An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and ...how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase II trial of ...PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis.
In a single-center, proof-of-concept phase II study, we enrolled women aged ≥18 with recurrent ovarian cancer. All patients were immune checkpoint inhibitor-naïve and had measurable disease per RECISTv1.1, ECOG performance status 0-2, and adequate organ and marrow function. Patients received olaparib 300 mg twice daily and durvalumab 1,500 mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment.
Thirty-five patients with ovarian cancer median, four prior therapies (IQR, 2-5.5), predominantly platinum-resistant (86%),
wild-type (77%) received at least one full cycle of treatment. ORR was 14% 5/35; 95% confidence interval (CI), 4.8%-30.3%. Disease control rate (PR+SD) was 71% (25/35; 95% CI, 53.7%-85.4%). Treatment enhanced
and
expression, systemic IFNγ/TNFα production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNγ production was associated with improved PFS HR, 0.37 (95% CI, 0.16-0.87),
= 0.023, while elevated VEGFR3 levels were associated with worse PFS (HR, 3.22 (95% CI, 1.23-8.40),
= 0.017.
The PARPi and anti-PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.
Abstract
Frailty, the state of increased vulnerability to physical stressors as a result of progressive and sustained degeneration in multiple physiological systems, is common in those with chronic ...kidney disease (CKD). In fact, the prevalence of frailty in the older adult population is reported to be 11%, whereas the prevalence of frailty has been reported to be greater than 60% in dialysis-dependent CKD patients. Frailty is independently linked with adverse clinical outcomes in all stages of CKD and has been repeatedly shown to be associated with an increased risk of mortality and hospitalization. In recent years there have been efforts to create an operationalized definition of frailty to aid its diagnosis and to categorize its severity. Two principal concepts are described, namely the Fried Phenotype Model of Physical Frailty and the Cumulative Deficit Model of Frailty. There is no agreement on which frailty assessment approach is superior, therefore, for the time being, emphasis should be placed on any efforts to identify frailty. Recognizing frailty should prompt a holistic assessment of the patient to address risk factors that may exacerbate its progression and to ensure that the patient has appropriate psychological and social support. Adequate nutritional intake is essential and individualized exercise programmes should be offered. The acknowledgement of frailty should prompt discussions that explore the future care wishes of these vulnerable patients. With further study, nephrologists may be able to use frailty assessments to inform discussions with patients about the initiation of renal replacement therapy.
Frailty is associated with adverse health outcomes in people with chronic kidney disease (CKD). Evidence supporting targeted interventions is needed. This pilot randomised controlled trial (RCT) ...aimed to inform the design of a definitive RCT evaluating the effectiveness of a home-based exercise intervention for pre-frail and frail older adults with CKD. Six hundred and sixty-five patients had an eligibility assessment with 217 (33%; 95% CI 29, 36) eligible. Thirty-five (16%; 95% CI 12, 22) participants were recruited. Six were categorised as robust and withdrawn prior to randomisation. Fifteen participants were randomised to exercise and 14 to usual care. Eleven (73%; 95% CI 45, 91) participants completed greater than or equal to2 exercise sessions/week. Retained participants completed all outcome measures (n = 21; 100%; 95% CI 81, 100). Eight (28%; 95% CI 13, 47) participants were withdrawn. Fifteen participated in interviews. Decision to participate/withdraw was influenced by perceived risk of exercise worsening symptoms. Participant perceived benefits included improved fitness, balance, strength, well-being, energy levels and confidence. This pilot RCT demonstrates that progression to definitive RCT is possible provided recruitment and retention challenges are addressed. It has also provided preliminary evidence that home-based exercise may be beneficial for people living with frailty and CKD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Regorafenib is an oral multikinase inhibitor targeting angiogenesis, oncogenesis, and cancer proliferation/metastasis. This study evaluated the efficacy of regorafenib in refractory ...biliary tract cancer (BTC) in a multi‐institutional phase 2 study.
Methods
Patients with BTC who progressed on at least 1 line of systemic therapy received regorafenib at 160 mg daily for 21 days on and 7 days off. The primary endpoint was 6‐month overall survival (OS), and the secondary endpoints were median OS, progression‐free survival (PFS), and objective response rates. Pretreatment plasma was collected for cytokine evaluation.
Results
A total of 39 patients were enrolled, and 33 were evaluable for efficacy. The median PFS and OS were 3.7 and 5.4 months, respectively, with survival rates of 46.2% at 6 months, 35.9% at 12 months, and 25.6% at 18 months for the intention‐to‐treat population. For the 33 evaluable patients who received regorafenib for at least 3 weeks, the median PFS and OS were 3.9 and 6.7 months, respectively, with survival rates of 51.5% at 6 months, 39.4% at 12 months, and 27.3% at 18 months. The objective response rate was 9.1%, and the disease control rate was 63.6%. Twenty‐eight patients (71.8%) experienced grade 3/4 adverse events. Among the 23 cytokines analyzed, elevated baseline vascular endothelial growth factor D (VEGF‐D) was associated with shorter PFS, whereas elevated baseline interleukin 6 (IL‐6) and glycoprotein 130 (GP130) were associated with shorter OS.
Conclusions
Regorafenib demonstrated modest clinical efficacy in heavily pretreated patients with BTC. Further exploration of biomarkers is warranted to identify a group of patients with BTC who may benefit from regorafenib.
Regorafenib can provide modest clinical efficacy and a manageable safety profile in heavily pretreated patients with advanced biliary tract cancer.
