scholarly journals Immunotherapy and pancreatic cancer: unique challenges and potential opportunities

2018 ◽  
Vol 10 ◽  
pp. 175883591881628 ◽  
Author(s):  
Kate Young ◽  
Daniel J. Hughes ◽  
David Cunningham ◽  
Naureen Starling
Keyword(s):  
Immune System ◽  
Tumour Growth ◽  
Therapeutic Option ◽  
Single Agent ◽  
Unmet Need ◽  
Tumour Microenvironment ◽  
Ductal Adenocarcinoma ◽  
First Line ◽  
Complex Interplay ◽  
Infiltrating Lymphocytes

Despite decades of research, pancreatic ductal adenocarcinoma (PDAC) continues to have the worst 5-year survival of any malignancy. With 338,000 new cases diagnosed and over 300,000 deaths per year globally there is an urgent unmet need to improve the therapeutic options available. Novel immunotherapies have shown promising results across multiple solid tumours, in a number of cases surpassing chemotherapy as a first-line therapeutic option. However, to date, trials of single-agent immunotherapies in PDAC have been disappointing and PDAC has been labelled as a nonimmunogenic cancer. This lack of response may in part be attributed to PDAC’s unique tumour microenvironment (TME), consisting of a dense fibrotic stroma and a scarcity of tumour infiltrating lymphocytes. However, as our understanding of the PDAC TME evolves, it is becoming apparent that the problem is not simply the immune system failing to recognize the cancer. There is a highly complex interplay between stromal signals, the immune system and tumour cells, at times possibly restraining tumour growth and at others supporting growth and metastasis. Understanding this complexity will enable the development of rational combinations with immunotherapy, priming the TME to offer immunotherapy the best chance of success. This review seeks to describe the unique challenges of the PDAC TME, the potential opportunities it may afford and the trials in progress capitalizing on recent insights in this area.

scholarly journals Stromal protein βig-h3 reprogrammes tumour microenvironment in pancreatic cancer

Gut ◽  
2018 ◽  
Vol 68 (4) ◽  
pp. 693-707 ◽  
Author(s):  
Delphine Goehrig ◽  
Jérémy Nigri ◽  
Rémi Samain ◽  
Zhichong Wu ◽  
Paola Cappello ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumour Growth ◽  
Matrix Protein ◽  
Immune Escape ◽  
Interaction Mechanism ◽  
Tumour Microenvironment ◽  
Extracellular Matrix Protein ◽  
Ductal Adenocarcinoma ◽  
The Impact

ObjectivePancreatic cancer is associated with an abundant stromal reaction leading to immune escape and tumour growth. This massive stroma drives the immune escape in the tumour. We aimed to study the impact of βig-h3 stromal protein in the modulation of the antitumoural immune response in pancreatic cancer.DesignWe performed studies with p48-Cre;KrasG12D, pdx1-Cre;KrasG12D;Ink4a/Arffl/fl, pdx1-Cre;KrasG12D; p53R172H mice and tumour tissues from patients with pancreatic ductal adenocarcinoma (PDA). Some transgenic mice were given injections of anti-βig-h3, anti-CD8, anti-PD1 depleting antibodies. Tumour growth as well as modifications in the activation of local immune cells were analysed by flow cytometry, immunohistochemistry and immunofluorescence. Tissue stiffness was measured by atomic force microscopy.ResultsWe identified βig-h3 stromal-derived protein as a key actor of the immune paracrine interaction mechanism that drives pancreatic cancer. We found that βig-h3 is highly produced by cancer-associated fibroblasts in the stroma of human and mouse. This protein acts directly on tumour-specific CD8+ T cells and F4/80 macrophages. Depleting βig-h3 in vivo reduced tumour growth by enhancing the number of activated CD8+ T cell within the tumour and subsequent apoptotic tumour cells. Furthermore, we found that targeting βig-h3 in established lesions released the tissue tension and functionally reprogrammed F4/80 macrophages in the tumour microenvironment.ConclusionsOur data indicate that targeting stromal extracellular matrix protein βig-h3 improves the antitumoural response and consequently reduces tumour weight. Our findings present βig-h3 as a novel immunological target in pancreatic cancer.

scholarly journals New Roads Open Up for Implementing Immunotherapy in Mesothelioma

