Search

Elevated chronic psychological stress is associated with weakened immune response to vaccines. B-lymphocyte development may provide a pathway by which psychological stress can weaken immune response to vaccines. The current study examined the effect of chronic psychological stress on B- and T-lymphocytes among doctoral students, after their qualifying exams, and matched community controls. Blood was drawn from 10 doctoral students immediately after their 3-day qualifying exams and from 10 age- and gender-matched community controls. B- (CD19+) and T- (CD3+) lymphocyte percentages were enumerated with flow cytometry. Psychological stress was measured with the Perceived Stress Scale (PSS). The mean PSS score was higher for the graduate students compared with the control group (p < 0.01). Mean CD19+ lymphocyte percentage for the students (5.82 per cent) was dramatically lower than the control group (15.32 per cent, p < 0.0001). CD3+ lymphocyte percentage did not differ between the two groups. There was a significant negative correlation between CD19+ lymphocyte percentage and PSS score (r = -0.60, p = 0.003). Chronic psychological stress is associated with significant reductions in B-lymphocytes among doctoral students undergoing qualifying exams and community participants. B-lymphocyte decrements are a potential mechanism linking psychological stress and reduced antibody response to vaccines. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors are cornerstones of first-line treatment for advanced renal cell carcinoma; however, optimal treatment sequencing after progression is unknown. This study aimed to assess clinical outcomes of tivozanib-nivolumab versus tivozanib monotherapy in patients with metastatic renal cell carcinoma who have progressed following one or two lines of therapy in the post-ICI setting., Methods: TiNivo-2 is a multicentre, randomised, open-label, phase 3 trial at 190 sites across 16 countries, in Australia, Europe, North America, and South America. Patients with advanced renal cell carcinoma and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0·89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1·34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category. The primary endpoint was progression-free survival (PFS), defined as the time from randomisation to first documentation of objective progressive disease according to RECIST 1·1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This trial was registered on ClinicalTrials.gov (NCT04987203) and is active and not recruiting., Findings: From Nov 4, 2021, to June 16, 2023, 343 patients were randomly assigned to tivozanib-nivolumab (n=171) or tivozanib monotherapy (n=172). Median follow-up was 12·0 months. Median PFS was 5·7 months (95% CI 4·0-7·4) with tivozanib-nivolumab and 7·4 months (5·6-9·2) with tivozanib monotherapy (hazard ratio 1·10, 95% CI 0·84-1·43; p=0·49). Among those with an ICI as their immediate previous therapy (n=244), median PFS was 7·4 months (95% CI 5·6-9·6) with tivozanib-nivolumab and 9·2 months (7·4-10·0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups (tivozanib-nivolumab 3·7 months [95% CI 2·7-5·4] and with tivozanib monotherapy 3·7 months [1·9-7·2]). Serious adverse events occurred in 54 (32%) of 168 patients receiving tivozanib-nivolumab and 64 (37%) of 171 patients receiving tivozanib monotherapy. One (<1%) treatment-related death occurred (tivozanib group)., Interpretation: These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting., Funding: Aveo Pharmaceuticals., Competing Interests: Declaration of interests TKC reports institutional and personal paid or unpaid support for research, advisory board participation, consultancy, and honoraria within the past 5 years from Alkermes, Arcus Bio, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Neomorph, Nuscan and Precede Bio, Novartis, Oncohost, Pfizer, Roche, Sanofi Aventis, Scholar Rock, Surface Oncology, Takeda, and Tempest and equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, and Primium. LA reports consulting fees from Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas, Merck, MSD, Janssen, Eisai, and Amgen and support for travel expenses from Bristol Myers Squibb, MSD, Ipsen, and Pfizer. PB reports grants or contracts from Roche, Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Exelixis, Ipsen, Merck, Gilead, Janssen, AAA Pharmaceutical, and Bayer; consulting fees from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca; and reports participation on a data safety monitoring board or advisory board for Astellas, Bayer, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Merck, Gilead, AAA Pharmaceutical, Eisai, and AstraZeneca. SE reports consulting fees from MSD, AstraZeneca, Eisai, Janssen, Bristol Myers Squibb, and Kephren and support for attending meetings and travel from MSD, Chugai, Pfizer, and Janssen. JM-C reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen, Pfizer, Roche, Bayer, Sanofi, Janssen, Astellas, Eisai, Adacap, Lilly, Novartis, Bristol Myers Squibb, MSD, Adium, and Asofarma; support for attending meetings and travel from Ipsen, Pfizer, Bristol Myers Squibb, and MSD; and participation on a data safety monitoring board or advisory board for Ipsen, Pfizer, Astellas, Eisai, Bristol Myers Squibb, and MSD. BG reports research funding grants from AbbVie, Accutar Biotechnology, Arcus Biosciences, Arvinas, AstraZeneca, AVEO Oncology, CRISPR Therapeutics, Eikon Therapeutics, Exelixis, Roche and Genentech, Flare Therapeutics, Harbour BioMed, IDEAYA Biosciences, Janssen, Janux Therapeutics, Jubilant Therapeutics, Kineta, Kinnate BioPharma, Loxo, Mink Therapeutics, Nuvation Bio, Profound Bio, Takeda Therapeutics, Teon Therapeutics, Tmunity Therapeutics, Xencor, and Zenshine and consulting fees from AbbVie, Adaptimmune, Adicent Therapeutics, AIQ Global, Amgen, Arcus Biosciences, Arvinas, AstraZeneca, AVEO Oncology, Bayer, Bicycle Therapeutics, Eisai, EMD Serono, Exelixis, Janssen, Merck, Novartis, Pfizer, Rondo Therapeutics, Sanofi–Aventis, Seagen, and Xencor. PB reports honoraria from UroToday; consulting or advising fees from Bayer, Bristol Myers Squibb, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, Aveo, Merck, Ipson, and Dendreon; speakers bureau funding from AstraZeneca, Caris Life Sciences, Bayer, Pfizer and Astellas, and Merck; and research funding from Exelixis, Aveo, Blue Earth, Pfizer, and Merck. AB reports honoraria from Gilead Sciences, Cardinal Health, Eisai, and Natera; consulting or advising fees from EMD Serono, Seattle Genetics, and Bristol Myers Squibb and Pfizer; speakers bureau funds from Eisai; and research funding from Merck, EMD Serono, Natera, Astellas Pharma, Bristol Myers Squibb and Celgene, Genentech and Roche, and Aveo. MTB reports consulting fees, payment or honoraria, and participation on a data safety monitoring board or advisory board from Bristol Myers Squibb. HM reports honoraria from EMD Serono and Pfizer; research funding from Bristol Myers Squibb, Amgen, Genentech, Seattle Genetics, Arcus Bioscience, Apollomics, Nektar, RevImmune, HUYA Bioscience International, Aveo, Xencor, and Pfizer; and travel accommodations or expenses from Aveo, Seagen, Bayer, and Genentech. RR reports honoraria