scholarly journals Hacking Pancreatic Cancer: Present and Future of Personalized Medicine

2021 ◽  
Vol 14 (7) ◽  
pp. 677
Author(s):  
Alessandro Di Federico ◽  
Valentina Tateo ◽  
Claudia Parisi ◽  
Francesca Formica ◽  
Riccardo Carloni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Personalized Medicine ◽  
Kinase Inhibitors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Wide Spectrum ◽  
Comprehensive Overview ◽  
Personalized Approach ◽  
Immune Escape Mechanisms

Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.

scholarly journals Strategies in Developing Immunotherapy for Pancreatic Cancer: Recognizing and Correcting Multiple Immune “Defects” in the Tumor Microenvironment

2019 ◽  
Vol 8 (9) ◽  
pp. 1472 ◽  
Author(s):  
Sireesha Upadhrasta ◽  
Lei Zheng
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Checkpoint Inhibitors ◽  
Immunosuppressive Tumor Microenvironment ◽  
Tumor Types ◽  
Cancer Immunotherapies ◽  
Immune Defects ◽  
Made In

With the advent of cancer immunotherapies, significant advances have been made in the treatment of many tumor types including melanoma, lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, bladder cancer, etc. However, similar success has not been observed with the treatment of pancreatic cancer and all other immunogenic “cold” tumors. This prompts the need for a better understanding of the complexity of the cold tumor microenvironment (TME) of pancreatic cancer and what are truly the “defects” in the TME making the cancer unresponsive to immune checkpoint inhibitors. Here we discuss four major immune defects that can be recognized in pancreatic cancer, including lack of high-quality effector intratumoral T cells, heterogeneous dense stroma as a barrier to effector immune cells infiltrating into the tumor, immunosuppressive tumor microenvironment, and failure of the T cells to accomplish tumor elimination. We also discuss potential strategies for pancreatic cancer treatment that work by correcting these immune defects.

scholarly journals Pancreatic Cancer and Immunotherapy: A Clinical Overview

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4138
Author(s):  
Florentine E. F. Timmer ◽  
Bart Geboers ◽  
Sanne Nieuwenhuizen ◽  
Madelon Dijkstra ◽  
Evelien A. C. Schouten ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Synergistic Effects ◽  
Oncolytic Viruses ◽  
Ductal Adenocarcinoma ◽  
Successful Implementation ◽  
Cell Therapies ◽  
Radio Therapy ◽  
Wide Range

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

scholarly journals The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 532
Author(s):  
Patrizia Leone ◽  
Antonio Giovanni Solimando ◽  
Rossella Fasano ◽  
Antonella Argentiero ◽  
Eleonora Malerba ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Kinase Inhibitors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Chemotherapeutic Agents ◽  
Protein Kinase Inhibitors ◽  
Great Promise ◽  
Chronic Injury

Hepatocellular carcinoma (HCC) is one of most common cancers and the fourth leading cause of death worldwide. Commonly, HCC development occurs in a liver that is severely compromised by chronic injury or inflammation. Liver transplantation, hepatic resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), and targeted therapies based on tyrosine protein kinase inhibitors are the most common treatments. The latter group have been used as the primary choice for a decade. However, tumor microenvironment in HCC is strongly immunosuppressive; thus, new treatment approaches for HCC remain necessary. The great expression of immune checkpoint molecules, such as programmed death-1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activating gene 3 protein (LAG-3), and mucin domain molecule 3 (TIM-3), on tumor and immune cells and the high levels of immunosuppressive cytokines induce T cell inhibition and represent one of the major mechanisms of HCC immune escape. Recently, immunotherapy based on the use of immune checkpoint inhibitors (ICIs), as single agents or in combination with kinase inhibitors, anti-angiogenic drugs, chemotherapeutic agents, and locoregional therapies, offers great promise in the treatment of HCC. This review summarizes the recent clinical studies, as well as ongoing and upcoming trials.

scholarly journals Immunotherapy in tumors failing check-point inhibitors:the sarcoma example – What we missed and where we are heading

2017 ◽  
Vol 5 (2) ◽  
pp. 22-32
Author(s):  
Alessandra Merlini ◽  
Francesco Tolomeo ◽  
Sara Miano ◽  
Lorenzo D’Ambrosio ◽  
Dario Sangiolo ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Host Immune System ◽  
Tumor Immune Escape ◽  
Cancer Subtypes ◽  
Complex Interactions ◽  
Innate Immunity Cells ◽  
Antigen Presenting ◽  
Shed Light

