Patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) primary breast cancer (BC) have low pathological complete response (pCR) rates with neoadjuvant chemotherapy. A subset of ER+/HER2− BC contains dense lymphocytic infiltration. We hypothesized that addition of an anti-programmed death 1 agent may increase pCR rates in this BC subtype. We conducted a randomized, multicenter, double-blind phase 3 trial to investigate the benefit of adding nivolumab to neoadjuvant chemotherapy in patients with newly diagnosed, high-risk, grade 3 or 2 (ER 1 to ≤10 NCT04109066 In the CheckMate 7FL trial, neoadjuvant nivolumab and chemotherapy in patients with newly diagnosed, high-risk estrogen receptor-positive breast cancer led to an increased pathological complete response rate compared with neoadjuvant chemotherapy alone, and this increase was associated with immune-related biomarkers and estrogen receptor expression.

The triple therapy expresses high levels of TNF-α and IL-12 β cytokines. The NanoString results showed significant increase in IL-12 and TNF-α with the triple therapy group compared to no treatment. On the other hand, IL-6 was not significantly modulated.

High dose RT induced higher apoptosis. Mice were inoculated in the right leg with 344SQ for establishment of primary tumor. Tumors were treated locally by intermediate dose RT (15 Gy in three 5-Gy fractions) or High dose RT (36 Gy in three 12-Gy fractions). Tumors were harvested 7 days after the last fraction of RT then sectioned for Immunohistochemistry using Caspase-3 staining.

L’étude CheckMate 743 (NCT02899299, CM743) de phase 3 randomisée a démontré que l’association NIVO + IPI prolonge significativement la survie globale (OS) des patients atteints d’un MPM non resecablevs chimio. L’identification des patients atteints d’un MPM pouvant bénéficier d’une immunothérapie reste un besoin non satisfait. Nous rapportons ici les résultats cliniques et l’analyse exploratoire des biomarqueurs avec un suivi de l’étude CM743 avec un suivi minimum de 4 ans. Les patients présentant un MPM non résécable non traité, sont stratifiés par histologie et genre et randomisés 1 : 1 pour recevoir NIVO (3 mg/kg/2 semaines) + IPI (1 mg/kg/6 semaines) pendant 2 ans maximum, ou de la chimio (/3 semaines) pour 6 cycles maximum. Le critère principal était l’OS ; les critères secondaires comprenaient la survie sans progression (PFS), le taux de réponse objective (ORR), et le taux de contrôle de la maladie (DCR) ; les critères exploratoires incluaient la tolérance et l’analyse des biomarqueurs. L’OS a été évaluée en fonction des taux de mésothéline soluble (MSLN) à l’inclusion (élevés, moyens, faibles via un test ELISA) et de l’expression des gènes suppresseurs de tumeurs spécifiques du MPM (TP53, BAP1, SETD2, NF2, LATS2 via séquençage de l’exome entier). Avec un suivi minimum de 47,5 mois (gel de la base de données [DBL] : 6 mai 2022), le bénéfice d’OS s’est maintenu pour NIVO + IPI vs chimio, avec des taux d’OS à 4 ans de 16,8 % vs 10,7 % ; les taux de PFS à 4 ans étaient de 9,0 % vs 0 %, respectivement (Tableau 1). Un taux élevé de MSLN à l’inclusion (vs faible ou moyen) a été associé à une OS plus courte dans les deux bras. Le bénéfice d’OS tend à être en faveur de NIVO + IPI vs chimio quel que soit le taux de MSLN à l’inclusion (HR [IC 95 %], élevé : 0,72 [0,53–0,98], moyen : 0,77 [0,56–1,06], faible : 0,77 [0,56–1,05], respectivement). L’OS était en faveur de NIVO + IPI vs chimio dans le sous-groupe sans mutation (HR = 0,67–0,72) et dans les différents sous-groupes avec une mutation des gènes suppresseurs de tumeur spécifiques au MPM (HR = 0,41–0,55), à l’exception de la mutation SETD2 (HR = 1,37). Les événements indésirables d’origine immunologique de grade 3/4 les plus fréquents pour NIVO + IPI étaient l’hépatite (5 %), la diarrhée/colite (4 %) et les éruptions cutanées (3 %), en accord avec les données de la DBL précédente. Avec un suivi minimum de 4 ans, NIVO + IPI continue d’apporter un bénéfice en survie durable et à long terme aux patients atteints d’un MPM non résécable vs chimio. Aucun nouveau signal de tolérance n’a été observé. Un taux élevé MSLN à l’inclusion est un facteur de mauvais pronostic pour OS. Le bénéfice d’OS avec NIVO + IPI vs chimio a été globalement observé quelles que soient les mutations des gènes suppresseurs de tumeurs spécifiques au MPM.