from Ipsen, MSD Oncology, AstraZeneca, Bristol Myers Squibb, Pfizer, Advanced Accelerator Applications, and Eisai; consulting or advisory fees from Astellas Pharma, Pfizer, Ipsen, and MSD; and travel accommodations or expenses from Ipsen, MSD Oncology, and Janssen. RRM reports consulting or advisory roles for Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion, Calithera, AstraZeneca, Myovant, Caris Life Sciences, Sorrento Therapeutics, Aveo, Seattle Genetics, Telix, Eli Lilly, Blue Earth Diagnostics, Ambrx, Arcus Biosciences, Sumitomo Pharma Oncology, Eisai, and NeoMorph and research funding from Bayer, Tempus, AstraZeneca, Exelixis, Bristol Myers Squibb, Oncternal Therapeutics, and Artera. AC-R reports honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from OncLive and MJH Life Sciences, ASCO Direct, Exelixis, Medical Oncology Association of Southern California, EPG Health, Eisai Co, Aveo, and Seagen. HH reports grants or contracts for clinical trial support from Merck, Bristol Myers Squibb, Eisai, Agenus, Hoosier, and Aveo and advisory consulting fees from Eisai, Aveo, Pfizer, and Bristol Myers Squibb. DYCH reports consultancy fees from Pfizer, Novartis, Bristol Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, and Merck and research funding from Pfizer, Novartis, Exelixis, Bristol Myers Squibb, and Ipsen. EB reports funding for the provision of study materials, medical writing, or article processing charges from Aveo Oncology and stock or stock options from Autolus. KEB reports grants funding from Bristol Myers Squibb–Lung Cancer Foundation of America–International Association for the Study of Lung Cancer, Aravive, Pionyr, and Arsenal Bio; consulting fees from Aravive, Aveo, Alpine Bioscience, Arcus, AstraZeneca, Adicet, Bristol Myers Squibb, Exelixis, Eisai, Merck, Nimbus, and Xencor; and honoraria funding from Merck. BAM reports grants to his institution from Aveo, Bristol Myers Squibb, Exelixis, Gilead, and Pfizer; consulting fees from Arcus, Bristol Myers Squibb, Exelixis, Gilead, Lily, and Pfizer; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Targeted Oncology, Dava Oncology, Aptitude Health, and Curio; and patents planned, issued, or pending with Gilead. RJM reports consulting fees from Aveo, Merck, Exelixis, and Takeda, grants or contracts from Pfizer, Genentech and Roche, Eisai, Merck, Bristol Myers Squibb, and Exelixis; and data safety monitoring and advisory board participation fees from Incyte. RI reports no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC)., Patients and Methods: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected., Results: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS., Conclusion: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC., Competing Interests: Disclosure Parvaneh Fallah Scientific advisor/consultant: BMS, Seagen, Pfizer, Astrazeneca, EMD Sereno Canada Honoraria: Astrazeneca, EMD Sereno Canada, Gilead, Merck, Janssen Rohit K Jain Receiving honoraria from FLASCO, Curio Science, DAVA Oncology, NCCN/Pfizer, and OncLive/MJH Life Sciences Consulting for AVEO, Bristol Myers Squibb, Sanofi, EMD Serono, Gilead Sciences, IDEOlogy Pfizer, and Seattle Genetics/Astellas In the speakers’ bureau of Gilead Sciences, Seagen, and Seattle Genetics/Astellas Receiving research funding from Bristol Myers Squibb, Gilead Sciences, and NCI. Praful Ravi Research funding to institution: Lilly, Bayer, Telix Speaker's fees: OncLive Charlene Mantia Consulting/advisory role: Aadi Bioscience, Synthekine, Nextech Institutional research funding: Bristol Myers Squibb Bradley Alexander McGregor Received funds for consulting: Arcus, BMS, Eisai, Exelixis, Gliead, Pfizer, SeaGen Funding to institution - BMS, Exelixis, Gilead, Pfizer, SeaGen Roger Li Research support: Predicine; Veracyte; CG Oncology; Valar labs; Merck. Clinical trial protocol committee: CG Oncology; Merck; Janssen. Scientific advisor/consultant: BMS, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, CG Oncology, Janssen, Thericon. Honoraria: SAI MedPartners, Solstice Health Communications, Putnam Associates, UroToday. Wassim Kassouf Consultant or advisory roles: Sesen Bio, Ferring, Roche, BMS, Merck, Janssen, Bayer, Astellas, Seagen, Pfizer/EMD Serono, Photocure Clinical trials: BMS, Roche, Janssen, Theralase, Pfizer, CG Oncology Gregory Russell Pond Received honorariums from Astra-Zeneca and Takeda Received consulting fees from Merck and Profound Medical. Close family member who is employed by Roche Canada, and who owns stock in Roche Ltd. Raskesh K. Jain Received consultant fees from Cur, DynamiCure, Elpis, Merck, SPARC, SynDevRx Owns equity in Accurius, Enlight, SynDevRx Served on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund Received grants from Boehringer Ingelheim and Sanofi. Research is supported by NIH R01CA259253, R01CA269672, R01-NS118929, U01CA261842, and grants from the National Foundation for Cancer Research, Jane's Trust Foundation, Niles Albright Research Foundation, and Harvard Ludwig Cancer Center. Guru Sonpavde Advisory Board: EMD Serono, BMS, Merck, Seattle Genetics/Astellas, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, Eli Lilly/Loxo Oncology, Vial, PrecisCa, Atkis, Kura Oncology, Daiichi-Sankyo Consultant/Scientific Advisory Board (SAB): Syapse, Merck, Servier, Syncorp Research Support to institution: EMD Serono, Jazz Therapeutics, BMS Speaker: Seagen, Gilead, Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Merck, Pfizer Data safety monitoring committee (honorarium): Mereo Employment: Spouse employed by Myriad Travel: BMS, Astellas, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Ovarian cancer (OC) survivors commonly experience chronic symptoms including anxiety, depression, sleep disturbances, fatigue, physical symptoms, poor health-related quality of life (HRQOL), and a generally poor prognosis. Additionally, factors such as social isolation, stress, and depression are associated with key biological processes promoting tumor progression and poorer survival. Accessible psychosocial interventions to improve HRQOL and clinical outcomes are needed. This need is particularly true in rural settings where survivors may have less access to clinic-based support systems., Methods: The Living Well Study, a cluster-randomized Phase II multi-site clinical trial, is designed to evaluate the efficacy of a group-based, web-delivered psychosocial intervention (Mindful Living) verses a Health Promotion active control (Healthy Lifestyles) in increasing HRQOL and decreasing perceived stress (primary outcomes), depressive mood, anxiety, and fatigue (secondary outcomes) for 256 OC survivors who are <5 years post-primary therapy. Mindful Living targets key concerns of OC survivors and teaches stress reduction skills and coping strategies utilizing cognitive behavioral, mindfulness, and acceptance and commitment therapies. Healthy Lifestyles provides lifestyle information including exercise, nutrition, sleep, and other survivorship topics. Interventions consist of 11 consecutive weekly group sessions lasting 1.5-2 h led by trained facilitators and two booster sessions. Participants complete psychosocial questionnaires at baseline, post-intervention, at 6-months, and at 12-months. A subset completes