Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

Jiang, Chen; Guo, Xiaozhong; Xingshun, QI

doi:10.1155/2017/8282391

Cited by 19 publications

(16 citation statements)

References 46 publications

(100 reference statements)

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“…An interesting meta-analysis gathering all clinical trials with immunotherapies in pancreatic cancer [ 136 ] found out that this strategy indeed significantly increases the 3-, 6-, 12-month and 3-year OS of patients. Importantly, immunotherapy significantly increases the immune response of patients with PDA and reduced CA19-9 levels.…”

Section: Pda and Immunotherapymentioning

confidence: 99%

Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Martínez-Bosch

Vinaixa

Navarro

2018

Cancers

163

154

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Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8+ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

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Section: Pda and Immunotherapymentioning

confidence: 99%

Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Martínez-Bosch

Vinaixa

Navarro

2018

Cancers

163

154

View full text Add to dashboard Cite

show abstract

“…A recent meta-analysis of specific immunotherapy trials employed in treatment of pancreatic cancer revealed that circulating IFN-gamma levels were significantly higher post-treatment versus pre-treatment (4 trials with 81 patients; pooled mean difference of 3.75 IU/mL; p=0.01), and circulating IL-4 levels were significantly lower (2 trials with 55 patients; pooled mean difference of −1.85 IU/mL; p<0.0001) [100]. Anti-tumor immunomodulatory effects are most likely maximized with multi-modal non-specific and specific immune therapies.…”

Section: Introductionmentioning

confidence: 99%

Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy

Maloney

Khokhlova

Pillarisetty

et al. 2017

International Reviews of Immunology

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Current clinical treatment regimens, including many emergent immune strategies (e.g. checkpoint inhibitors) have done little to affect the devastating course of pancreatic ductal adenocarcinoma (PDA). Clinical trials for PDA often employ multi-modal treatment, and have started to incorporate stromal-targeted therapies, which have shown promising results in early reports. Focused ultrasound (FUS) is one such therapy that is uniquely equipped to address local and systemic limitations of conventional cancer therapies as well as emergent immune therapies for PDA. FUS methods can non-invasively generate mechanical and/or thermal effects that capitalize on the unique oncogenomic/proteomic signature of a tumor. Potential benefits of FUS therapy for PDA include: 1) emulsification of targeted tumor into undenatured antigens in situ, increasing dendritic cell maturation, and increasing intra-tumoral CD8+/ T regulatory cell ratio and CD8+ T cell activity; 2) reduction in intra-tumoral hypoxic stress; 3) modulation of tumor cell membrane protein localization to enhance immunogenicity; 4) modulation of the local cytokine milieu toward a Th1-type inflammatory profile; 5) up-regulation of local chemoattractants; 6) remodeling the tumor stroma; 7) localized delivery of exogenously packaged immune-stimulating antigens, genes and therapeutic drugs. While not all of these results have been studied in experimental PDA models to date, the principles garnered from other solid tumor and disease models have direct relevance to the design of optimal FUS protocols for PDA. In this review, we address the pertinent limitations in current and emergent immune therapies that can be improved with FUS therapy for PDA.

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“…In recent studies of effective immunotherapy, the development of antibodies to tumor-associated antigens has been associated with a positive response ( 23 , 24 ). However, the importance of antibodies as a component of effective antitumor responses has long been recognized ( 25 ). In this study, ranitidine is thought to function at least in part through modulation of tumor-associated immune suppression and would be predicted to impact multiple arms of acquired immune function, including antibody development.…”

Section: Discussionmentioning

confidence: 99%

Ranitidine Inhibition of Breast Tumor Growth Is B Cell Dependent and Associated With an Enhanced Antitumor Antibody Response

et al. 2018

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BackgroundThe histamine receptor 2 antagonist ranitidine is a commonly used, non-prescription, medication. It limits the development, growth, and metastasis of breast cancers in mouse models of disease. In this study, we examined the role of B cells in this response, the impact of ranitidine on the development of antitumor antibodies and subpopulations of natural killer cells using murine breast cancer models.MethodsPeripheral blood granulocyte populations were assessed in both E0771-GFP and 4T1 orthotopic tumor-bearing mice by evaluation of stained blood smears. Antibody responses were assessed both in terms of the levels of anti-GFP antibodies detected by enzyme-linked immunosorbent assay and also by antibody binding to the surface of tumor cells evaluated by flow cytometry. B cell and NK cell populations were examined in the draining lymph nodes and spleens of tumor-bearing animals, by flow cytometry with and without ranitidine treatment.ResultsOral ranitidine treatment was not associated with changes in peripheral blood granulocyte populations in tumor-bearing mice. However, ranitidine treatment was associated with the development of enhanced antitumor antibody responses. This was not limited to the tumor setting since ranitidine-treated mice immunized with ovalbumin also demonstrated increased IgG antibody responses. Analysis of B cell populations indicated that while B1 cell populations remained unchanged there was a significant decrease in B2 cells in the tumor-draining inguinal lymph nodes. Notably, ranitidine did not significantly inhibit primary tumor growth in B cell-deficient animals. Examination of NK cell populations revealed a significant decrease in the proportion of intermediately functionally mature NK cells populations (CD27+CD11b−) in ranitidine-treated tumor-bearing mice compared with untreated tumor-bearing controls.ConclusionThese data demonstrate an important role for B cells in the enhanced antitumor immune response that occurs in response to ranitidine treatment. Our findings are consistent with a model, whereby ranitidine reduces tumor-associated immune suppression allowing for the development of more effective antitumor responses mediated by B cells which may include the participation of NK cells. These data underline the importance of considering widely used histamine receptor antagonists as modulators of antitumor immunity to breast cancer.

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Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

Cited by 19 publications

References 46 publications

Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy

Ranitidine Inhibition of Breast Tumor Growth Is B Cell Dependent and Associated With an Enhanced Antitumor Antibody Response

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