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
R. Cornelissen ◽  
M. E. Heuvers ◽  
A. P. Maat ◽  
R. W. Hendriks ◽  
H. C. Hoogsteden ◽  
...  
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Tumour Growth ◽  
Treatment Options ◽  
Cell Types ◽  
Tumour Microenvironment ◽  
Evidence Based ◽  
Evidence Based Treatment ◽  
Good Clinical Condition ◽  
Defence Strategies

Treatment options for malignant mesothelioma are limited, and the results with conventional therapies have been rather disappointing to this date. Chemotherapy is the only evidence-based treatment for mesothelioma patients in good clinical condition, with an increase in median survival of only 2 months. Therefore, there is urgent need for a different approach to battle this malignancy. As chronic inflammation precedes mesothelioma, the immune system plays a key role in the initiation of this type of tumour. Also, many immunological cell types can be found within the tumour at different stages of the disease. However, mesothelioma cells can evade the surveillance capacity of the immune system. They build a protective tumour microenvironment to harness themselves against the immune system's attacks, in which they even abuse immune cells to act against the antitumour immune response. In our opinion, modulating the immune system simultaneously with the targeting of mesothelioma tumour cells might prove to be a superior treatment. However, this strategy is challenging since the tumour microenvironment possesses numerous forms of defence strategies. In this paper, we will discuss the interplay between immunological cells that can either inhibit or stimulate tumour growth and the challenges associated with immunotherapy. We will provide possible strategies and discuss opportunities to overcome these problems.

scholarly journals Heterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Brian Y. Lee ◽  
Elizabeth K. J. Hogg ◽  
Christopher R. Below ◽  
Alexander Kononov ◽  
Adrian Blanco-Gomez ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Smooth Muscle Actin ◽  
Tumour Microenvironment ◽  
Oncostatin M ◽  
Ductal Adenocarcinoma ◽  
Cancer Growth ◽  
Inflammatory Gene Expression ◽  
T Cell Phenotypes ◽  
Cell Phenotypes ◽  
Oncostatin M Receptor

AbstractPancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a complex microenvironment. Dichotomous tumour-promoting and -restrictive roles have been ascribed to the tumour microenvironment, however the effects of individual stromal subsets remain incompletely characterised. Here, we describe how heterocellular Oncostatin M (OSM) - Oncostatin M Receptor (OSMR) signalling reprograms fibroblasts, regulates tumour growth and metastasis. Macrophage-secreted OSM stimulates inflammatory gene expression in cancer-associated fibroblasts (CAFs), which in turn induce a pro-tumourigenic environment and engage tumour cell survival and migratory signalling pathways. Tumour cells implanted in Osm-deficient (Osm−/−) mice display an epithelial-dominated morphology, reduced tumour growth and do not metastasise. Moreover, the tumour microenvironment of Osm−/− animals exhibit increased abundance of α smooth muscle actin positive myofibroblasts and a shift in myeloid and T cell phenotypes, consistent with a more immunogenic environment. Taken together, these data demonstrate how OSM-OSMR signalling coordinates heterocellular interactions to drive a pro-tumourigenic environment in PDA.

NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from PIVOT-02.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 388-388 ◽  
Author(s):  
Arlene O. Siefker-Radtke ◽  
Mayer N. Fishman ◽  
Arjun Vasant Balar ◽  
Giovanni Grignani ◽  
Adi Diab ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Unmet Need ◽  
Standard Of Care ◽  
Target Lesion ◽  
Clinical Activity ◽  
First Line ◽  
Evaluable Population ◽  
Grade 3 ◽  
Tumor Biopsies