The introduction of immune checkpoint inhibitors represented a true revolution in the treatment of melanoma and a few other cancer subtypes. Unfortunately, the use of these drugs did not achieve the same beneficial results in other neoplasms, such as soft tissue sarcoma and gastrointestinal stromal tumor. These failures encouraged deeper research into the complex interactions between cancer and host immune system, to try to shed light on the ability of cancer cells to escape immunologic surveillance. Key elements to explain tumor immune escape were found in the tumor microenvironment. The main actors in this complex network are lymphocytes, cytokines and innate immunity cells such as macrophages and antigen presenting cells. Thus, immuno-oncologists are studying the different components of the tumor microenvironment to identify possible new therapeutic targets. In this paper, we summarize the most important aspects of these interactions, and provide an overview of the newer and more promising immunotherapeutic strategies.

scholarly journals Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response

2021 ◽  
Vol 118 (24) ◽  
pp. e2103240118
Author(s):  
Yuping Zhang ◽  
Sathiya P. Narayanan ◽  
Rahul Mannan ◽  
Gregory Raskind ◽  
Xiaoming Wang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Renal Cell ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Wide Spectrum ◽  
Response To Therapy ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Cell Of Origin

Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy.

scholarly journals Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hong-Bo Li ◽  
Zi-Han Yang ◽  
Qing-Qu Guo
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Immune Effector ◽  
Effector Cells ◽  
Pathological Subtype

AbstractPancreatic cancer is an extremely malignant tumor with the lowest 5-year survival rate among all tumors. Pancreatic ductal adenocarcinoma (PDAC), as the most common pathological subtype of pancreatic cancer, usually has poor therapeutic results. Immune checkpoint inhibitors (ICIs) can relieve failure of the tumor-killing effect of immune effector cells caused by immune checkpoints. Therefore, they have been used as a novel treatment for many solid tumors. However, PDAC is not sensitive to monotherapy with ICIs, which might be related to the inhibitory immune microenvironment of pancreatic cancer. Therefore, the way to improve the microenvironment has raised a heated discussion in recent years. Here, we elaborate on the relationship between different immune cellular components in this environment, list some current preclinical or clinical attempts to enhance the efficacy of ICIs by targeting the inhibitory tumor microenvironment of PDAC or in combination with other therapies. Such information offers a better understanding of the sophisticated tumor-microenvironment interactions, also providing insights on therapeutic guidance of PDAC targeting.

A phase Ib dose-escalation and cohort-expansion study of safety and activity of the transforming growth factor (TGF) β receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4124-4124 ◽  
Author(s):  
Davide Melisi ◽  
Antoine Hollebecque ◽  
Do-Youn Oh ◽  
Emiliano Calvo ◽  
Anna M. Varghese ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dose Escalation ◽  
Kinase Inhibitors ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Third Line ◽  
Grade 3 ◽  
Immunosuppressive Microenvironment

4124 Background: Pancreatic cancer (PC) is characterized by a highly immunosuppressive microenvironment, and immune checkpoint inhibitors as monotherapy have been ineffective to date. TGFβ is commonly viewed as a powerful immunosuppressive cytokine, and inhibition of its signaling reverses this suppression and activates adaptive immune responses. A combination of TGFβ and PD-L1 inhibition may act synergistically to induce immune restoration and to improve antitumor responses. This Phase 1b study (NCT02734160) evaluated the combination of galunisertib plus durvalumab in recurrent or refractory metastatic PC. Methods: Eligible patients (pts) were ≥18 years old, had ECOG status ≤1, and had not received treatment with anti-PD-1, anti-PD-L1, or TGFβ R1 kinase inhibitors. The primary objective was to assess the safety and the recommended dose of galunisertib given 14 days on/14 days off in combination with durvalumab 1500 mg every 4 weeks. Four dose levels of galunisertib were tested in the dose escalation portion of the study: 50 mg QD, 50 mg BID, 80 mg BID and 150 mg BID, followed by the cohort expansion portion of the study at the recommended Phase 2 dose (RP2D). Secondary objectives included preliminary assessment of activity by response rate, (RECIST v1.1), median PFS (mPFS), and OS (mOS). Results: 42 pts (25F/17M) were treated in the study (median age 56.5 y; 71.4% had received ≥2 prior systemic regimens). There was no dose limiting toxicity and galunisertib 150 mg BID was chosen as the RP2D. In the 32 pts treated at this dose, Grade ≥3 related AEs included AST and GGT elevations (2 pts each), and ALT and alkaline phosphatase elevations, and neutropenia (1 pt each). One partial response and 7/32 stable diseases were observed (disease control rate 25%); mPFS was 1.9 months (95% CI: 1.5, 2.2) and mOS was NR (95% CI: 3.6, NR). Biomarker data will be presented at the meeting. Conclusions: The combination of galunisertib plus durvalumab had an acceptable tolerability and safety profile. The activity of this combination in second and third line PC patients warrants further consideration. Clinical trial information: NCT02734160.