Supplementary Figure and Table Legends 1-2 from Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer

CD8+ CD103+ TRM cells express high levels of PD1. Flow cytometric analysis for TILs on day 29 from the triple therapy group (RT + α-PD1 + α-MerTK). Cells were gated on CD45 population then on CD4 and CD8, followed by CD8 and CD103 to check for PD1 expression in the final gate.

Supplementary Table 2 from Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer

We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study.

BACKGROUND:Better risk stratification strategies are needed to enhance clinical care and trial design in heart failure with preserved ejection fraction (HFpEF).OBJECTIVES:The purpose of this study was to assess the value of a targeted plasma multi-marker approach to enhance our phenotypic characterization and risk prediction in HFpEF.METHODS:In this study, the authors measured 49 plasma biomarkers from TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial participants (n = 379) using a Multiplex assay. The relationship between biomarkers and the risk of all-cause death or heart failure-related hospital admission (DHFA) was assessed. A tree-based pipeline optimizer platform was used to generate a multimarker predictive model for DHFA. We validated the model in an independent cohort of HFpEF patients enrolled in the PHFS (Penn Heart Failure Study) (n = 156).RESULTS:Two large, tightly related dominant biomarker clusters were found, which included biomarkers of fibrosis/tissue remodeling, inflammation, renal injury/dysfunction, and liver fibrosis. Other clusters were composed of neurohormonal regulators of mineral metabolism, intermediary metabolism, and biomarkers of myocardial injury. Multiple biomarkers predicted incident DHFA, including 2 biomarkers related to mineral metabolism/calcification (fibroblast growth factor-23 and OPG [osteoprotegerin]), 3 inflammatory biomarkers (tumor necrosis factor-alpha, sTNFRI [soluble tumor necrosis factor-receptor I], and interleukin-6), YKL-40 (related to liver injury and inflammation), 2 biomarkers related to intermediary metabolism and adipocyte biology (fatty acid binding protein-4 and growth differentiation factor-15), angiopoietin-2 (related to angiogenesis), matrix metalloproteinase-7 (related to extracellular matrix turnover), ST-2, and N-terminal pro-B-type natriuretic peptide. A machine-learning-derived model using a combination of biomarkers was strongly predictive of the risk of DHFA (standardized hazard ratio: 2.85; 95% confidence interval: 2.03 to 4.02; p < 0.0001) and markedly improved the risk prediction when added to the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure Risk Score) risk score. In an independent cohort (PHFS), the model strongly predicted the risk of DHFA (standardized hazard ratio: 2.74; 95% confidence interval: 1.93 to 3.90; p < 0.0001), which was also independent of the MAGGIC risk score.CONCLUSIONS:Various novel circulating biomarkers in key pathophysiological domains are predictive of outcomes in HFpEF, and a multimarker approach coupled with machine-learning represents a promising strategy for enhancing risk stratification in HFpEF.

well as in those with advanced fibrosis compared to those with stages £2 (263±20 vs. 200±7 ng/ml, p<0.001).However, VCAM-1 only showed a significant difference between advanced fibrosis and stages £2 (986±54 vs. 836±23 ng/ml, p=0.008), but not when NASH was compared to NAFL.More interestingly, as can be observed in Figure 1, increasing ICAM-1 levels were significantly associated with worsening of each of the histological parameters assessed in NASH.This robust association was not observed when the same analysis was repeated for VCAM-1.Conclusions Plasma ICAM-1 was strongly associated with histological severity of liver disease in NAFLD.This finding suggests that endothelial cell activation may play an important role in the development and progression of liver disease in NAFLD.Future in vitro studies will need to address the pathophysiologic role of this association.In the meantime, this molecule should be taken into account when developing potential noninvasive biomarkers for NASH and/or advanced fibrosis.

