Immunotherapy has led to a paradigm shift in the treatment of many advanced malignancies. Despite the success in treatment of tumors like non-small cell lung cancer (NSCLC) and melanoma, checkpoint ...inhibition-based immunotherapy has limitations. Many tumors, such as pancreatic cancer, are less responsive to checkpoint inhibitors, where patients tend to have a limited duration of benefit and where clinical responses are more robust in patients who are positive for predictive biomarkers. One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME), which contains a heterogeneous composition of immunosuppressive cells. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) alter the immune landscape of the TME and serve as facilitators of tumor proliferation, metastatic growth and immunotherapy resistance. Small molecule inhibitors that target these components of the TME have been developed. This special issue review focuses on two promising classes of immunomodulatory small molecule inhibitors: colony stimulating factor-1 receptor (CSF-1R) and focal adhesion kinase (FAK). Small molecule inhibitors of CSF-1R reprogram the TME and TAMs, and lead to enhanced T-cell-mediated tumor eradication. FAK small molecule inhibitors decrease the infiltration MDSCs, TAMs and regulatory T-cells. Additionally, FAK inhibitors are implicated as modulators of stromal density and cancer stem cells, leading to a TME more conducive to an anti-tumor immune response. Immunomodulatory small molecule inhibitors present a unique opportunity to attenuate immune escape of tumors and potentiate the effectiveness of immunotherapy and traditional cytotoxic therapy.
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest malignancies among all cancers. Despite curative intent, surgery and the use of standard cytotoxic chemotherapy and radiation therapy, ...PDAC remains treatment-resistant. In recent years, more contemporary treatment modalities such as immunotherapy via checkpoint inhibition have shown some promise in many other malignancies, yet PDAC still eludes an effective curative treatment. In investigating these phenomena, research has suggested that the significant desmoplastic and adaptive tumor microenvironment (TME) of PDAC promote the proliferation of immunosuppressive cells and act as major obstacles to treatment efficacy. In this review, we explore challenges associated with the treatment of PDAC, including its unique immunosuppressive TME. This review examines the role of surgery in PDAC, recent advances in surgical approaches and surgical optimization. We further focus on advances in immunotherapeutic approaches, including checkpoint inhibition, CD40 agonists, and discuss promising immune-based future strategies, such as therapeutic neoantigen cancer vaccines as means of overcoming the resistance mechanisms which underly the dense stroma and immune milieu of PDAC. We also explore unique signaling, TME and stromal targeting via novel small molecule inhibitors, which target KRAS, FAK, CCR2/CCR5, CXCR4, PARP and cancer-associated fibroblasts. This review also explores the most promising strategy for advancement in treatment of pancreatic cancer by reviewing contemporary combinatorial approaches in efforts to overcome the treatment refractory nature of PDAC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Obesity is a known risk factor for PDA and recent reports suggest obesity has a negative impact on clinical outcomes in patients with PDA. Pretreatment body mass index (BMI) and serum albumin (SA) ...have been shown to be associated with worse overall survival in patients with advanced and metastatic PDA. However, minimal data exists on the impact of BMI and SA on perioperative and long-term clinical outcomes in patients with early-stage resected PDA. Herein, we report on the impact of these variables on perioperative clinical outcomes, overall survival (OS) and disease free survival (DFS) in patients with resected PDA. With IRB approval, we evaluated 1,545 patients with PDA treated at a single institution from 2007-2013 and identified 106 patients who underwent upfront resection with curative intent. BMI and SA were calculated preoperatively and at the time of last clinical evaluation. Influence of preoperative BMI, SA, change in either variable, and influence of other clinical and pathologic variables on perioperative morbidity and mortality was assessed. The impact of these variables on DFS and OS was assessed with cox regression modeling and ANOVA. Actuarial estimates for DFS and OS were calculated using Kaplan-Meier methods. Median follow up time was 16 months (3-89). Mean age was 68 years. Median survival was 14 months (3-65) and median time to recurrence was 11 months (1-79). Length of hospital stay was associated with BMI (p = .023), change in BMI (p = .003) and SA (p = .004). Post-operative transfusion rate was associated with SA (p = .021). There was a strong correlation between BMI change and positive margin (p = .04) and lymph node status (p = .01). On multivariate analysis, change in SA (p = .03) and node positivity (p = .008) were associated with decreased DFS. Additionally, preoperative SA (p = .023), node positivity (p = .026) and poor differentiation (p = .045) were associated with worse OS on multivariate analysis. Low preoperative SA was associated with worse DFS and OS in patients with resected PDA. Lower BMI and SA were associated with longer post-operative hospital stay. Our study is one of the first to describe how pre-operative BMI and SA and post-operative changes in these variables impact clinical and perioperative outcomes. This data supports nutritional status and weight loss as predictors of outcome in resected pancreatic cancer patients and warrants further prospective investigation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection ...margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA.
