthritis and pneumonitis in mice was monitored longitudinally and the pathological changes in the joints and lungs were histologically analyzed and the contents of lung hydroxyproline were measured. The frequency of different subsets of T cells was analyzed by flow cytometry and multiplex immunofluorescency.ResultsCompared with the control, the ICI group of mice developed the delayed onset of moderate degrees of arthritis while the CAIA+ICI group of mice exhibited the early onset of severe arthritis. Treatment with ICI caused severe pneumonitis, especially in the mice with CA. Flow cytometry analysis indicated a significantly higher frequency of splenic TNF-α+CD4+ and TNF-α+CD8+ T cells, but not other subsets of T cells tested, in the CAIA+ICI group of mice, relative to that in other groups of mice. Treatment with anti-TNF-α significantly mitigated the severity of arthritis and pneumonitis as well as deposition of collagen in lung of mice. The treatment also decreased the frequency of TNF-α+CD4+ and TNF-α+CD8+ T cells as well as effector memory T cells in the periphery lymph orangs and lungs of mice.ConclusionsWe successfully established a humanized mouse model of ICI-related severe arthritis and pneumonitis with a higher frequency of TNF-α+ T cells, which were significantly mitigated by anti-TNF-α treatment. Conceptually, ICI treatment can induce multiple autoimmune-like diseases in autoimmune-prone individuals and TNF-α+ T cells may be therapeutic targets for intervention of immune-related arthritis and pneumonitis.

Effectiveness of an integrated primary care intervention in improving psychosocial outcomes among Latino adults with diabetes: the LUNA-D study.

To compare the effectiveness of usual care (UC) versus a culturally tailored integrated care model in improving mental health symptoms for Latino patients with Type 2 diabetes mellitus (T2DM). We conducted a two-arm randomized controlled trial from 2015 to 2019 at a federally qualified health center. Participants were 456 adults ages 23-80 years who had a previous diagnosis of T2DM and were not currently using insulin. Participants were randomly assigned to Integrated Care Intervention (ICI; including behavioral/mental healthcare, medical visits, health education and care coordination) or UC; standard of care including referrals for health education and behavioral/mental health care where appropriate. Intention-to-treat, multilevel models were used to compare group × time changes in depression and anxiety symptoms (PHQ-8; GAD-7) and perceived stress (PSS-10) across 6 months. Participant mean age was 55.7 years, 36.3% were male, and 63.7% were primarily Spanish speaking. Baseline sociodemographic factors and mental health symptoms across study arms were balanced. Significant group × time interaction effects were observed for anxiety and depression symptoms (p < .05). Within the ICI and UC groups, mean depression symptom changes were -0.93 and -0.39 (p < .01); anxiety symptom changes were -0.97 (p < .01) and -0.11 (p = .35); and perceived stress changes were -1.56 and -1.27 (p < .01), respectively. Although both ICI and UC showed decreases over time, the ICI group evidenced larger, statistically significant changes in both depression and anxiety. Adapted integrated models of behavioral and chronic disease management appear to be effective and could be considered for usual care practices. NCT03983499.

Outcomes of patients with advanced non-clear cell renal cell carcinoma treated with first-line immune checkpoint inhibitor therapy