388 Background: Single-agent checkpoint inhibitors have changed the mUC treatment landscape; however, unmet need remains in first-line (1L) cisplatin ineligible mUC, particularly for PD-L1 negative (–) patients (pts). NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the IL-2 βγ receptor. PIVOT-02 is an ongoing study of NKTR-214 + nivolumab (nivo) in pts with advanced cancers, including mUC. Methods: Pts with mUC who were 1L cisplatin ineligible or refused standard of care (SOC) received NKTR-214 IV 0.006 mg/kg + nivo IV 360 mg q3w. Responses were assessed every 8 wks. Matched blood and tumor biopsies were evaluated for biomarkers including PD-L1 expression (assessed by Dako 28-8 PharmaDx IHC; PD-L1+ defined as ≥ 1% tumor cell staining). Results: As of 11 Oct. 2018, 34 pts received ≥ 1 dose of treatment (cisplatin ineligible [n=22]; refused SOC [n=12]). Median age was 70. Of 34 pts, 23 were efficacy evaluable (defined per protocol as having ≥ 1 post-treatment scan), 7 were pending a first scan, 1 pt was excluded for non-eligibility (no target lesion), and 3 discontinued prior to first scan. Thresholds for efficacy were exceeded in all 1L mUC cohorts under a pre-specified Fleming ORR analysis. In the efficacy evaluable population, overall ORR was 48% (11/23; 95% CI 27–69%) with a 17% CR rate (4/23) and 70% (16/23) DCR. The ORR was 50% in PD-L1– pts (5/10; 95% CI 19–81%) and 56% in PD-L1+ pts (5/9; 95% CI 21–86%). PD-L1 status was unknown in 4 efficacy-evaluable pts. The most common treatment-related AEs (TRAE, >30%) were fatigue (59%), pyrexia (38%), chills (32%), and flu-like symptoms (32%). Grade ≥ 3 TRAEs occurred in 18% of pts and 8.8% discontinued due to TRAEs. No G4/G5 TRAEs occurred. 22 pts had available baseline PD-L1 results (PD-L1+ [n=11]; PD-L1– [n=11]). 10 of the 11 PD-L1– baseline samples had matched wk 3 biopsies. Of these, 6/10 (60%) converted to PD-L1+ at wk 3. Updated results will be presented. Conclusions: NKTR-214 + nivo showed encouraging clinical activity, including CRs, and an acceptable preliminary safety profile in pts with mUC. Efficacy appears independent of PD-L1 status with a similar ORR in PD-L1– and + tumors. These data support further evaluation of the combination. Clinical trial information: NCT02983045.

Investigating real-world treatment sequencing outcomes in advanced pancreatic cancer: A purple translational registry analysis.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 386-386 ◽  
Author(s):  
Jordan Santucci ◽  
Belinda Lee ◽  
Shehara Ramyalini Mendis ◽  
Benjamin N Thomson ◽  
Michael Michael ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
De Novo ◽  
Performance Status ◽  
Single Agent ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Survival Outcomes ◽  
First Line ◽  
Treatment Sequencing

386 Background: Current standard combination first line palliative chemotherapy regimens in advanced pancreatic ductal adenocarcinoma (PDAC) have not been compared in head-to-head trials. Data on optimum treatment sequencing is also lacking. Methods: To assess whether first line (1L) treatment with gemcitabine/nab-paclitaxel (Gem/Nab-P)(SEQ1) or FOLFIRINOX (SEQ2) in the palliative treatment setting impacts survival outcomes, data for patients receiving palliative intent combination chemotherapy between 2016 and May 2020 was extracted from PURPLE, a prospective pancreatic cancer registry enrolling consecutive patients across multiple institutions. Results: Of 637 patients, 180 (28%) who received 1L single agent therapy and/or palliative radiotherapy were excluded. Of the remaining 449 patients, 132 (29%) had locally advanced disease (LA PDAC), 67 had local recurrence (15%), and 250 (56%) had de novo metastatic disease (mPDAC). Patients receiving 1L Gem/Nab-P (n=376, 84%) were older (median 67 vs 59 years, P<0.001), had a higher Charlson Comorbidity Index (CCI) (CCI ≥2: 18% vs 3%, Odds Ratio [OR] 8.0, P=0.002), and poorer performance status (ECOG≥2: 10% vs 1%, OR 8.4, P=0.01) compared to the 1L FOLFIRINOX group (n=73, 16%). 140 (37%) patients receiving 1L Gem/Nab-P (SEQ1) and 32 (44%) patients receiving 1L FOLFIRINOX (SEQ2) received second line (2L) chemotherapy. SEQ1 2L regimens included FOLFIRINOX (n=14), FOLFIRI (n=49), FOLFOX (n=35) and 5FU alone (n=3). SEQ2 2L regimens included Gem/Nab-P (n=19), Gem/5FU (n=4), Gem/Cisplatin (n=1) and gemcitabine alone (n=5). Median progression free survival (mPFS) did not differ between patients receiving 1L Gem/Nab-P vs 1L FOLFIRINOX (5.7 vs 5.1 months, P=0.54); nor did median overall survival (mOS; 11.3 vs 12.3 months, P=0.37). In the subset of patients who went on to receive 2L chemotherapy, mPFS in 2L was shorter for SEQ1 compared to SEQ2 (2.9 vs 5.2 months, Hazard Ratio [HR] 1.3, P=0.03) but mOS did not differ (15.9 vs 17.3 months P=0.91). In the subset with LA PDAC, mPFS in 2L was comparable (2.9 vs 3.3 months, P=0.55) but mOS was significantly longer with SEQ1 (22.5 vs 13.8 months, HR 0.50, P=0.01). In mPDAC, mPFS in 2L was shorter with SEQ1 (2.3 vs 5.6 months, HR 1.64, P=0.03), but mOS did not differ by sequence (13 vs 17 months, P=0.23). Conclusions: There were no significant differences in survival outcomes between 1L choices of chemotherapy, despite patients offered 1L FOLFIRINOX (SEQ2) being younger and fitter. Survival differences observed for LA PDAC versus mPDAC will be further explored. Given the multiple potential confounders, randomised clinical trials are needed to make firmer conclusions regarding the optimal initial treatment for each patient subset.

