The microbiome and cancer for clinicians Picardo, Sarah L.; Coburn, Bryan; Hansen, Aaron R.
Critical reviews in oncology/hematology,
09/2019, Volume:
141
Journal Article
Peer reviewed
•Microorganisms might play a role in cancer development and progression.•Bacteria are found in tumor tissue, adjacent “normal” tissue and adjacent feces, urine and mucus.•The microbiome can be ...modulated and exploited to improve cancer therapeutics.•Modulation might increase treatment efficacy, reduce toxicity and prevent carcinogenesis.
The human microbiome is an emerging target in cancer development and therapeutics. It may be directly oncogenic, through promotion of mucosal inflammation or systemic dysregulation, or may alter anti-cancer immunity/therapy. Microorganisms within, adjacent to and distant from tumors may affect cancer progression, and interactions and differences between these populations can influence the course of disease. Here we review the microbiome as it pertains to cancer for clinicians. The microbiota of cancers including colorectal, pancreas, breast and prostate are discussed. We examine “omics” technologies, microbiota associated with tumor tissue and tumor-site fluids such as feces and urine, as well as indirect effects of the gut microbiome. We describe roles of the microbiome in immunotherapy, and how it can be modulated to improve cancer therapeutics. While research is still at an early stage, there is potential to exploit the microbiome, as modulation may increase efficacy of treatments, reduce toxicities and prevent carcinogenesis.
Tumour heterogeneity in the clinic Bedard, Philippe L; Hansen, Aaron R; Ratain, Mark J ...
Nature (London),
09/2013, Volume:
501, Issue:
7467
Journal Article
Peer reviewed
Open access
Recent therapeutic advances in oncology have been driven by the identification of tumour genotype variations between patients, called interpatient heterogeneity, that predict the response of patients ...to targeted treatments. Subpopulations of cancer cells with unique genomes in the same patient may exist across different geographical regions of a tumour or evolve over time, called intratumour heterogeneity. Sequencing technologies can be used to characterize intratumour heterogeneity at diagnosis, monitor clonal dynamics during treatment and identify the emergence of clinical resistance during disease progression. Genetic interpatient and intratumour heterogeneity can pose challenges for the design of clinical trials that use these data.
Immune checkpoint inhibitors (ICIs), including antibodies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1), have shown durable treatment ...responses in multiple tumor types by enhancing antitumor immunity. However, removal of self-tolerance can induce autoimmunity and produce a unique immune-driven toxicity profile, termed immune-related adverse events (irAEs). As ICIs gain approval for a growing number of indications, it is imperative clinicians increase their knowledge of and ability to manage irAEs. This review examines the etiology, presentation, kinetics, and treatment of irAEs and aims to provide practical guidance for clinicians.
Highlights • Although prostate cancer expresses many tumor associated antigens, its microenvironment is relative immunosuppressive. • Sipuleucel-T is the only approved immunotherapy for prostate ...cancer and has driven major enthusiasm for testing new agents in this disease. • Various other immune agents have been tested but failed to show clinical benefit in prostate cancer. • Appropriate patient selection and trial design are crucial; and need to be tailored to account for the unique pharmacodynamics and clinical outcomes of immunotherapies. • Here we review the data on completed trials and conclude with future directions, highlighting important aspects that need to be addressed to improve the evaluation of immunotherapies in prostate cancer.
Pembrolizumab demonstrated durable antitumor activity in patients with previously treated, advanced microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) tumors, including ...endometrial cancer, in the nonrandomized, open-label, multicohort, phase II KEYNOTE-158 study (NCT02628067). We report efficacy and safety outcomes for patients with MSI-H/dMMR endometrial cancer enrolled in KEYNOTE-158.
Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously treated, advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary end point was objective response rate per RECIST version 1.1 by independent central radiologic review. Secondary end points included duration of response, progression-free survival, overall survival, and safety.
As of October 5, 2020, 18 of 90 treated patients (20%) had completed 35 cycles of pembrolizumab and 52 (58%) had discontinued treatment. In the efficacy population (patients who received ≥ 1 dose of pembrolizumab and had ≥ 26 weeks of follow-up; N = 79), the median time from first dose to data cutoff was 42.6 (range, 6.4-56.1) months. The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.7+ months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached). Among all treated patients, 76% had ≥ 1 treatment-related adverse event (grades 3-4, 12%). There were no fatal treatment-related events. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (grades 3-4, 7%; no fatal events).