bloodspots for analysis of inflammatory biology., Conclusion: Easily accessible psychosocial interventions addressing key concerns of OC survivors are an unmet need. The Mindful Living intervention has the potential to substantially enhance HRQOL and decrease distress in OC survivors. Trial registrationclinicaltrials.gov Identifier: NCT04533763., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was -0.7 (range: -9.3 to 4.7) with R223+P and 0.1 (-11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was -0.6 (-7.4 to 5.3) with R223+P and -1.3 (-3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7-11.0) and 16.9 months [12.7-not reached (NR)], respectively, with R223+P and 5.7 (2.6-NR) and 16.0 (9.0-NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Comprehensive profiling of autoantibodies (AAbs) in metastatic urothelial cancer (mUC) has not been performed to date. This may aid in diagnosis of UC, uncover novel therapeutic targets in this disease as well as identify associations between AAbs and response and toxicity to systemic therapies., Methods: We used serum from patients with mUC collected prior to and after systemic therapy (immune checkpoint inhibitor (ICI) or platinum-based chemotherapy (PBC)) at Dana-Farber Cancer Institute. 38 age-matched and sex-matched healthy controls (HCs) from healthy blood donors were also evaluated. The SeroTag immuno-oncology discovery array (Oncimmune) was used, with quantification of the AAb reactivity toward 1132 antigens. Bound AAbs were detected using an anti-immunoglobulin G-specific detection antibody conjugated to the fluorescent reporter dye phycoerythrin. The AAb reactivity was reported as the median fluorescence intensity for each color and sample using a Luminex FlexMAP3D analyzer. Clinical outcomes of interest included radiographic response and development of immune-related adverse events (irAEs). Significance analysis of microarray was used to compare mUC versus HC and radiographic response. Associations with irAE were evaluated using a logistic regression model. P<0.05 was considered statistically significant., Results: 66 patients were included with a median age of 68 years; 54 patients (82%) received ICI and 12 patients (18%) received PBC. Compared with HCs, AAbs against the cancer/testis antigens (CTAG1B, CTAG2, MAGEB18), HSPA1A, TP53, KRAS, and FGFR3 were significantly elevated in patients with mUC. AAbs against BRCA2, TP53, and CTNBB1 were associated with response, and those against BICD2 and UACA were associated with resistance to ICI therapy. AAbs against MITF, CDH3, and KDM4A were associated with development of irAEs in patient who received an ICI. A higher variance in pre-to-post treatment fold change in AAb levels was seen in patients treated with ICI versus PBC and was associated with response to ICI., Conclusions: This is the first report of comprehensive AAb profiling of patients with mUC and identified key AAbs that were elevated in patients with mUC versus HCs as well as AAbs associated with therapeutic response to ICI. These findings are hypothesis generating and further mechanistic studies evaluating humoral immunity in UC are required., Competing Interests: Competing interests: PR: research funding (to institution) from Lilly, Bayer, and Telix and speaker’s fees from OncLive. BAM: consulting fees from BMS, Eisai, Exelixis, Gilead, Pfizer, and Seagen and research funding (to institution) from BMS, Exelixis, Pfizer, and Seagen. JEB: speaker honoraria from Guardant Health; consulting fees from Guardant Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo, and JucaBio; equity in Cityblock Health, Genome Medical, Oncotect, Precede, TracerDx, and Musculo; and filed an institutional patent on methods to detect neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis. GS: in advisory board of BMS, Genentech, EMD Serono, Merck, AstraZeneca, Sanofi, Seattle Genetics/Astellas, AstraZeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma, PrecisCa, and Primum; in consultant/scientific advisory board of Suba Therapeutics, Syapse, Servier, Merck, and Syncorp; received research support (to institution) from Sanofi, AstraZeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, and Jazz Therapeutics; received speaker's fees from Seagen, Gilead, Natera, Exelixis, Janssen, Bayer, and Aveo; received data safety monitoring committee honorarium from Mereo; received writing/editor fees from UpToDate, Practice Update, and Onviv; and spouse employed in Myriad. PB, BAA, ER, JG, AS-S, ALK, MB, and H-DZ are employees of Oncimmune., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Opinion Statement: Urothelial carcinoma is the predominant cancer of the urinary tract but when divergent and subtype histology (non-urothelial) are identified at time of pathologic diagnosis, therapeutic and diagnostic challenges transpire. To this end, pathologic review to confirm any non-urothelial histology is key since these subtypes can often be overlooked. Few prospective trials are dedicated to understanding these non-urothelial histologic types; however, current, and past trials did allow patients with these non-urothelial histologic types to enroll, and inferences can be made about treatment efficacy and survival. Existing treatment regimens for non-urothelial bladder cancers are akin to standard urothelial cancer regimens using surgical approaches for localized disease and platinum-based chemotherapy for advanced disease. The reported clinical trials, that will be discussed, center on non-urothelial histologic types. These studies, albeit limited, provide critical insight into tumor biology and response to standard platinum-based chemotherapy, immune checkpoint inhibitors, and antibody drug conjugates. The inclusion of non-urothelial histologic types will be essential for clinical trials in development to provide further therapeutic advances and provide essential efficacy data., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: We conducted a systematic literature review to identify evidence for use of vascular endothelial growth factor (VEGF)-targeted (anti-VEGF) treatment in patients with renal cell carcinoma (RCC) following prior checkpoint inhibitor (CPI)-based therapy., Methods: This was a PRISMA-standard systematic literature review; registered with PROSPERO (CRD42021255568). Literature searches were conducted in MEDLINE®, Embase, and the Cochrane Library (January 28, 2021; updated September 13, 2022) to identify publications reporting efficacy/effectiveness and safety/tolerability evidence for anti-VEGF treatment in patients with RCC who had received prior CPI therapy., Results: Of 2,639 publications screened, 48 were eligible and featured 2,759 patients treated in trials and 2,209 in real-world studies (RWS). Most patients with available data were treated with anti-VEGF tyrosine kinase inhibitor-based regimens (trials: 93 %; RWS: 100 %), most commonly cabozantinib, which accounted for 46 % of trial and 62 % of RWS patients in publications with available data. Collectively, there was consistent evidence of anti-VEGF treatment activity after prior CPI therapy. Activity was reported for all anti-VEGF regimens and regardless of prior CPI-based regimen. No new safety signals were detected