scholarly journals Retrospective Cohort Study of Caveolin-1 Expression as Prognostic Factor in Unresectable Locally Advanced or Metastatic Pancreatic Cancer Patients

2021 ◽  
Vol 28 (5) ◽  
pp. 3525-3536
Author(s):  
Alessandro Bittoni ◽  
Riccardo Giampieri ◽  
Federica Pecci ◽  
Giada Pinterpe ◽  
Alessandra Mandolesi ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Prognostic Impact ◽  
Prognostic Role ◽  
First Line ◽  
Caveolin 1 ◽  
Different Response

Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients.

Overall survival (OS) achieved with gemcitabine (G) or gemcitabine-abraxane (GA) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) who received first line modified FOLFIRINOX (m-FFX) palliative chemotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15715-e15715 ◽  
Author(s):  
Kyaw Lwin Aung ◽  
Sean Creighton ◽  
Adriana Fraser ◽  
Anna Dodd ◽  
Shari Moura ◽  
...  
Keyword(s):  
Median Duration ◽  
Palliative Chemotherapy ◽  
Single Agent ◽  
Ductal Adenocarcinoma ◽  
Line Treatment ◽  
First Line ◽  
Duration Of Treatment ◽  
Line Therapy ◽  
The Cost

e15715 Background: The standard second line treatment in advanced PDAC pts after m-FFX first line palliative chemotherapy is not clearly defined. G is the standard 2nd line treatment in Canada and GA can only be prescribed for pts with a private fund or private drug plan that covers the cost of Abraxane. More data is needed to establish OS achieved with 2ndline G or GA. Methods: The OS of PDAC pts treated with G or GA after m-FFX palliative chemotherapy given between 01-Dec-2011 and 30-Nov-2015 at the Princess Margaret Cancer Centre (PM), Toronto, Canada were retrospectively reviewed. OS was calculated from date of commencement of 2ndline treatment until death or date of last oncology follow up. Results: Over the 4-year study period, 132 pts were treated with 1st line palliative m-FFX at PM. Of them, at disease progression, 78 (59%) pts received a 2ndline therapy (50 G, 17 GA, 9 clinical trials, and 2 other). The results including demographics, treatment details and survival outcomes of patients treated with G and GA are summarized in the Table 1. Conclusions: Our results do not support single agent G after m-FFX 1st line palliative chemotherapy as median duration of treatment was too short and OS observed with G in this setting is very much limited. The median duration of treatment on GA and OS achieved with GA seem superior but sample size was too small to make a conclusion. [Table: see text]

PROSPECTS FOR HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN THE FIRST LINE OF THERAPY FOR AGGRESSIVE NON-HODGKIN’S LYMPHOMAS

2017 ◽  
Vol 63 (2) ◽  
pp. 326-328
Author(s):  
Larisa Filatova ◽  
Yevgeniya Kharchenko ◽  
Sergey Alekseev ◽  
Ilya Zyuzgin ◽  
Anna Artemeva ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Therapeutic Option ◽  
B Cell Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
First Line ◽  
Hematopoietic Stem ◽  
Hodgkin's Lymphomas

Currently there is no single approach to treatment for aggressive diffuse large-cell B-cell lymphoma (Double-HIT and Triple-HIT). Accumulated world data remain controversial and, given the unfavorable prognosis in this subgroup, high-dose chemotherapy with autologous stem cell transplantation in the first line of treatment is a therapeutic option.

New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

2018 ◽  
Vol 25 (36) ◽  
pp. 4758-4784 ◽  
Author(s):  
Amy L. Wilson ◽  
Magdalena Plebanski ◽  
Andrew N. Stephens
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Immune System ◽  
Cancer Therapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Tumour Microenvironment ◽  
Immune Checkpoints ◽  
Tumour Regression ◽  
Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

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