Pembrolizumab demonstrated robust and durable antitumor activity and encouraging survival outcomes with manageable toxicity in patients with previously treated, advanced MSI-H/dMMR endometrial cancer.
Atrazine, one of the most widely used herbicides in the world, threatens human health along with terrestrial and aquatic biota. Recent reports have found atrazine in drinking water to be associated ...with increased birth defects and incidences of Non-Hodgkin's Lymphoma, with higher levels of significance from exposure to both atrazine and nitrate-N. The Midwest region of the United States, which includes Nebraska, is one of the leading regions for high nitrate-N concentrations and agrochemicals, including atrazine, in surface waters. Therefore, the objective of this study was to provide a case study for completing an environmental risk analysis for the potential exposure of atrazine and nitrate-N to ecosystems and humans through interaction with surface waters using two approaches: (1) Identify watersheds across Nebraska that were at risk for exceeding atrazine and nitrate-N maximum contaminant limits (MCLs) in surface water; and (2) Determine the specific times of year where risks were greatest. Factors were then analyzed using Geographic Information System (GIS) software to identify areas of high risk. Impairments for both nitrate-N and atrazine in the surface water were found predominately during the early growing season in the southeastern region of Nebraska, in watershed areas with the highest amount of corn production and annual precipitation. Further, the methodology developed in this study has the potential for application in regions with higher dependency on surface water to determine multiple agrochemical load influxes from upstream regions and evaluate other surface water contaminants during the same time periods.
•A dual risk methodology was developed to assess surface water quality.•Atrazine risks were observed in high agricultural production regions.•Dual atrazine and nitrate risks were highest in the early growing season.•Methodology fosters a new strategy for seasonal assessments of surface water.
Purpose To establish the safety profile and antitumor activity of the anti-programmed death 1 receptor monoclonal antibody, pembrolizumab, in patients with recurrent or metastatic nasopharyngeal ...carcinoma (RM-NPC) that expressed programmed death-ligand 1 (PD-L1). Patients and Methods KEYNOTE-028 (NCT02054806) is a nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors. Key eligibility criteria for the NPC cohort included unresectable or metastatic disease, failure on prior standard therapy, and PD-L1 expression in 1% or more of tumor cells or tumor-infiltrating lymphocytes. Patients received pembrolizumab 10 mg/kg every 2 weeks up to 2 years or until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR) per investigator review. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) every 8 weeks for the first 6 months and every 12 weeks thereafter. Results Twenty-seven patients received pembrolizumab. Median age was 52.0 years (range, 18 to 68 years); 92.6% received prior therapies for RM-NPC; 70.4% had received three or more therapies. Partial response and stable disease were observed in seven and 14 patients, respectively, for an ORR of 25.9% (95% CI, 11.1 to 46.3) over a median follow-up of 20 months. ORR by central review was similar (26.3%). Drug-related adverse events that occurred in 15% or more of patients included rash (25.9%), pruritus (25.9%), pain (22.2%), hypothyroidism (18.5%), and fatigue (18.5%). Grade ≥ 3 drug-related adverse events occurred in eight patients (29.6%), and there was one drug-related death (sepsis). As of the data cutoff (June 20, 2016), two patients remained on pembrolizumab treatment. Conclusion Pembrolizumab demonstrated antitumor activity and a manageable safety profile in patients with RM-NPC.
Metastatic castrate resistant prostate cancer (mCRPC) continues to have poor survival rates due to limited treatment options. Bi-specific T cell engagers (BiTEs) are a promising class of novel ...immunotherapies with demonstrated success in haematological malignancies and melanoma. BiTEs developed for tumour associated antigens in prostate cancer have entered clinical testing. These trials have been hampered by high rates of treatment related adverse events, minimal or transient anti-tumour efficacy and generation of high titres of anti-drug antibodies. This paper aims to analyse the challenges faced by the different BiTE therapy constructs and the mCRPC tumour microenvironment that result in therapeutic resistance and identify possible strategies to overcome these issues.
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