Drugs and antibodies that interrupt vascular endothelial growth factor (VEGF) signaling pathways improve outcomes in patients with a variety of cancers by inhibiting tumor angiogenesis. A major ...adverse effect of these treatments is hypertension, suggesting a critical role for VEGF in blood pressure (BP) regulation. However, the physiological mechanisms underlying the control of BP by VEGF are unclear. To address this question, we administered a specific antibody against the major VEGF receptor, VEGFR2, to normal mice and assessed the consequences on BP. Compared with vehicle-treated controls, administration of the anti-VEGFR2 antibody caused a rapid and sustained increase in BP of ≈10 mm Hg. This increase in BP was associated with a significant reduction in renin mRNA expression in the kidney (P=0.019) and in urinary excretion of aldosterone (P<0.05). Treatment with the anti-VEGFR2 antibody also caused a marked reduction in the expression of endothelial and neuronal NO synthases in the kidney. To examine the role of NO in the hypertension caused by blocking VEGFR2, mice were treated with Nω-nitro-l-arginine methyl ester (l-NAME) (20 mg/kg per day), an inhibitor of NO production. l-NAME administration abolished the difference in BP between the vehicle- and anti-VEGFR2–treated groups. Our data suggest that VEGF, acting via VEGFR2, plays a critical role in BP control by promoting NO synthase expression and NO activity. Interfering with this pathway is likely to be one mechanism underlying hypertension caused by antiangiogenic agents targeting VEGF.
Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat ...SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues.
The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated
using SCLC cell lines and primary human effector cells and
in an SCLC xenograft model reconstituted with human CD3
T-cells.
Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3.
This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical
model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.
Frail patients with chronic kidney disease (CKD) have an increased hospitalisation and mortality rate. However, many popular frailty screening methods have not been validated in patients with CKD. ...This study evaluates the diagnostic accuracy of several frailty screening methods in patients with CKD G4-5 and those established on haemodialysis (G5D).
Ninety participants with CKD G4-5D were recruited from Nephrology Outpatient Clinics and 2 Haemodialysis Units between December 2016 and December 2017. Frailty was diagnosed using the Fried Frailty Phenotype. The following frailty screening tests were evaluated: Clinical Frailty Scale, PRISMA-7, CKD Frailty Index, CKD FI-LAB, walking speed, hand grip strength and Short Physical Performance Battery.
The mean age of participants was 69 years (SD ±13). One-third of participants were dialysis-dependent. Nineteen (21%) patients were categorised as frail, 42 (47%) as pre-frail and 29 (32%) as robust. Overall, walking speed was the most discriminative measure (AUC 0.97 95% CI 0.93-1.00, sensitivity 0.84 95% CI 0.62-0.94, specificity 0.96 95% CI 0.88-0.99). The Clinical Frailty Scale had the best performance of the non-physical assessment frailty screening methods (AUC 0.90 95% CI 0.84-0.97, sensitivity 0.79 95% CI 0.57-0.91, specificity 0.87 95% CI 0.78-0.93).
Walking speed can be used to accurately screen for frailty in CKD populations. If it is not practical to perform a physical assessment to screen for frailty, the Clinical Frailty Scale is a useful alternative.
The immunologic landscape of the host and tumor play key roles in determining how patients will benefit from immunotherapy, and a better understanding of these factors could help inform how well a ...tumor responds to treatment. Recent advances in immunotherapy and in our understanding of the immune system have revolutionized the treatment landscape for many advanced cancers. Notably, the use of immune checkpoint inhibitors has demonstrated durable responses in various malignancies. However, the response to such treatments is variable and currently unpredictable, the availability of predictive biomarkers is limited, and a substantial proportion of patients do not respond to immune checkpoint therapy. Identification and investigation of potential biomarkers that may predict sensitivity to immunotherapy is an area of active research. It is envisaged that a deeper understanding of immunity will aid in harnessing the full potential of immunotherapy, and allow appropriate patients to receive the most appropriate treatments. In addition to the identification of new biomarkers, the platforms and assays required to accurately and reproducibly measure biomarkers play a key role in ensuring consistency of measurement both within and between patients. In this review we discuss the current knowledge in the area of peripheral immune-based biomarkers, drawing information from the results of recent clinical studies of a number of different immunotherapy modalities in the treatment of cancer, including checkpoint inhibitors, bispecific antibodies, chimeric antigen receptor T cells, and anti-cancer vaccines. We also discuss the various technologies and approaches used in detecting and measuring circulatory biomarkers and the ongoing need for harmonization.
Approximately 30 years ago, endoglin was identified as a transforming growth factor (TGF)-β coreceptor with a crucial role in developmental biology and tumor angiogenesis. Its selectively high ...expression on tumor vessels and its correlation with poor survival in cancer patients led to the exploration of endoglin as a therapeutic target for cancer. The endoglin neutralizing antibody TRC105 (Carotuximab
, Tracon Pharmaceuticals (San Diego, CA, USA) was subsequently tested in a wide variety of preclinical cancer models before being tested in phase I-III clinical studies in cancer patients as both a monotherapy and in combination with other chemotherapeutic and anti-angiogenic therapies. The combined data of these studies have revealed new insights into the role of endoglin in angiogenesis and its expression and functional role on other cells in the tumor microenvironment. In this review, we will summarize the preclinical work, clinical trials and biomarker studies of TRC105 and explore what these studies have enabled us to learn and what questions remain unanswered.
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