AbstractPurpose: Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (α-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy. Experimental Design: We tested the efficacy of this triple therapy (Radiation + α-PD1 + α-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response. Results: The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8+ and NK cells populations measured by granzyme B expression with upregulation of CD8+CD103+ tissue-resident memory cells (TRM) within the abscopal tumor microenvironment relative to radiation only. Conclusions: The addition of α-PD1 + α-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of TRM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients.

Tyro3, Axl, and Mertk (TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS -> TAM receptor -> PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance. In this study, we tested combinations of TAM inhibitors and PD-1 mAbs in a syngeneic orthotopic E0771 murine triple-negative breast cancer model, whereby tumor-bearing mice were treated with pan-TAM kinase inhibitor (BMS-777607) or anti-PD-1 alone or in combination. Tyro3, Axl, and Mertk were differentially expressed on multiple cell subtypes in the tumor microenvironment. Although monotherapeutic administration of either pan-TAM kinase inhibitor (BMS-777607) or anti-PD-1 mAb therapy showed partial antitumor activity, combined treatment of BMS-777607 with anti-PD-1 significantly decreased tumor growth and incidence of lung metastasis. Moreover, combined treatment with BMS-777607 and anti-PD-1 showed increased infiltration of immune stimulatory T cells versus either monotherapy treatment alone. RNA NanoString profiling showed enhanced infiltration of antitumor effector T cells and a skewed immunogenic immune profile. Proinflammatory cytokines increased with combinational treatment. Together, these studies indicate that pan-TAM inhibitor BMS-777607 cooperates with anti-PD-1 in a syngeneic mouse model for triple-negative breast cancer and highlights the clinical potential for this combined therapy. Significance: These findings show that pan-inhibition of TAM receptors in combination with anti-PD-1 may have clinical value as cancer therapeutics to promote an inflammatory tumor microenvironment and improve host antitumor immunity.

Little data are available regarding the determinants and prognostic significance of serum albumin in Heart Failure with Preserved Ejection Fraction (HFpEF). We sought to examine the phenotypic correlates of albumin and its independent prognostic implications in HFpEF. We analyzed data from 3,254 subjects enrolled the TOPCAT trial. We stratified subjects according to tertiles of albumin and examined differences in various phenotypic traits between these strata, including 8 protein biomarkers selected ad hoc and measured from frozen samples available in a subset of participants (n = 372). We also assessed the relationship between albumin and the trial primary endpoint. Lower albumin was associ- ated with older age, black race, and greater prevalence of NYHA class III-IV peripheral arterial disease, atrial fibrillation and diabetes mellitus. Lower albumin was also associated with increased levels of several inflammatory biomarkers, markers of liver fibrosis, albuminuria, and greater arterial stiffness, diastolic dysfunction and pulmonary hypertension. Albumin was a strong predictor of the primary trial endpoint, even after adjustment for the MAGGIC risk score (hazard ratio [HR] 0.72, confidence interval [CI] 0.67 to 0.78; p <0.0001) and prespecified traditional risk factors (HR 0.78, CI 0.71 to 0.85; p <0.0001). Lower albumin was strongly associated with a worse prognosis even well within normal ranges (>3.5 g/dL), with a sharp increase in risk between 4.6 and 3.6 g/dL. In conclusion, albumin is an integrated marker of various adverse processes in HFpEF, including inflammation, subclinical liver disease, arterial stiffness, and renal disease. Albumin is a powerful risk predictor independent of traditional risk prediction models, even within normal ranges. (C) 2019 Elsevier Inc. All rights reserved.