BackgroundImmune checkpoint inhibitors (ICI) have demonstrated impressive activity in metastatic clear-cell renal cell carcinoma (ccRCC) and have become standard treatment options for patients with advanced disease. Data supporting the effectiveness of ICI-based therapy in advanced non-clear cell RCC (nccRCC) is more limited. MethodsWe performed a retrospective analysis using the International Metastatic RCC Database Consortium (IMDC) to evaluate the outcomes of patients with advanced nccRCC. Patients were classified into three groups based on first-line therapy: ICI-based therapy (monotherapy or combination), vascular endothelial growth factor (VEGF) inhibitor monotherapy, or mammalian target of rapamycin (mTOR) inhibitor monotherapy. The primary outcome was overall survival (OS). Secondary outcomes were time to treatment failure (TTF) and objective response rate (ORR). We used the Kaplan–Meier method to compare OS and TTF between treatment groups and Cox proportional hazards models to adjust for prognostic covariates. ResultsWe identified a total of 1145 patients with metastatic nccRCC. The most common subtype was papillary RCC (54.9%). For first-line therapy, 74.3% received VEGF monotherapy, 15% received mTOR monotherapy, and 10.7% received ICI-based therapy. Median OS in the ICI group was 28.6 months, versus 16.4 months in the VEGF group and 12.2 months in the mTOR group. Median TTF in the ICI group was 6.9 months, versus 5.0 months in the VEGF group and 3.9 months in the mTOR group. ORR was 27.2% in the ICI group, 14.5% in the VEGF group, and 9% in the mTOR group. After adjusting for the IMDC risk group, histological subtype, and age, the hazard ratio for OS was 0.57 (95% CI 0.42–0.78, p < 0.0001) for ICI versus VEGF and 0.50 (95% CI 0.36–0.71, p < 0.0001) for ICI versus mTOR. ConclusionsIn advanced nccRCC, first-line ICI-based treatment appears to be associated with improved OS compared to VEGF and mTOR targeted therapy. These results should be confirmed in prospective randomised trials.

Cytomegalovirus infection among patients with cancer receiving immune checkpoint inhibitors.

BackgroundImmune checkpoint inhibitors (ICIs), used for the treatment of solid and hematologic malignancies, come with the risk of immune-related adverse events (irAEs). Opportunistic infections (e.g., cytomegalovirus [CMV]) mimic irAE symptoms and are understudied in this population. We aimed to describe the incidence, characteristics, treatment and outcomes of CMV infection in ICI-treated patients.MethodsWe conducted a single-center retrospective review of all adult patients who were CMV-positive after ICI therapy between 06/2011 and 05/2020. A CMV-positive non-ICI cohort was matched to the ICI group based on age, sex and cancer type. Variables of interest were collected through electronic medical records.ResultsThe study population comprised 192 patients overall. CMV infection incidence was 7.7% in ICI patients and 12.9% in non-ICI patients (P<0.001). Rates of infection clearance (83% vs. 50%, P=0.002) and recurrence (20% vs. 3%, P=0.037) were higher in ICI patients with hematologic vs. solid tumors, despite similar treatments. All-cause mortality was higher in solid rather than hematologic malignancies in ICI patients (83% vs. 54%, P=0.009); CMV-related mortality was low (3-4%) in both groups.ConclusionsCMV infection occurred in about 7.7% of the ICI-treated cancer population. The infection can be disseminated in multiple organs and has a wide spectrum of clinical symptoms. ICI-treated patients with a hematologic malignancy had higher viral clearance and recurrence than those with solid tumors. In this study, CMV itself did not lead to high mortality in cancer patients. Further study is needed to investigate the role of CMV infection in patients’ irAEs and cancer outcome.

Safety and immunogenicity of the COVID-19 vaccine BNT162b2 in patients undergoing chemotherapy for solid cancer

BackgroundAlthough COVID-19 severity in cancer patients is high, the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing chemotherapy for solid cancers in Japan have not been reported. MethodsWe investigated the safety and immunogenicity of BNT162b2 in 41 patients undergoing chemotherapy for solid cancers and in healthy volunteers who received 2 doses of BNT162b2. We evaluated serum IgG antibody titers for S1 protein by ELISA at pre-vaccination, prior to the second dose and 14 days after the second vaccination in 24 cancer patients undergoing cytotoxic chemotherapy (CC group), 17 cancer patients undergoing immune checkpoint inhibitor therapy (ICI group) and 12 age-matched healthy volunteers (HV group). Additionally, inflammatory cytokine levels were compared between the HV and ICI groups at pre and the next day of each vaccination. ResultsAnti-S1 antibody levels were significantly lower in the ICI and CC groups than in the HV group after the second dose (median optimal density: 0.241 [0.063–1.205] and 0.161 [0.07–0.857] vs 0.644 [0.259–1.498], p = 0.0024 and p < 0.0001, respectively). Adverse effect profile did not differ among the three groups, and no serious adverse event occurred. There were no differences in vaccine-induced inflammatory cytokines between the HV and ICI groups. ConclusionAlthough there were no significant differences in adverse events in three groups, antibody titers were significantly lower in the ICI and CC groups than in the HV group. Further protection strategies should be considered in cancer patients undergoing CC or ICI.