for subsequent anti-VEGF therapy; no studies suggested increased immune-related adverse events associated with prior CPI therapy. The results were limited by data quality; study heterogeneity prohibited meta-analyses., Conclusion: Based on the available data (most commonly for cabozantinib), anti-VEGF therapy appears to be a rational treatment choice in patients with RCC who have progressed despite prior CPI-based therapy. Results from ongoing trials of combination anti-VEGF plus CPI regimen post prior CPI therapy trials will contribute more definitive evidence., Plain Language Summary: Anticancer treatments that work by reducing levels of a substance in the body called Vascular Endothelial Growth Factor are known as anti-VEGF drugs. Reducing VEGF levels helps to reduce blood supply to tumors, which can slow the speed at which the cancer grows. Some other types of anticancer drugs that help the immune system to fight cancer cells are called checkpoint inhibitors. Here, we looked at published studies that investigated how anti-VEGF drugs work, and what side effects they cause, in people who have already been treated with checkpoint inhibitors for a type of kidney cancer called renal cell carcinoma. We aimed to summarize the available evidence to help doctors decide how best to use anti-VEGF drugs in these patients. We found 48 studies that included almost 5,000 patients. The results of the studies showed that anti-VEGF drugs have anticancer effects in people with renal cell carcinoma who had already been treated with checkpoint inhibitors. All of the VEGF-targeting drugs had anticancer effects, irrespective of what checkpoint inhibitor treatment people had received before. There were different amounts of evidence available for the different anti-VEGF drugs. The anti-VEGF cabozantinib had the largest amount of evidence. Importantly, previous checkpoint inhibitor treatment did not seem to affect the number or type of side-effects associated with anti-VEGF drugs. Results from ongoing, well-designed studies will be helpful to confirm these results. Our findings may be useful for doctors considering using anti-VEGF drugs in patients with renal cell carcinoma who have received checkpoint inhibitor treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018)., Patients and Methods: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints., Results: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months., Conclusions: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted., Competing Interests: Disclosure BAM reports consulting fees from BMS, Eisai, Exelixis, Gilead, Pfizer, SeaGen and research funding to institution from BMS, Exelixis, Pfizer, SeaGen. GPS reports consulting fees from, Genentech, EMD Serono, Merck, Astrazeneca, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Gilead, Scholar Rock, G1 Therapeutics, Eli Lilly/Loxo Oncology, Infinity Pharmaceuticals, Lucence Health, IMV, Vial, Syapse, Tempus, Ellipses Pharma, PrecisCa, Primum. He serves on scientific advisory board for Suba Therapeutics, Syapse, Servier, Merck, Syncorp and reports research support to institution from Sanofi, Astrazeneca, Gilead, Helsinn, Lucence, BMS, EMD Serono, Jazz Therapeutics. He is a paid speaker for BIO – INFORMAÇÃO BRASILEIRA DE ONCOLOGIA Ltda, OLE Forum (Mexico), Seagen, Gilead, Natera, Exelixis, Janssen, Bayer, Aveo and serves on data safety monitoring committee honorarium for Mereo. His spouse is employed by Myriad. XG reports consulting fees from Bayer, Flare Therapeutics, Myovant, PathAI, PureTech Bio, Silverback Therapeutics. CMM reports consulting fees from Aadi Bioscience, Synthekine and research funding to institution from BMS. XXW reports consulting fees from Novartis and research funding to institution from BMS. JEB reports speaker honoraria from Guardant Health with consulting fees from Guardant Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo, JucaBio. He has equity in Cityblock Health, Genome Medical, Oncotect, Precede, TracerDx, Musculo and institutional patent filed on methods to detect neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis. SAB reports consulting fees from BMS, Eisai, Exelixis, Seagen. PKR reports research funding to institution from Bayer, Telix, and Lilly. MDM reports scientific advisory boards for Merck and Janssen. TKC reports consulting fees from Alkermes, AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Oncohost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (Peerview, OncLive, MJH, CCO and others), outside the submitted work. He has institutional patents filed on molecular alterations and immunotherapy response/toxicity, and ctDNA and equity in Tempest, Pionyr, Osel, Precede Bio, CureResponse, InnDura Therapeutics, Primium. He is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, Hinda, Arthur Marcus Fund, and Loker Pinard Funds for Kidney Cancer Research at DFCI. JB reports personal and institutional financial interests with Genentech, Pfizer, Bristol-Myers Squibb, AstraZeneca, Merck, Takeda, Eisai, Scholar Rock, Surface Oncology, Gilead, Ipsen, and Pierre-Fabre, trial sponsorship through Associació per a la Recerca Oncológia (APRO), royalties from UpToDate, stocks from Rainier Therapeutics, and a nonfinancial interest as President of APRO. All other authors have declared no conflicts of interest., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Purpose: Germline genetic testing (GT) is recommended for men with prostate cancer (PC), but testing through traditional models is limited. The ProGen study examined a novel model aimed at providing access to GT while promoting education and informed consent., Methods: Men with potentially lethal PC (metastatic, localized with a Gleason score of ≥8, persistent prostate-specific antigen after local therapy), diagnosis age ≤55 years, previous malignancy, and family history suggestive of a pathogenic variant (PV) and/or at oncologist's discretion were randomly assigned 3:1 to video education (VE) or in-person genetic counseling (GC). Participants had 67 genes analyzed (Ambry), with results disclosed via telephone by a genetic counselor. Outcomes included GT consent, GT completion, PV prevalence, and survey measures of satisfaction, psychological impact, genetics knowledge, and family communication. Two-sided Fisher's exact tests were used for between-arm comparisons., Results: Over a 2-year period, 662 participants at three sites were randomly assigned and pretest VE (n = 498) or GC (n = 164) was completed by 604 participants (VE, 93.1%; GC, 88.8%), of whom 596 participants (VE, 98.9%; GC, 97.9%) consented to GT and 591 participants completed GT (VE, 99.3%; GC, 98.6%). These differences were not statistically significant although subtle differences in satisfaction and psychological impact were. Notably, 84 PVs were identified in 78 participants (13.2%), with BRCA1/2 PV comprising 32% of participants with a positive result ( BRCA2 n = 21, BRCA1 n = 4)., Conclusion: Both VE and traditional GC yielded high GT uptake without significant differences in outcome measures of completion, GT uptake, genetics knowledge, and family communication. The increased demand for GT with limited genetics resources supports consideration of pretest VE for patients with PC.