Methods
We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5–1, >1–2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS).
Results
Among all margins, PM clearance up to 2 mm was prognostic of DFS (
p
= 0.01) and OS (
p
= 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival hazard ratio HR 0.20, 95% confidence interval CI 0.048–0.881,
p
= 0.033), DFS (HR 0.46, 95% CI 0.22–0.96,
p
= 0.03), and OS (HR 0.31, 95% CI 0.14–0.74,
p
= 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11–0.89,
p
= 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10–1.58,
p
= 0.19).
Conclusion
These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The efficacy and safety of combined immunotherapy and transarterial radioembolization (TARE) were suggested in preclinical and early-phase trials, but these were limited by small sample sizes. We ...sought to compare the efficacy of combined therapy and immunotherapy alone in patients with advanced hepatocellular carcinoma (HCC).
The National Cancer Database was used to identify patients with advanced HCC diagnosed between January 1, 2017, and December 31, 2019. We included patients who received combined therapy or immunotherapy alone as first-line treatment. Multivariable logistic regression was conducted to determine predictors of combined therapy. Kaplan-Meier and Cox regression approaches were used to identify predictors of overall survival and to compare hazards of mortality between the patients who received combined therapy and immunotherapy alone.
Of 1,664 eligible patients with advanced-stage HCC, 142 received combined TARE/immunotherapy and 1,522 received immunotherapy alone. Receipt of combination therapy was associated with care at an academic center and inversely associated with racial/ethnic minority status (Hispanic and Black individuals). The median overall survival was significantly higher in the combination group than in the immunotherapy alone group (19.8 vs 9.5 months). In multivariable analysis, combined therapy was independently associated with reduced mortality (adjusted hazard ratio 0.50, 95% confidence interval: 0.36-0.68, P < 0.001). Results were consistent across subgroups and in sensitivity analyses using propensity score matching and inverse probability of treatment weighting.
The combination of TARE and immunotherapy was associated with improved survival compared with immunotherapy alone in patients with advanced-stage HCC. Our findings underly the importance of large clinical trials evaluating combination therapy in these patients.
Pancreatic ductal adenocarcinoma (PDAC) is associated with significant morbidity and mortality as most patients present with advanced disease. The development of ascites has been associated with poor ...outcomes and further characterization and contemporary management strategies are needed. 437 patients enrolled in the Gastrointestinal Biobank at Cedars-Sinai Medical Center who had epithelial pancreatic malignancy were included in the prospective cohort group. 41.7% of patients included in the study developed ascites. The majority (>80%) of ascites patients had high serum-ascites albumin gradient (SAAG) ascites. In both univariate and multivariate analysis, history of >=1 form of chemotherapy was significantly associated with ascites. Estimated median OS in patients with ascites was significantly lower than in patients without ascites, 473 days vs. 573 days, and ascites had a HR of 1.37. Patients with ascites who received diuretics and indwelling peritoneal catheter had an estimated median survival of 133 days from diagnosis of ascites, and those that received only the indwelling peritoneal catheter without diuretics had an estimated median survival of only 54 days. The estimated median survival from the diagnosis of ascites was 92 days and median time to puncture was 7 days. Median time from first tap to death was 45 days. The use of diuretics is lower than would be expected for PDAC patients with elevated SAAG. Other therapies such as beta blockers should be investigated in this subset of patients. The etiology of ascites in these patients is poorly understood and further research is needed to establish treatment guidelines and improve outcomes.
Immunotherapy has demonstrated a limited clinical efficacy in approximately 5% of cholangiocarcinoma. The main challenges for an effective immunotherapy response in cholangiocarcinoma arise from the ...tumor microenvironment, which is poorly understood.