scholarly journals Association between Inflammation and Function of Cell Adhesion Molecules Influence on Gastrointestinal Cancer Development

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 67
Author(s):  
Hsiang-Wei Huang ◽  
Cheng-Chih Chang ◽  
Chia-Siu Wang ◽  
Kwang-Huei Lin
Keyword(s):  
Cell Adhesion ◽  
Tumor Microenvironment ◽  
Adhesion Molecules ◽  
Inflammatory Cytokines ◽  
Gastrointestinal Cancer ◽  
Cell Adhesion Molecules ◽  
Immune Cell ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells

Gastrointestinal cancer is highly associated with inflammatory processes inducing the release of cytokines from cancer or immune cells, including interferons, interleukins, chemokines, colony-stimulating factors, and growth factors, which promote or suppress tumor progression. Inflammatory cytokines within the tumor microenvironment promote immune cell infiltration. Infiltrating immune, and tumor-surrounding stromal cells support tumor growth, angiogenesis, metastasis, and immunosuppression through communication with inflammatory cytokines and cell adhesion molecules. Notably, infiltrating immune and tumor cells present immunosuppressive molecules, such as programmed death-ligand 1 (PD-L1) and CD80/CD86. Suppression of cytotoxic T cells promotes tumor avoidance of immune surveillance and greater malignancy. Moreover, glycosylation and sialylation of proteins hyperexpressed on the cancer cell surface have been shown to enhance immune escape and metastasis. Cytokine treatments and immune checkpoint inhibitors are widely used in clinical practice. However, the tumor microenvironment is a rapidly changing milieu involving several factors. In this review, we have provided a summary of the interactions of inflammation and cell adhesion molecules between cancer and other cell types, to improve understanding of the tumor microenvironment.

scholarly journals The regulation of immune checkpoints by the hypoxic tumor microenvironment

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11306
Author(s):  
Min Hu ◽  
Yongfu Li ◽  
Yuting Lu ◽  
Miao Wang ◽  
Yingrui Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
New Drugs ◽  
Immune Checkpoints ◽  
Mesenchymal Transition ◽  
Programmed Death ◽  
Domain 3

The tumor microenvironment (TME) influences the occurrence and progression of tumors, and hypoxia is an important characteristic of the TME. The expression of programmed death 1 (PD1)/programmed death-ligand 1 (PDL1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and other immune checkpoints in hypoxic malignant tumors is often significantly increased, and is associated with poor prognosis. The application of immune checkpoint inhibitors (ICIs) for treating lung cancer, urothelial carcinoma, and gynecological tumors has achieved encouraging efficacy; however, the rate of efficacy of ICI single-drug treatment is only about 20%. In the present review, we discuss the possible mechanisms by which the hypoxic TME regulates immune checkpoints. By activating hypoxia-inducible factor-1α (HIF-1α), regulating the adenosine (Ado)-A2aR pathway, regulating the glycolytic pathway, and driving epithelial-mesenchymal transition (EMT) and other biological pathways, hypoxia regulates the expression levels of CTLA4, PD1, PDL1, CD47, lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3), and other immune checkpoints, which interfere with the immune effector cell anti-tumor response and provide convenient conditions for tumors to escape immune surveillance. The combination of HIF-1α inhibitors, Ado-inhibiting tumor immune microenvironment regulatory drugs, and other drugs with ICIs has good efficacy in both preclinical studies and phase I-II clinical studies. Exploring the effects of TME hypoxia on the expression of immune checkpoints and the function of infiltrating immune cells has greatly clarified the relationship between the hypoxic TME and immune escape, which is of great significance for the development of new drugs and the search for predictive markers of the efficacy of immunotherapy for treating malignant tumors. In the future, combination therapy with hypoxia pathway inhibitors and ICIs may be an effective anti-tumor treatment strategy.

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