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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.
Bassani-Sternberg, M, Digklia, A, Huber, F, Wagner, D, Sempoux, C, Stevenson, BJ, Thierry, AC, Michaux, J, Pak, H, Racle, J, et al
Frontiers in immunology. 2019;:1832
Abstract
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.
2.
[Aspirin and colorectal cancer].
Grancher, A, Michel, P, Di Fiore, F, Sefrioui, D
Bulletin du cancer. 2018;(2):171-180
Abstract
Colorectal cancer is a worldwide public health problem. Aspirin has been identified as a protective factor against the apparition of colorectal cancer. There are several mechanisms about the actions by aspirin on colorectal tumorogenesis. These are not perfectly known nowadays. On one hand, there are direct mechanisms on colorectal mucosa, on the other hand there are indirect mechanisms through platelet functions. Aspirin also plays a role by its anti-inflammatory action and the stimulation of antitumor immunity. Several studies show that long-term treatment with low-doses of aspirin decreases the incidence of adenomas and colorectal cancers. In the United States, aspirin is currently recommended for primary prevention of the risk of colorectal cancer in all patients aged 50 to 59, with a 10-year risk of cardiovascular event greater than 10 %. However, primary prevention with aspirin should not be a substitute for screening in colorectal cancer. Furthermore, aspirin seems to be beneficial when used in post-diagnosis of colorectal cancer. It could actually decrease the risk of metastasis in case of a localized colorectal cancer, and increase the survival in particular, concerning PIK3CA mutated tumors. The association of aspirin with neoadjuvant treatment of colorectal cancer by radiochimiotherapy seems to have beneficial effects. French prospective randomized study is currently being conducted to investigate postoperative aspirin in colorectal cancers with a PIK3CA mutation.
3.
Regular Aspirin Use Associates With Lower Risk of Colorectal Cancers With Low Numbers of Tumor-Infiltrating Lymphocytes.
Cao, Y, Nishihara, R, Qian, ZR, Song, M, Mima, K, Inamura, K, Nowak, JA, Drew, DA, Lochhead, P, Nosho, K, et al
Gastroenterology. 2016;(5):879-892.e4
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Abstract
BACKGROUND & AIMS Aspirin use reduces colorectal cancer risk. Aspirin, a nonsteroidal anti-inflammatory drug, inhibits prostaglandin-endoperoxide synthase 2 (PTGS2 or cyclooxygenase-2); PTGS2 promotes inflammation and suppresses T-cell-mediated adaptive immunity. We investigated whether the inverse association of aspirin use with colorectal carcinoma risk was stronger for tumors with lower degrees of lymphocytic infiltrates than for tumors with higher degrees of lymphocytic infiltrates. METHODS We collected aspirin use data biennially from participants in the Nurses' Health Study and Health Professionals Follow-up Study. Participants were asked whether they took aspirin in most weeks, the number of tablets taken per week, and years of aspirin use. We collected available tumor specimens (n = 1458) from pathology laboratories in the United States. A pathologist confirmed the diagnosis of colorectal adenocarcinoma (excluding anal squamous cell carcinoma), and evaluated histopathology features, including patterns and degrees of lymphocytic infiltrates within and around tumor areas. Person-years of follow-up evaluation were accrued from the date of return of questionnaires until dates of colorectal cancer diagnosis, death, or the end of follow-up evaluation (June 2010). Duplication-method Cox proportional hazards regression was used to assess the association of aspirin with the incidence of colorectal carcinoma subgroups according to the degree of tumor-infiltrating lymphocytes (TILs), intratumoral periglandular reaction, peritumoral reaction, or Crohn's-like reaction. RESULTS We documented 1458 rectal and colon cancers. The inverse association between regular aspirin use and colorectal cancer risk significantly differed by concentrations of TILs (Pheterogeneity = .007). Compared with nonregular use, regular aspirin use was associated with a lower risk of tumors that had low levels of TILs (relative risk, 0.72; 95% confidence interval, 0.63-0.81), and strength of the association depended on aspirin dose and duration (both Ptrend < .001). In contrast, aspirin use was not associated with a risk of tumors having intermediate or high levels of TILs. This differential association was consistent regardless of the status of tumor microsatellite instability, mutations in BRAF, or expression of PTGS2. Regular aspirin use was associated with a lower risk of tumors that contained low levels of CD3+ T cells, CD8+ T cells, or CD45RO (PTPRC)+ T cells (measured by immunohistochemistry and computer-assisted image analysis). CONCLUSIONS Based on data from the prospective cohort studies, regular use of aspirin is associated with a lower risk of colorectal carcinomas with low concentrations of TILs. These findings indicate that the immune response in the tumor microenvironment could be involved in the chemopreventive effects of aspirin.
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Role of vitamin and mineral supplementation and aspirin use in cancer survivors.
Giovannucci, E, Chan, AT
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;(26):4081-5
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Abstract
Multivitamins and multiminerals are widely used in the United States, but their efficacy and, perhaps more importantly, the potential for harm in individuals who have cancer have received relatively little study. Beyond their general effects on health, the use of vitamins and minerals by patients with cancer has unique implications because of their potential direct effects on existing cancers, effects on factors that may influence carcinogenesis, such as immunity, and interactions with treatment. Some evidence suggests that vitamin D at higher than standard doses may improve cancer-specific and overall survival for several cancer sites. Besides vitamin D, there is little evidence that nutritional supplements lower the risk of recurrence or improve survival from cancer, although some benefits may be possible in specific subgroups. Some data suggest that higher than standard doses of some vitamins or minerals could even enhance carcinogenesis or worsen survival in patients with cancer. For example, evidence suggests that although folate supplementation administered in preneoplastic stages may lower the risk of colorectal cancer, excessive folic acid in patients with established cancer may be harmful. For prostate cancer, some preliminary evidence indicates that excess consumption of one or a combination of components in a multivitamin/multimineral may accelerate cancer progression and increase fatality. Use of aspirin is proven to lower risk of colorectal cancer, and recent evidence suggests that aspirin use in patients with colorectal cancer improves cancer-specific and overall survival, especially in patients with tumors that express cyclooxygenase-2 (COX-2). The potential beneficial or adverse effects of dietary supplements and aspirin in survivors of cancer warrant further study.