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Systemic Inflammation Is a Determinant of Outcomes to CD40 Agonist-Based Therapy in Pancreatic Cancer Patients

Inflammation in the blood could serve as a new biomarker to help identify patients with advanced pancreatic cancer who won't respond to the immune-stimulating drugs known as CD40 agonists, suggests a new study (JCI Insight 2021; The research team found that patients with systemic inflammation had worse overall survival rates than patients without inflammation when treated with both a CD40 agonist and the chemotherapy gemcitabine. Identifying systemic inflammation as a mechanism of resistance could help guide treatment decisions and future studies, as well as offer up new targets for researchers to explore. The researchers analyzed blood samples from 22 patients with pancreatic ductal adenocarcinoma (PDAC) to gain insight into the immunological mechanisms underway after treatment with chemoimmunotherapy. The team observed a depletion of B cells, monocytes, and dendritic cells, as well as activation of CD4+ T cells, over 8 days in most patients. Surprisingly, a closer look revealed no consistent evidence of CD8+ T-cell activation and no association between T-cell activation and outcomes. These findings challenge preclinical studies that have suggested that T-cell activation sparked by CD40 agonists would associate with outcomes. Rather, overall survival outcomes were associated with a measurable characteristic in the patients' blood found before treatment: systemic inflammation. Systemic inflammation is marked by the increased presence of neutrophils, inflammatory cytokines (including IL-6 and IL-8), and acute phase reactants in the peripheral blood, and it is a known symptom of pancreatic cancer and other cancer types. Patients with systemic inflammation before treatment with a CD40 agonist and gemcitabine, the authors report, had a median overall survival of 5.8 months versus 12.3 months for patients without inflammation from the start of treatment. Also surprising, the data suggest that gemcitabine chemotherapy may eliminate monocytes and dendritic cells, which are fundamental to facilitating T-cell immune responses. However, the team has previously shown that a CD40 agonist can sensitize PDAC to gemcitabine chemotherapy, and thus, T cells may not always be needed for successful outcomes with treatment using CD40 agonists in combination with chemotherapy.



Comparison of Multiparametric Magnetic Resonance Imaging-Targeted Biopsy With Systematic Transrectal Ultrasonography Biopsy for Biopsy-Naive Men at Risk for Prostate Cancer

The results of a Phase III randomized clinical trial show that when it comes to detecting clinically significant prostate cancer, magnetic resonance imaging (MRI) with targeted biopsies (MRI-TBx) matches the current standard and brings a multitude of advantages (JAMA Oncol 2021; doi:10.1001/jamaoncol.2020.7589). The PRostate Evaluation for Clinically Important Disease: MRI vs Standard Evaluation Procedures (PRECISE) study will help make prostate cancer diagnosis more accurate and less invasive. PRECISE included 453 participants at Canadian academic cancer centers who were either assigned to receive MRI imaging followed by MRI-TBx of suspicious areas (identified by MRI), or the current standard of care of a systematic 12-core transrectal ultrasound-guided (TRUS) biopsy (TRUS-Bx). The MRI with targeted biopsy found 5 percent more clinically significant prostate cancers compared to those receiving systematic TRUS-Bx biopsies, conclusively demonstrating the method can at least match the performance of the current standard of care. Furthermore, compared to standard TRUS-Bx, the MRI-TBx were found to be better in identifying clinically significant cancers. More than a third of patients in the MRI arm of the trial avoided biopsies altogether following negative imaging results. Those individuals received a follow-up MRI in 2 years. Those who did have biopsies in the MRI arm had significantly fewer samples taken when compared to systematic TRUS-Bx, resulting in less pain and discomfort for patients. Moreover, the MRI arm had a decreased adverse event profile, including less hematuria and incontinence. There is a major unmet need for a test that identifies clinically significant prostate cancer while avoiding overdiagnosing clinically insignificant cancers. Use of MRI reduced the unnecessary diagnosis of slow growing, clinically insignificant prostate cancers by 55 percent. These findings show decisively that MRI together with targeted biopsies offer patients a less-invasive procedure, the chance to avoid a biopsy all together, and possibly avoiding the overtreatment of clinically insignificant prostate cancer-all while detecting a higher rate of clinically significant cancers.



Fecal Microbiota Transplant Overcomes Resistance to Anti-PD-1 Therapy in Melanoma Patients

For patients with cancers that do not respond to immunotherapy drugs, adjusting the composition of the gut microbiome through the use of fecal transplants may help some of these individuals respond to the immunotherapy drugs, a new study suggests (Science 2021; doi: 10.1126/science.abf33630). In the study, some patients with advanced melanoma who initially did not respond to treatment with an immune checkpoint inhibitor did respond to the drug after receiving a transplant of fecal microbiota from a patient who had responded to the drug. The results suggest that introducing certain fecal microorganisms into a patient's colon may help the patient respond to drugs that enhance the immune system's ability to recognize and kill tumor cells. To test whether fecal transplants are safe and may help patients with cancer better respond to immunotherapy, researchers developed a small, single-arm clinical trial for patients with advanced melanoma. The patients' tumors had not responded to one or more rounds of treatment with the immune checkpoint inhibitors pembrolizumab or nivolumab, which were administered alone or in combination with other drugs. In the study, the fecal transplants, which were obtained from patients with advanced melanoma who had responded to pembrolizumab, were analyzed to ensure that no infectious agents would be transmitted. After treatment with saline and other solutions, the fecal transplants were delivered to the colons of patients through colonoscopies, and each patient also received pembrolizumab. After these treatments, six out of 15 patients who had not originally responded to pembrolizumab or nivolumab responded with either tumor reduction or long-term disease stabilization. One of these patients has exhibited an ongoing partial response after more than 2 years and is still being followed by researchers, while four other patients are still receiving treatment and have shown no disease progression for over a year. The treatment was well-tolerated, though some of the patients experienced minor side effects that were associated with pembrolizumab, including fatigue. The investigators analyzed the gut microbiota of all of the patients. The six patients whose cancers had stabilized or improved showed increased numbers of bacteria that have been associated with the activation of T cells and with responses to immune checkpoint inhibitors. In addition, by analyzing data on proteins and metabolites in the body, the researchers observed biological changes in patients who responded to the transplant. Levels of immune system molecules associated with resistance to immunotherapy declined, and levels of biomarkers associated with response increased. Based on the study findings, the researchers suggest that larger clinical trials should be conducted to confirm the results and identify biological markers that could eventually be used to select patients who are most likely to benefit from treatments that alter the gut microbiome.