Diabetic kidney disease (DKD) and diabetic peripheral neuropathy (DPN) are common complications of type 1 (T1D) and type 2 (T2D) diabetes. However, the mechanisms underlying pathogenesis of these complications are unclear. In this study, we optimized a streptozotocin-induced db/+ murine model of T1D and compared it to our established db/db T2D mouse model of the same C57BLKS/J background. Glomeruli and sciatic nerve transcriptomic data from T1D and T2D mice were analyzed by self-organizing map and differential gene expression analysis. Consistent with prior literature, pathways related to immune function and inflammation were dysregulated in both complications in T1D and T2D mice. Gene-level analysis identified a high degree of concordance in shared differentially expressed genes (DEGs) in both complications and across diabetes type when using mice from the same cohort and genetic background. As we have previously shown a low concordance of shared DEGs in DPN when using mice from different cohorts and genetic backgrounds, this suggests that genetic background may influence diabetic complications. Collectively, these findings support the role of inflammation and indicate that genetic background is important in complications of both T1D and T2D., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations., (©2023 American Association for Cancer Research.)

Background: The mechanisms underlying the clinical outcome disparity during human infection with Giardia duodenalis are still unclear. In recent years, evidence has pointed to the roles of host factors as well as parasite's genetic heterogeneity as major contributing factors in the development of symptomatic human giardiasis. However, it remains contested as to how only a small fraction of individuals infected with G. duodenalis develop clinical gastrointestinal manifestations, whereas the majority of infected individuals remain asymptomatic. Here, we demonstrate that diversity in the fecal microbiome correlates with the clinical outcome of human giardiasis., Methods: The genetic heterogeneity of G. duodenalis clinical isolates from human subjects with asymptomatic and symptomatic giardiasis was determined using a multilocus analysis approach. We also assessed the genetic proximity of G. duodenalis isolates by constructing phylogenetic trees using the maximum likelihood. Total genomic DNA (gDNA) from fecal specimens was utilized to construct DNA libraries, followed by performing paired-end sequencing using the HiSeq X platform. The Kraken2-generated, filtered FASTQ files were assigned to microbial metabolic pathways and functions using HUMAnN 3.04 and the UniRef90 diamond annotated full reference database (version 201901b). Results from HUMAnN for each sample were evaluated for differences among the biological groups using the Kruskal-Wallis non-parametric test with a post hoc Dunn test., Results: We found that a total of 8/11 (72.73%) human subjects were infected with assemblage A (sub-assemblage AII) of G. duodenalis, whereas 3/11 (27.27%) human subjects in the current study were infected with assemblage B of the parasite. We also found that the parasite's genetic diversity was not associated with the clinical outcome of the infection. Further phylogenetic analysis based on the tpi and gdh loci indicated that those clinical isolates belonging to assemblage A of G. duodenalis subjects clustered compactly together in a monophyletic clade despite being isolated from human subjects with asymptomatic and symptomatic human giardiasis. Using a metagenomic shotgun sequencing approach, we observed that infected individuals with asymptomatic and symptomatic giardiasis represented distinctive microbial diversity profiles, and that both were distinguishable from the profiles of healthy volunteers., Conclusions: These findings identify a potential association between host microbiome disparity with the development of clinical disease during human giardiasis, and may provide insights into the mechanisms by which the parasite induces pathological changes in the gut. These observations may also lead to the development of novel selective therapeutic targets for preventing human enteric microbial infections., (© 2023. The Author(s).)