For a comprehensive analysis of the tumor microenvironment in cholangiocarcinoma, we performed multiplex immunohistochemistry with two 15-marker immune panels and Nanostring assays for a comprehensive analysis of 104 surgically resected cholangiocarcinomas including intrahepatic, hilar, and distal cholangiocarcinoma. We also validated some key findings with a batch integration analysis of published single cell RNA sequencing data.
This study found that natural killer cells occupy the largest immune cell compartment in cholangiocarcinoma. Granzyme-B
CD8
effector T cells are significantly associated with better overall survival in both intrahepatic and distal cholangiocarcinoma. Above 85% of intrahepatic cholangiocarcinomas with higher density of PD-1
EOMES
CD8
effector T cells are associated with long-term survival. However, only the density of PD-1
EOMES
CD8
T cells in the tumor areas, but not in the peripheries of the tumors, is prognostic. In all three cholangiocarcinoma subtypes, T regulator cells are significantly associated with a poor prognosis; however, M1 and M2 tumor-associated macrophages or PD-L1
tumor-associated macrophage demonstrate different prognostic values. Combining PD-L1
M1 or M2, PD-L1
M1 or M2 tumor-associated macrophages, and T regulator cells to subgroup intrahepatic and distal cholangiocarcinoma, the prognosis is significantly better distinguished. Moreover, PD-L1
M2 tumor-associated macrophages is associated with a good prognosis in intrahepatic and distal cholangiocarcinoma, suggesting this subtype of M2 tumor-associated macrophages may be antitumoral. Interestingly, lower densities of various types of immunosuppressive cells are associated with decreased infiltration of effector T cells in distal and hilar cholangiocarcinoma, but not in intrahepatic cholangiocarcinoma. In intrahepatic cholangiocarcinoma, PD-L1
tumor-associated macrophages exert their immunosuppressive function likely through promoting T cell exhaustion.
This study suggests that the densities of Granzyme-B
CD8
effector T cells and non-exhausted PD-1
EOMES
CD8
T cells and the PD-L1 status in the tumor-associated macrophages are prognostic makers in cholangiocarcinomas. The study also supports targeting PD-L1
tumor-associated macrophages as the immunotherapy for cholangiocarcinoma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In this phase I dose-escalation trial, we assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nanoliposomal Irinotecan (Nal-Iri) and 5-Fluorouracil/Folinic Acid (5-FU/FA). ...Secondarily, we investigate effects on weight, lean body mass, quality-of-life, the gut microbiome composition, inflammatory biomarkers, progression-free survival, and overall survival. This was a single-arm, open-label adaptive Bayesian dose-escalation study of Bermekimab combined with Nal-Iri and 5FU/FA in patients with advanced or locally advanced PDAC who failed gemcitabine-based chemotherapy. 22 patients enrolled between 2017 and 2019. 3 of 21 patients experienced dose-limiting toxicities attributable to the chemotherapy backbone. 58% (10/17) of patients exhibited weight stability. Physical performance status was preserved among all subjects. Patients reported improvements in quality-of-life metrics via QLQ-PAN26 questioner (-3.6, p = 0.18) and functional well-being (1.78, p = 0.02). Subjects exhibited a decrease in inflammatory cytokines, notably, vascular endothelial growth factor (-0.86, p = 0.017) with Bermekimab. Bermekimab treatment was associated with an increased abundance of gut health-promoting bacterial genera Akkermansia, with 3.82 Log2-fold change from baseline. In sum, Bermekimab is safe to be used in conjunction with Nal-Iri and 5-FU/FA chemotherapy. This benign toxicological profile warrants further Phase I/II investigation of Bermekimab in combinatorial strategies, and the impact of anti-IL-1α antibodies on the gut microbiome.Clinical trials registration: NCT03207724 05/07/2017.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Landmark molecular profiling efforts have identified multiple targetable alterations in cholangiocarcinoma. Among the molecular-driven subsets of cholangiocarcinoma, targeting the fibroblast growth ...factor receptor (FGFR) has shown promise and represents the first targeted therapy to be approved in treatment-refractory, advanced cholangiocarcinoma. In this review, we provide an up-to-date overview of the clinical development of FGFR inhibitors in advanced cholangiocarcinoma. We review the FGFR pathway and discuss emerging issues including resistance to FGFR inhibitors. We end with a discussion on future considerations to optimize the potential of this class of therapeutics in advanced cholangiocarcinoma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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