Abstract: Immune checkpoint molecules represent physiological brakes of the immune system that are essential for the maintenance of immune homeostasis and prevention of autoimmunity. By inhibiting these negative regulators of the immune response, immune checkpoint blockade can increase anti-tumor immunity, but has been primarily successful in solid cancer therapy and Hodgkin lymphoma so far. Allogeneic hematopoietic cell transplantation (allo-HCT) is a well-established cellular immunotherapy option with the potential to cure hematological cancers, but relapse remains a major obstacle. Relapse after allo-HCT is mainly thought to be attributable to loss of the graft-versus-leukemia (GVL) effect and hence escape of tumor cells from the allogeneic immune response. One potential mechanism of immune escape from the GVL effect is the inhibition of allogeneic T cells via engagement of inhibitory receptors on their surface including PD-1, CTLA-4, TIM3, and others. This review provides an overview of current evidence for a role of immune checkpoint molecules for relapse and its treatment after allo-HCT, as well as discussion of the immune mediated side effect graft-vs.-host disease. We discuss the expression of different immune checkpoint molecules on leukemia cells and T cells in patients undergoing allo-HCT. Furthermore, we review mechanistic insights gained from preclinical studies and summarize clinical trials assessing immune checkpoint blockade for relapse after allo-HCT

Abstract: Due to increasing life expectancy and improved diagnostic sensitivity, a growing number of older patients are presenting with resectable pancreatic disease entities and are being evaluated for surgery. Intended as an internal quality control for patient selection, we aimed at evaluating septuagenarians and octogenarians compared with patients younger than 70 years of age regarding early postoperative outcome in general, and long-term oncologic outcome in the case of resection for pancreatic adenocarcinoma. A total number of 1231 patients who underwent pancreatic resection for any entity between 2007 and 2019 at our tertiary university medical center in Germany were retrospectively analyzed, accessing a prospectively maintained database. Participants were divided into three groups based on age (70 years: N = 761; 70-79 years: N = 385; 80-89 years: N = 85) and were evaluated with regard to perioperative variables, postoperative morbidity, mortality and overall survival for the subgroup of patients with pancreatic adenocarcinoma. Pancreatic resection in older individuals was not infrequent. When surgery was performed for carcinoma, patients 70 years of age even constituted almost half of the cases. In spite of increased American Society of Anesthesiologists physical status classification (ASA)-scores and more frequent comorbidities in older patients, similar rates for postoperative morbidity and mortality were observed in all age groups. A significant disparity in the use of (neo-) adjuvant therapy between younger and older pancreatic adenocarcinoma patients was detected. However, median overall survival did not significantly differ between all age groups (

Abstract: Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with high potential of metastases and therapeutic resistance. Although genetic mutations drive PDAC initiation, they alone do not explain its aggressive nature. Epigenetic mechanisms, including aberrant DNA methylation and histone modifications, significantly contribute to inter- and intratumoral heterogeneity, disease progression and metastasis. Thus, increased understanding of the epigenetic landscape in PDAC could offer new potential biomarkers and tailored therapeutic approaches. In this review, we shed light on the role of epigenetic modifications in PDAC biology and on the potential clinical applications of epigenetic biomarkers in liquid biopsy. In addition, we provide an overview of clinical trials assessing epigenetically targeted treatments alone or in combination with other anticancer therapies to improve outcomes of patients with PDAC