Pulmonary Lymphoepithelioma-Like Carcinoma Treated with Immunotherapy or Chemotherapy: A Single Institute Experience.

BackgroundLymphoepithelioma-like carcinoma (LELC) is a rare malignant tumor of the lung. It is related to EB virus infection. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are rarely found in this disease, while high level programmed cell death ligand 1 (PD-L1) expression is observed. Here a series of patients with advanced LELC treated with immunotherapy were summarized.MethodsThis retrospective, observational study was conducted in patients who were pathologically confirmed, metastatic or recurrent LELC patients. Patients were prescribed with either chemotherapy or immunotherapy, according to treating physicians’ discretion.ResultsA total of 27 patients were included in our study, 10 with immunotherapy (ICI group) and 17 with chemotherapy (Chemo group). The objective response rates (ORR) of the two groups were 80.0% and 70.5% (p=0.678), and disease control rates (DCR) were 100% and 88.2% (p=0.516). However, the response depth was better in the ICI group. Although the cohort of patients in the ICI group was in a disadvantageous state (both up-front and salvage), the progression-free survival (PFS) was much longer (15.0 and 7.9 m, p=0.005). The 1-year PFS rate in the ICI group was also much higher (40% and 5.9%, p=0.047).ConclusionThis study implicated the high efficiency of ICI therapy in this disease.

1769. The Impact of Checkpoint Inhibitor Immunotherapy on Infections in Lung Cancer Patients

BackgroundImmune checkpoint inhibitors (ICI) therapy has ushered cancer treatment into a potentially curative era. However, infectious complications remain largely unknown and the few studies that described infectious complications associated with ICI had no comparative control groups. We assessed the rate of infections in patients with non-small cell lung cancer (NSCLC) treated with ICI plus conventional chemotherapy (CC) vs. CC alone.MethodsWe performed a comparative single-center retrospective cohort study of patients with NSCLC who received de novo treatment with either Pembrolizumab or Nivolumab, and/or Ipilimumab combined with CC including Pemetrexed and Carboplatin vs. patients treated with CC alone between August 2016 and January 2019. We excluded all patients who were switched from CC to ICI or vice-versa. We evaluated patients’ characteristics, treatment modality, immune-related adverse events (irAEs), and outcome. Infections were defined by clinical signs and symptoms, microbiologic documentation, and/or imaging studies.ResultsA group of 126 patients who received ICI concurrently with CC were compared with 126 patients who received CC alone (control group). Patients in the ICI group were more likely to have stage IV NSCLC compared with the control group (P < 0.0001). Pembrolizumab was most commonly used as a single ICI agent in 107 patients (85%), followed by Ipilimumab and Nivolumab as dual therapy (9%). Confirmed infections were identified in 20 (16%) patients in the ICI group and 18 (14%) in the control group (P = 0.7). The control group had a higher rate of multiple infections at different times compared with the ICI group (P = 0.014). However, there was no significant difference in the types of infections (bacterial, fungal or viral) that occurred between the two groups. The irAEs were reported in 14 (11%) patients, 13 of them received corticosteroids with a median duration of 32 days (range, 15–64 days). Out of these patients, three (21%) developed confirmed infections of which two were viral upper respiratory tract infections and one was a bacterial urinary tract infection.ConclusionPatients with NSCLC treated with the combination of Immune Checkpoint Inhibitors plus Conventional Chemotherapy have comparable risk of developing infections compared with those on Conventional Chemotherapy alone.Disclosures All authors: No reported disclosures.

