The role of the tumor endothelium in leukocyte recruitment in pancreatic cancer

Schmidt, Jan; Mocevicius, Paulius; Werner, Jens; Ryschich, Eduard

doi:10.1016/j.surg.2012.05.027

Cited by 5 publications

(4 citation statements)

References 48 publications

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“…In pancreatic cancer, a possible explanation for the therapeutic failure of PD-1/PD-L1 blockade therapy is the lack of natural infiltration of effector immune cells in most cases (17, 18, 20). Vaccine-based immunotherapy is a potential strategy to activate effector T cell trafficking into the TME.…”

Section: Discussion and Innovationmentioning

confidence: 99%

“…Several studies have reported that dysfunction of the immune system is one of the key contributors for the development of PDAC (15, 16). Moreover, PDAC is known to have an immunosuppressive tumor microenvironment characterized by (i) the absence of intratumoral effector T-cells (17, 18), (ii) the presence of an inflammatory tumor micro-environment led by the RAS oncogene (19), and (iii) massive infiltration of immunosuppressive leukocytes into the tumor microenvironment, which predicts poor survival (18, 20, 21). Additionally, the analysis of immune infiltrates in human tumors has demonstrated a positive correlation between prognosis and the presence of humoral response to pancreatic antigens (MUC-1 and mesothelin) (22, 23) or of tumor-infiltrating T cells (20, 24).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma—A Proof of Antigen Discovery Feasibility in Three Patients

et al. 2019

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Despite the promising therapeutic effects of immune checkpoint blockade (ICB), most patients with solid tumors treated with anti-PD-1/PD-L1 monotherapy do not achieve objective responses, with most tumor regressions being partial rather than complete. It is hypothesized that the absence of pre-existing antitumor immunity and/or the presence of additional tumor immune suppressive factors at the tumor microenvironment are responsible for such therapeutic failures. It is therefore clear that in order to fully exploit the potential of PD-1 blockade therapy, antitumor immune response should be amplified, while tumor immune suppression should be further attenuated. Cancer vaccines may prime patients for treatments with ICB by inducing effective anti-tumor immunity, especially in patients lacking tumor-infiltrating T-cells. These “non-inflamed” non-permissive tumors that are resistant to ICB could be rendered sensitive and transformed into “inflamed” tumor by vaccination. In this article we describe a clinical study where we use pancreatic cancer as a model, and we hypothesize that effective vaccination in pancreatic cancer patients, along with interventions that can reprogram important immunosuppressive factors in the tumor microenvironment, can enhance tumor immune recognition, thus enhancing response to PD-1/PD-L1 blockade. We incorporate into the schedule of standard of care (SOC) chemotherapy adjuvant setting a vaccine platform comprised of autologous dendritic cells loaded with personalized neoantigen peptides (PEP-DC) identified through our own proteo-genomics antigen discovery pipeline. Furthermore, we add nivolumab, an antibody against PD-1, to boost and maintain the vaccine's effect. We also demonstrate the feasibility of identifying personalized neoantigens in three pancreatic ductal adenocarcinoma (PDAC) patients, and we describe their optimal incorporation into long peptides for manufacturing into vaccine products. We finally discuss the advantages as well as the scientific and logistic challenges of such an exploratory vaccine clinical trial, and we highlight its novelty.

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Section: Discussion and Innovationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma—A Proof of Antigen Discovery Feasibility in Three Patients

et al. 2019

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“…Moreover, chronic pancreatitis model seems to express more CRMP4 and pCRMP4‐S522 than that of acute pancreatitis model (Table ). Because pancreatic cancer has a high degree of heterogeneity in the distribution of tumor‐infiltrating leukocytes and T cells , the expression of CRMP4 in the infiltrated T cells in our pancreatitis model may suggest the possible role of CRMP4 in immune‐suppression during pancreatic cancer progression .…”

Section: Discussionmentioning

confidence: 99%

Caerulein‐induced pancreatitis augments the expression and phosphorylation of collapsin response mediator protein 4

Sato

Nakamura

Hiroshima

et al. 2016

J Hepato Biliary Pancreat

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Pancreatitis induces CRMP4 expression in the pancreas parenchyma and in the infiltrated lymphocytes. Overlapping expression of CRMP4 and Cdk5 may suggest that the Cdk5 is at least, in part, responsible for the phosphorylation of CRMP4. The results suggest that CRMP4 is involved in the inflammatory response in pancreatitis. Understanding the mechanisms of CRMP4 would help us to develop novel therapeutic strategies against acute or chronic pancreatitis, and pancreatic cancer.

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“…Many patients with cancer initially do not response to anti-PD-1 inhibitors, possibly because of "cold" tumors, which are with no or few immune cells in tumor tissues and insensitive to ICIs (10,(39)(40)(41). In these tumors, tumor antigen cannot effectively prime and activate T cells, and further lead to the cycle halting at step 1 or 2.…”

Section: Improve Sensitivity and Efficacy Of Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Safety and Efficacy of Personalized Cancer Vaccines in Combination With Immune Checkpoint Inhibitors in Cancer Treatment

Liao

Zhang

2021

Front. Oncol.

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Cancer immunotherapy can induce sustained responses in patients with cancers in a broad range of tissues, however, these treatments require the optimized combined therapeutic strategies. Despite immune checkpoint inhibitors (ICIs) have lasting clinical benefit, researchers are trying to combine them with other treatment modalities, and among them the combination with personalized cancer vaccines is attractive. Neoantigens, arising from mutations in cancer cells, can elicit strong immune response without central tolerance and out-target effects, which is a truly personalized method. Growing studies show that the combination can elevate the antitumor efficacy with acceptable safety and minimal additional toxicity compared with single agent vaccine or ICI. Herein, we have searched these preclinical and clinical trials and summarized safety and efficacy of personalized cancer vaccines combined with ICIs in several malignancies. Meanwhile, we discuss the rationale of the combination and future challenges.

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The role of the tumor endothelium in leukocyte recruitment in pancreatic cancer

Cited by 5 publications

References 48 publications

A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma—A Proof of Antigen Discovery Feasibility in Three Patients

A Phase Ib Study of the Combination of Personalized Autologous Dendritic Cell Vaccine, Aspirin, and Standard of Care Adjuvant Chemotherapy Followed by Nivolumab for Resected Pancreatic Adenocarcinoma—A Proof of Antigen Discovery Feasibility in Three Patients

Caerulein‐induced pancreatitis augments the expression and phosphorylation of collapsin response mediator protein 4

Safety and Efficacy of Personalized Cancer Vaccines in Combination With Immune Checkpoint Inhibitors in Cancer Treatment

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