CV301 comprises recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding CEA, MUC-1, and co-stimulatory Molecules (TRICOM) ICAM-1, LFA-3, and B7-1. MVA-BN-CV301 is used for priming and FPV-CV301 is used for boosting. A Phase 2, single-arm trial was designed to evaluate CV301 plus atezolizumab as first-line treatment for cisplatin-ineligible advanced urothelial carcinoma (aUC) (Cohort 1) or progressing after platinum chemotherapy (Cohort 2). MVA-CV301 was given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC from day 43 every 21 days for 4 doses, then tapered gradually over up to 2 years. Atezolizumab 1200 mg IV was given every 21 days. The primary endpoint was objective response rate (ORR). Overall, 43 evaluable patients received therapy: 19 in Cohort 1; 24 in Cohort 2; nine experienced ≥ Grade 3 therapy-related adverse events. In Cohort 1, one had partial response (PR) (ORR 5.3%, 90% CI 0.3, 22.6). In Cohort 2, 1 complete response and 1 PR were noted (ORR 8.3%, 90% CI 1.5, 24.0). The trial was halted for futility. Patients exhibiting benefit demonstrated T-cell response to CEA and MUC-1. The trial illustrates the challenges in the development of vaccines, which should be guided by robust preclinical data., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: There are limited data evaluating the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor inhibitor (VEGFi) combinations (IOVE)., Materials and Methods: Using the IMDC database, we sought to identify the objective response rate, time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, IOVE combinations, pazopanib or sunitinib (PAZ/SUN) or other first line (1L) therapies. Multivariable Cox regression, adjusted for underlying differences in IMDC groups, was used to compare differences in OS for 2L CABO based on preceding therapy., Results: Three hundred and forty-six patients received 2L CABO (78 post IPI NIVO, 46 post IOVE, 161 post PAZ/SUN, 61 post Other). Of the entire cohort, 12.6%, 62.6%, and 24.8% were IMDC favourable, intermediate, and poor risk, respectively. Patients that received 1L IPI-NIVO had a median OS of 21.4 (95% CI, 12.1 - NE [Not evaluable]) months compared to 15.7 (95% CI, 9.3 - NE) months in 1L IOVE and 20.7 (95% CI, 15.6 - 35.6) months in 1L PAZ/SUN, P = .28. Median TTF from the initiation of 2L CABO in the overall population was 7.6 (95% CI, 6.6 - 9.0) months. We were unable to detect a significant difference in 2L CABO OS based on type of 1L therapy received: 1L IPI-NIVO (reference group) vs. 1L IOVE HR 1.73 (95% CI, 0.83 - 3.62 P = .14), 1L PAZ/SUN 1.16 (95% CI, 0.67 - 2.00 P = .60), however given the retrospective observational nature of this work a lack of sufficient power may contribute to this., Conclusion: In a large real world dataset, we identified clinically meaningful activity of 2L CABO after all evaluated contemporary 1L therapies, irrespective of whether the 1L regimen included a VEGFi. These are real world benchmarks with which to counsel our patients., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Treatment advances in kidney cancer continually evolve. The focus of treatment options continues with oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) or intravenous immune checkpoint inhibitors (ICIs). Multiple trials exploring the role of adjuvant treatment after cytoreductive nephrectomy in high-risk clear cell renal cell carcinoma are currently ongoing. The discovery of biomarkers may help determine which patients benefit from these treatments, but these are not yet available outside clinical studies. Trials with combination therapies are also ongoing, especially using novel therapies with new mechanisms of action, and will hopefully provide more clues on proper patient and therapy selection in the adjuvant setting.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489., (© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Renin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI., Methods: This multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR)., Results: Overall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034)., Conclusions: RASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients., Competing Interests: Disclosures Ziad Bakouny: Research support from Bristol-Myers Squibb and Genentech/imCORE. Honoraria from UpToDate. Toni K: Choueiri reports grants, personal fees, nonfinancial support, and other from BMS, Merck, Roche, Pfizer, EMD, Exelixis, Novartis, and AstraZeneca [advisory board, consultancy, honorarium, payments (personal and for institution)], and a patent for IO biomarkers pending, issued, and licensed to DFCI (related to IO). Rana R: McKay received research funding from Bayer, Pfizer, Tempus; serves on Advisory Board for AstraZeneca, Bayer, Bristol Myers Squibb, Calithera, Exelixis, Janssen, Merck, Novartis, Pfizer, Sanofi, Tempus; is a consultant for Dendreon, Vividion. Guru Sonpavde: Advisory Board: BMS, Genentech, EMD Serono, Merck, Sanofi, Seattle Genetics/Astellas, Astrazeneca, Exelixis, Janssen, Bicycle Therapeutics, Pfizer, Immunomedics/Gilead, Scholar Rock, G1 Therapeutics; Research Support to Institution: Sanofi, Astrazeneca, Immunomedics/Gilead, QED, Predicine, BMS; Steering committee of studies: BMS, Bavarian Nordic, Seattle Genetics, QED, G1 Therapeutics (all unpaid), and Astrazeneca, EMD Serono, Debiopharm (paid).; Data safety monitoring committee: Mereo; Travel costs: BMS (2019), Astrazeneca (2018); Writing/Editor fees: Uptodate, Editor of Elsevier Practice Update Bladder Cancer Center of Excellence; Speaking fees: Physicians Education Resource (PER), Onclive, Research to Practice, Medscape (all educational). Rakesh Jain has received an Honorarium from Amgen; Consultant fees from Elpis, SPARC, SynDevRx; Owns equity in Accurius, Enlight, SynDevRx; Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a Research Grant from Boehringer Ingelheim. The remaining authors have stated that they have no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Prostanoids are potent inflammatory mediators that play a regulatory role in the innate immune activation of the adaptive immune response to determine the duration of protection against infection. We aim to quantify the modulation of prostanoids profiles in lipopolysaccharide (LPS)-stimulated THP-1 cells treated with the novel pertussis antigen BscF. We compared the effect with pertussis antigens present in the current Tdap vaccine to understand the immunomodulatory effect that might contribute to the diminished Tdap vaccine effectiveness. The inflammatory challenge with LPS induced a robust elevation of most prostanoid family members compared to the control treatment. Treatment with BscF and Tdap significantly reduced the LPS-stimulated elevation of prostaglandins (PGs) D2, E2, and F2α, as well as thromboxane (TX) A2 levels. An opposite trend was observed for PGI2, as both antigens accelerated the LPS-stimulated upregulation. Further, we quantified cyclooxygenases (COXs) that catalyze the biosynthesis of prostanoids and found that both antigens significantly reduced LPS-stimulated COX-1 and COX-2, demonstrating that the waning of acellular pertussis vaccines' protective immunity may be due to other downstream enzymes not related to COXs. Our present study validates the potential role of BscF as an adjuvant, resulting in the next-generation pertussis vaccine discovery., (Copyright © 2022. Published by Elsevier Ltd.)

Serial evaluation of circulating tumor DNA may allow noninvasive assessment of drivers of resistance to immune checkpoint inhibitors (ICIs) in advanced urothelial cancer (aUC). We used a novel, amplicon-based next-generation sequencing assay to identify genomic alterations (GAs) pre- and post-therapy in 39 patients with aUC receiving ICI and 6 receiving platinum-based chemotherapy (PBC). One or more GA was seen in 95% and 100% of pre- and post-ICI samples, respectively, commonly in TP53 (54% and 54%), TERT (49% and 59%), and BRCA1/BRCA2 (33% and 33%). Clearance of ≥1 GA was seen in 7 of 9 patients responding to ICI, commonly in TP53 (n = 4), PIK3CA (n = 2), and BRCA1/BRCA2 (n = 2). A new GA was seen in 17 of 20 patients progressing on ICI, frequently in BRCA1/BRCA2 (n = 6), PIK3CA (n = 3), and TP53 (n = 3), which seldom emerged in patients receiving PBC. These findings highlight the potential for longitudinal circulating tumor DNA evaluation in tracking response and resistance to therapy., (© The Author(s) 2022. Published by Oxford University Press.)