Hypoxia Limits the Growth of Bovine Follicles in Vitro by Inhibiting Estrogen Receptor α.

Simple SummaryIt is well documented that a hypoxic environment at high altitudes decreased the fertility of female domestic animals because of embryonic or fetal losses, intrauterine growth restriction, and birth weight reduction. However, little study has been performed on for the effects of hypoxia on bovine ovary function. In this study, we found that the hypoxia plays an important role in regulating follicular survival and genes expression. Hypoxia limits the growth of bovine follicles cultured in vitro through inhibition of ERα, which could provide useful information for future studies relating to reproduction of cattle.Female animals living in the Qinghai-Tibet Plateau have lower ovulation rates because of the hypoxic environment, however, the mechanism of hypoxia on animal follicles is unclear. In this study, the effects of hypoxia on bovine follicles were investigated using an in vitro follicular culture system. The results show that there was a significant decrease in follicular diameter from day 3 to day 6 in both hypoxia and hypoxia with estrogen (E2) and fulvestrant (ICI 182780) (hypoxia + E2 + ICI) groups, when compared with a normoxia group (p < 0.05). We also observed significant downregulation of ERα and FSHR, while upregulation of LHCGR expression in the hypoxia group and hypoxia + E2 + ICI groups compared to the normoxia group (p < 0.05). The expression of IGF1 gene was significantly downregulated in hypoxia + E2 + ICI group when compared to the hypoxia + E2 group (p < 0.05). The expression of HIF1A, ADAMTS1, VEGFA, and EDN2 were upregulated in both hypoxia and hypoxia + E2 + ICI groups in comparison to normoxia group (p < 0.05). Under hypoxic conditions, the addition of E2 resulted in a decrease of HIF1A protein but an increase of ERα protein in cultured bovine follicles (p < 0.05). In summary, hypoxia limits the growth of bovine follicle cultured in vitro through inhibition of ERα.

The role of β-adrenergic receptors and p38MAPK signaling pathways in physiological processes of cardiosphere-derived cells.

The effects of β adrenergic receptors (β-ARs) and p38 mitogen-activated protein kinases (MAPK) pathways on cardiosphere-derived cells (CDCs) are largely unknown. This study aimed to investigate the roles of β-ARs and p38MAPK pathways on the proliferation, apoptosis, and differentiation capacity of CDCs. The CDCs were treated with β1-AR blocker (Met group), β2-AR antagonist (ICI group), and p38MAPK inhibitor (SB group), non-selective β-AR blocker (PRO group), and β-AR agonist (ISO group). The viability, apoptotic rate and differentiation status of CDCs were determined by MST-1 assay, flow cytometery, and Western blot, respectively. The CDCs viability significantly reduced in ICI group (all P < 0.05), and SB group had a significant high viability after 48 h treatment (P < 0.05). Compared with control group, all treated groups had a low apoptotic rate. After treatment for 72 h, ISO treatment elevated the expression of Nkx2.5, and could partially or fully attenuate the inhibitory effects of β-AR antagonists and/or p38MAPK inhibitor. A similar overall trend of protein expression levels among all groups could be observed between protein pairs of cTnT and β1-AR as well as c-Kit and β2-AR, respectively. These results suggested that β-ARs and p38MAPK signaling pathways play crucial roles in the proliferation and differentiation of CDCs. Our findings should be helpful for better understanding the molecular mechanism underlying the physiological processes of CDCs.

Estrogen receptor antagonism exacerbates cardiac structural and functional remodeling in female rats.

We assessed the estrogen receptor (ER) dependence of female-specific cardioprotection using a rat model of chronic volume-overload stress. ER antagonism worsened ventricular wall stress, ventricular dilation, and cardiac dysfunction induced by volume overload. Further, blocking ERs resulted in cardiac remodeling and functional changes similar to that previously found in ovariectomized rats.