BscF is a type III secretion system (T3SS) needle protein from Bordetella pertussis and has previously been shown to induce a sufficient Th1 and Th17 response in human monocytes and mice as a prerequisite for long-lasting protective immunity against pertussis infection. In our current study, we aim to compare the modulation of inflammatory signaling molecules as a direct measure of the immune response to the B. pertussis antigens BscF and Tdap in the presence or absence of the adrenergic receptor agonists phenylephrine (PE) or isoproterenol (ISO) to observe differences that may contribute to the diminished protective immunity of the current acellular pertussis (aP) vaccine, Tdap. Stimulation of human monocyte THP-1 cells with LPS, BscF, and Tdap induced a robust elevation of CCL20, CXCL10, PGE2, and PGF2α among most chemokine and prostanoid members when compared with the control treatment. Treatment with the adrenergic agonist PE or ISO significantly enhanced the BscF- and Tdap-stimulated modulation of CCL20 and CXCL10 but not PGE2 and PGF2α, suggesting that adrenergic modulation of pertussis antigen responses might be a new therapeutic strategy to improve the longevity of pertussis immunity. Stimulation of THP-1 cells with BscF alone initiated significant expression of CXCL10 and PGF2α but not when Tdap was used, suggesting that BscF might be an important pertussis antigen for next-generation pertussis vaccines or when combined with the current aP vaccine. Our data offer opportunities for designing new therapeutic approaches against pertussis infection.

Purpose: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and efficacy of avelumab plus axitinib or sunitinib., Experimental Design: Adult patients with untreated advanced renal cell carcinoma (RCC) with a clear-cell component, ≥1 measurable lesions, Eastern Cooperative Oncology Group performance status of 0 or 1, fresh or archival tumor specimen, and adequate renal, cardiac, and hepatic function were included. Retrospective analyses of the association between baseline NLR and progression-free survival (PFS) and overall survival (OS) in the avelumab plus axitinib or sunitinib arms were performed using the first interim analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006). Multivariate Cox regression analyses of PFS and OS were conducted. Translational data were assessed to elucidate the underlying biology associated with differences in NLR., Results: Patients with below-median NLR had longer observed PFS with avelumab plus axitinib [stratified HR, 0.85; 95% confidence interval (CI), 0.634-1.153] or sunitinib (HR, 0.56; 95% CI, 0.415-0.745). In the avelumab plus axitinib or sunitinib arms, respectively, median PFS was 13.8 and 11.2 months in patients with below-median NLR, and 13.3 and 5.6 months in patients with median-or-higher NLR. Below-median NLR was also associated with longer observed OS in the avelumab plus axitinib (HR, 0.51; 95% CI, 0.300-0.871) and sunitinib arms (HR, 0.30; 95% CI, 0.174-0.511). Tumor analyses showed an association between NLR and key biological characteristics, suggesting a role of NLR in underlying mechanisms influencing clinical outcome., Conclusions: Current data support NLR as a prognostic biomarker in patients with advanced RCC receiving avelumab plus axitinib or sunitinib., (©2021 The Authors; Published by the American Association for Cancer Research.)

Purpose: Sapanisertib is a kinase inhibitor that inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. In this multicenter, single-arm phase II trial, we evaluated the efficacy of sapanisertib in patients with treatment-refractory metastatic renal cell carcinoma (mRCC; NCT03097328)., Methods: Patients with mRCC of any histology progressing through standard therapy (including prior mTOR inhibitors) had baseline biopsy and received sapanisertib 30 mg by mouth once weekly until unacceptable toxicity or disease progression. The primary end point was objective response rate by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored., Results: We enrolled 38 patients with mRCC (clear cell = 28; variant histology = 10) between August 2017 and November 2019. Twenty-four (63%) had received ≥ 3 prior lines of therapy; 17 (45%) had received prior rapalog therapy. The median follow-up was 10.4 (range 1-27.4) months. Objective response rate was two of 38 (5.3%; 90% CI, 1 to 15.6); the median progression-free survival (PFS) was 2.5 months (95% CI, 1.8 to 3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events, with no grade 4 or 5 toxicities. Alterations in the mTOR pathway genes were seen in 5 of 29 evaluable patients ( MTOR n = 1, PTEN n = 3, and TSC1 n = 1) with no association with response or PFS. Diminished or loss of PTEN expression by immunohistochemistry was seen in 8 of 21 patients and trended toward shorter PFS compared with intact PTEN (median 1.9 v 3.7 months; hazard ratio 2.5; 95% CI, 0.9 to 6.7; P = .055)., Conclusion: Sapanisertib had minimal activity in treatment-refractory mRCC independent of mTOR pathway alterations. Additional therapeutic strategies are needed for patients with refractory mRCC., Competing Interests: Bradley A. McGregorConsulting or Advisory Role: Bayer, Seattle Genetics/Astellas, Exelixis, AstraZeneca, Astellas Pharma, Genentech/Roche, Nextar, Janssen Oncology, Pfizer, EMD Serono, Eisai, Dendreon, Bristol Myers Squibb, Calithera BiosciencesResearch Funding: Bristol Myers Squibb (Inst), Exelixis (Inst), Calithera Biosciences (Inst), Seattle Genetics/Astellas (Inst), Pfizer/EMD Serono (Inst) Wanling XieConsulting or Advisory Role: Convergent Therapeutics Elio AdibEmployment: Amgen (I) Walter M. StadlerLeadership: EMA WellnessConsulting or Advisory Role: CVS Caremark, Sotio, AstraZeneca, Eisai, Bayer, Pfizer, Merck, Treadwell Therapeutics, CalicoResearch Funding: Bayer (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Exelixis (Inst), Novartis (Inst), Genentech/Roche (Inst), GlaxoSmithKline (Inst), Pfizer (Inst), Merck (Inst), Millennium (Inst), Janssen (Inst), Johnson & Johnson (Inst), AstraZeneca (Inst), AbbVie (Inst), X4 Pharma (Inst), Calithera Biosciences (Inst), Clovis Oncology (Inst), Eisai (Inst), Seattle Genetics (I), Tesaro (Inst), Corvus Pharmaceuticals (Inst), Astellas Medivation (Inst), Amgen (Inst)Expert Testimony: TevaOther Relationship: UpToDate, American Cancer Society Yousef ZakhariaConsulting or Advisory Role: Roche/Genentech, Eisai, Amgen, Castle Biosciences, Novartis, Exelixis, Pfizer, Cardinal Health, Bayer, Janssen, TTC Oncology, Clovis Oncology, EMD Serono, Seattle GeneticsResearch Funding: Pfizer (Inst), Exelixis (Inst), Eisai (Inst)Travel, Accommodations, Expenses: Newlink Genetics Aijai AlvaConsulting or Advisory Role: AstraZeneca, Merck, Pfizer, BMSResearch Funding: Genentech (Inst), Bristol Myers Squibb (Inst), Merck Sharp & Dohme (Inst), Prometheus (Inst), Mirati Therapeutics (Inst), AstraZeneca (Inst), Roche (Inst), Bayer (Inst), Progenics (Inst), Astellas Pharma (Inst), Arcus Biosciences (Inst), Harpoon Therapeutics (Inst), Progenics (Inst), Celgene (Inst), Janssen (Inst)Travel, Accommodations, Expenses: Merck, BMS M. Dror MichaelsonEmployment: Cullinan Oncology (I)Stock and Other Ownership Interests: Jounce Therapeutics (I), Cullinan Oncology (I)Honoraria: Pfizer, Exelixis, Merck, EisaiConsulting or Advisory Role: Pfizer, Exelixis, Eisai, MerckResearch Funding: Pfizer (Inst), Eisai (Inst), Millennium (Inst), Exelixis (Inst), Merck (Inst), Bristol Myers Squibb (Inst)Expert Testimony: BayerOpen Payments Link: https://openpaymentsdata.cms.gov/physician/193824 Shilpa GuptaStock and Other Ownership Interests: Nektar, Moderna Therapeutics (I)Honoraria: Bristol Myers SquibbConsulting or Advisory Role: Gilead Sciences, Guardant Health, AVEO, EMD Serono, Pfizer, Merck, Loxo/LillySpeakers' Bureau: Bristol Myers Squibb, Janssen Oncology Elaine T. LamConsulting or Advisory Role: Calithera BiosciencesResearch Funding: Bristol Myers Squibb (Inst), Roche/Genentech (Inst), Pfizer (Inst), Exelixis (Inst), Merck (Inst), Argos Therapeutics (Inst), Peloton Therapeutics (Inst), Calithera Biosciences (Inst), Astellas Pharma (Inst), Advaxis (Inst), Constellation Pharmaceuticals (Inst), Harpoon Therapeutics (Inst), Decibel Therapeutics (Inst), OnQuality Pharmaceuticals (Inst), Amgen (Inst), FORMA Therapeutics (Inst), Phosplatin Therapeutics (Inst), Arrowhead Pharmaceuticals (Inst)Travel, Accommodations, Expenses: Decibel Therapeutics Xiao X. WeiHonoraria: OncLiveConsulting or Advisory Role: NovartisResearch Funding: Bristol Myers SquibbTravel, Accommodations, Expenses: Corvus Pharmaceuticals Kerry L. KilbridgeResearch Funding: Pfizer American Cancer Society Lauren HarshmanEmployment: Surface OncologyStock and Other Ownership Interests: Surface OncologyConsulting or Advisory Role: Pfizer, Genentech, Corvus Pharmaceuticals, Merck, Exelixis, Bayer, Novartis, Jounce Therapeutics, EMD Serono, Michael J. Hennessy Associates, Ology Medical Education, Bristol Myers Squibb, Advanced Accelerator ApplicationsResearch Funding: Medivation/Astellas (Inst), Bayer (Inst), Sotio (Inst), Genentech/Roche (Inst), Dendreon (Inst), Bristol Myers Squibb (Inst), Takeda (Inst), Merck (Inst), Janssen Oncology (Inst), Pfizer (Inst), Endocyte (Inst)Travel, Accommodations, Expenses: Genentech Sabina SignorettiConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, CRISPR therapeuticsResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Exelixis (Inst), Novartis (Inst)Patents, Royalties, Other Intellectual Property: Receives royalties from BioGenexOther Relationship: AACR, NCI Lynette ShollStock and Other Ownership Interests: Moderna TherapeuticsConsulting or Advisory Role: GenentechSpeakers' Bureau: LillyResearch Funding: Roche/Genentech David J. KwiatkowskiConsulting or Advisory Role: Genentech/Roche, AADIResearch Funding: AADi, Revolution Medicines, Genentech/Roche Rana R. McKayConsulting or Advisory Role: Janssen, Novartis, Tempus, Exelixis, Pfizer, Bristol Myers Squibb, Astellas Medivation, Dendreon, Bayer, Sanofi, Merck, Vividion Therapeutics, Calithera Biosciences, AstraZeneca, Myovant Sciences, Caris Life Sciences, Sorrento TherapeuticsResearch Funding: Pfizer (Inst), Bayer (Inst), Tempus (Inst) Toni K. ChoueiriEmployment: Dana-Farber Cancer HospitalLeadership: Dana-Farber Cancer Hospital, NCCN, KidneyCAN, ASCO, ESMOStock and Other Ownership Interests: Pionyr, Tempest Therapeutics, Osel, NuScanHonoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Health, Kidney Cancer Association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, Alligent, EMD Serono, HERON, Lilly, Janssen Oncology, IQVIA, Aveo, NCI Genitourinary Cancers Steering CommitteeConsulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, Aravive, Tempest Therapeutics, NuScan, Arcus BiosciencesResearch Funding: Pfizer (Inst), Novartis (Inst), Merck (Inst), Exelixis (Inst), TRACON Pharma (Inst), GlaxoSmithKline (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Peloton Therapeutics (Inst), Roche/Genentech (Inst), Celldex (Inst), Agensys (Inst), Eisai (Inst), Takeda (Inst), Prometheus (Inst), Ipsen (Inst), Corvus Pharmaceuticals (Inst), Cerulean Pharma (Inst), Seattle Genetics/Astellas (Inst), Bayer (Inst), Foundation Medicine (Inst), Roche (Inst), Calithera Biosciences (Inst), Analysis Group (Inst), NCI (Inst), GATEWAY for Cancer Research (Inst), Congressionally Directed Medical Research Programs (DOD) (Inst)Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy (Inst); International Patent Application No. PCT/US2018/12209, titled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response (Inst), ctDNA technologiesTravel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, EMD Serono, HERON, Lilly, ESMOOther Relationship: Medical writing and editorial assistance support was provided by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, and ParexelNo other potential conflicts of interest were reported.